Aptose Reports Results for the Fourth Quarter and Full Year 2022 – GlobeNewswire

APTIVATE Expansion Trial of Tuspetinib as Single Agent in Relapsed/Refractory AML Patients is Up and Running; Initiated Enrollment of Combination Treatment Arm with Venetoclax

RAS Mutated AML Clinically Sensitive to Tuspetinib

Continuous Dosing of G3 Formulation of Luxeptinib Ongoing

Conference Call and Webcast at 5:00 pm ET Today

SAN DIEGO and TORONTO, March 23, 2023 (GLOBE NEWSWIRE) -- Aptose Biosciences Inc. (Aptose or the Company) (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral kinase inhibitors to treat hematologic malignancies, today announced financial results for the fourth quarter and year ended December 31, 2022, and provided a corporate update.

The net loss for the quarter ended December 31, 2022, was $10.0 million ($0.11 per share) compared with $24.3 million ($0.27 per share) for the quarter ended December 31, 2021. The net loss for the year ended December 31, 2022, was $41.8 million ($0.45 per share) compared with $65.4 million ($0.73 per share) for the year ended December 31, 2021. Total cash and cash equivalents and investments as of December 31, 2022, were $47.0 million. Based on current operations, Aptose expects that cash on hand and available capital provide the Company with sufficient resources to fund planned Company operations including research and development into the first quarter of 2024.

To expand on the clinically significant response data observed across a broad population of acute myeloid leukemia (AML) patients during the dose escalation and exploration phase of our trial, we rapidly transitioned to our APTIVATE Phase 1/2 expansion trial with tuspetinib. APTIVATE already is running smoothly with several AML patients being treated in the monotherapy arm, and patient enrollment now is underway in the doublet combination treatment arm with tuspetinib and venetoclax (TUS/VEN). And we are eager to bring additional data to you throughout the year, said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. We anticipate enrolling up to 100 patients in the APTIVATE study, from which we expect to demonstrate single agent activity that can guide multiple paths for potential accelerated approval in patients with adverse mutations, and to demonstrate activity in doublet and then triplet combination therapies, which we believe represent the future directions of AML treatment. Tuspetinibs single agent activity targets more AML populations than SYK inhibitors, IRAK4 inhibitors, or menin inhibitors, and, its distinctly favorable safety profile also lends itself to an ideal combination treatment to potentially treat larger AML patient populations in earlier lines of therapy.

Key Corporate Highlights

Tuspetinib is designed to simultaneously target SYK, JAK1/2, FLT3, RSK and other kinases operative in AML. As a monotherapy treatment during dose escalation and exploration in our Phase 1/2 trial, tuspetinib safely delivered multiple complete remissions and clinical responses across four dose levels (40mg, 80mg, 120mg, and 160mg) in AML patients that previously had been failed by chemotherapy, BCL2 inhibitors, hypomethylating agents, FLT3 inhibitors, and hematopoietic stem cell transplants. Data presented in December at the 2022 American Society of Hematology (ASH) annual meeting by lead investigator Naval G. Daver, M.D., Associate Professor in the Department of Leukemia at MD Anderson Cancer Center, showed tuspetinib delivers single agent responses without prolonged myelosuppression or life-threatening toxicities in these very ill and heavily pretreated R/R AML patients. Responses were observed in a broad range of mutationally-defined populations, including those with mutated forms of NPM1, MLL, TP53, DNMT3A, RUNX1, wild-type FLT3, ITD or TKD mutated FLT3, various splicing factors, and other genes. Unexpectedly, we observed a 29% CR/CRh response rate with tuspetinib monotherapy in patients having mutations in the RAS gene or other genes in the RAS pathway. Responses in RAS-mutated patients are important because the RAS pathway is often mutated in response to therapy by other agents as the AML cells mutate toward resistance to those other agents.

With dose escalation and exploration successfully completed, we now are focusing on execution of the APTIVATE Phase 1/2 expansion trial. While we plan to report data throughout the year, we also will plan an incremental update from APTIVATE around the European Hematology Association (EHA) conference in June, a more complete dataset at the European School of Haematology (ESH) meeting in October, and even more data, including from the TUS/VEN combination cohort, during the ASH meeting in December.

Separately, a small number of B-cell patients are still receiving the original G1 formulation of luxeptinib at the 900 mg dose level. During ASH in December, we announced that a CR was achieved with a diffuse large B-cell lymphoma patient at the 900 mg dose level of the original G1 formulation, and we had previously reported an MRD-negative CR with a R/R AML patient receiving 450 mg BID of the original G1 formulation. Together, these findings demonstrate activity of luxeptinib in lymphoid malignancies and AML.

Research on luxeptinib continues, and a non-clinical paper was published earlier this month in PLOS One, a highly respected online scientific publication. Titled, Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma, the paper helps to elucidate the mechanism by which Lux suppresses the B-cell receptor pathway in a manner distinct from the BTK inhibitor ibrutinib. Lux was more effective than ibrutinib at reducing both steady state and anti-IgM-induced phosphorylation of the LYN and SYK kinases upstream of BTK where ibrutinib has little or no effect, suggesting Lux can play a role in B-cell malignancies and inflammatory diseases distinct from ibrutinib and other BTK inhibitors.

RESULTS OF OPERATIONS

A summary of the results of operations for the years ended December 31, 2022 and 2021 is presented below:

Net loss of $41.8 million for the year ended December 31, 2022 decreased by approximately $23.5 million as compared with $65.4 million for the year ended December 31, 2021, primarily as of a result of a reduction in research and development program costs and personnel expenses of $5.4 million, the $12.5 million in license fees paid to Hanmi in 2021 for development rights of tuspetinib, and a $5.0 million decrease in general and administrative costs.

Research and Development Expenses

Research and development expenses consist primarily of costs incurred related to the research and development of our product candidates. Costs include the following:

We have ongoing clinical trials for our product candidates tuspetinib and luxeptinib. Tuspetinib was licensed into Aptose in November 2021 and we assumed sponsorship, and the related costs, of the tuspetinib study effective January 1, 2022. In December 2021, we discontinued the APTO-253 program and are exploring strategic alternatives for this compound.

We expect our research and development expenses to be higher as compared to 2022 for the foreseeable future as we continue to advance tuspetinib into larger clinical trials.

The research and development (R&D) expenses for the years ended December 31, 2022 and 2021 were as follows:

R&D expenses decreased by $17.9 million to $28.1 million for the year ended December 31, 2022 as compared with $46.0 million for the comparative period in 2021. Changes to the components of our R&D expenses presented in the table above are primarily as a result of the following activities:

General and Administrative Expenses

General and administrative expenses consist primarily of salaries, benefits and travel, including stock-based compensation for our executive, finance, business development, human resource, and support functions. Other general and administrative expenses and professional fees for auditing, and legal services, investor relations and other consultants, insurance and facility related expenses.

We expect that our general and administrative expenses will increase for the foreseeable future as we incur additional costs associated with being a publicly traded company and to support our expanding pipeline of activities. We also expect our intellectual property related legal expenses to increase as our intellectual property portfolio expands.

The general and administrative expenses for the years ended December 31, 2022 and 2021 are as follows:

COVID-19 did not have a significant impact on our results of operations for the years ended December 31, 2022 and 2021. We have not experienced and do not foresee material delays to the enrollment of patients or timelines for the tuspetinib Phase 1/2 trial or the luxeptinib Phase 1a/b trials due to the variety of clinical sites that we have actively recruited for these trials. As of the date of this press release, we have not experienced material delays in the manufacturing of tuspetinib or luxeptinib related to COVID-19. Should our manufacturers be required to shut down their facilities due to COVID-19 for an extended period of time, our trials may be negatively impacted.

Conference Call & Webcast:

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The audio webcast also can be accessed through a link on the Investor Relations section of Aptoses website here. A replay of the webcast will be available on the companys website for 30 days.

The press release, the financial statements and the managements discussion and analysis for the quarter and year ended December 31, 2022 will be available on SEDAR at http://www.sedar.com and EDGAR at http://www.sec.gov/edgar.shtml.

About Aptose

Aptose Biosciences is a clinical-stage biotechnology company committed to developing precision medicines addressing unmet medical needs in oncology, with an initial focus on hematology. The Company's small molecule cancer therapeutics pipeline includes products designed to provide single agent efficacy and to enhance the efficacy of other anti-cancer therapies and regimens without overlapping toxicities. The Company has two clinical-stage oral kinase inhibitors under development for hematologic malignancies: tuspetinib (HM43239), an oral, myeloid kinase inhibitor being studied as monotherapy and in combination therapy in the APTIVATE international Phase 1/2 expansion trial in patients with relapsed or refractory acute myeloid leukemia (AML); and luxeptinib (CG-806), an oral, dual lymphoid and myeloid kinase inhibitor in Phase 1 a/b stage development for the treatment of patients with relapsed or refractory hematologic malignancies. For more information, please visit http://www.aptose.com.

Forward Looking Statements

This press release contains forward-looking statements within the meaning of Canadian and U.S. securities laws, including, but not limited to, statements regarding the expected cash runway of the Company, the clinical development plans, the clinical potential, anti-cancer activity, therapeutic potential and applications and safety profile of tuspetinib and luxeptinib, the APTIVATE clinical trial, patient enrollment, potential accelerated approval, the luxeptinib Phase 1 a/b clinical trials and the upcoming milestones of such trials, the development and clinical potential of a new formulation (G3) for luxeptinib, expected variations in expenses, upcoming updates regarding the clinical trials, the exploration of strategic alternatives for the APTO-253 program, the expected impact of COVID-19 on results and operations and statements relating to the Companys plans, objectives, expectations and intentions and other statements including words such as continue, expect, intend, will, hope should, would, may, potential and other similar expressions. Such statements reflect our current views with respect to future events and are subject to risks and uncertainties and are necessarily based upon a number of estimates and assumptions that, while considered reasonable by us, are inherently subject to significant business, economic, competitive, political and social uncertainties and contingencies. Many factors could cause our actual results, performance or achievements to be materially different from any future results, performance or achievements described in this press release. Such factors could include, among others: our ability to obtain the capital required for research and operations; the inherent risks in early stage drug development including demonstrating efficacy; development time/cost and the regulatory approval process; the progress of our clinical trials; our ability to find and enter into agreements with potential partners; our ability to attract and retain key personnel; changing market and economic conditions; inability of new manufacturers to produce acceptable batches of GMP in sufficient quantities; unexpected manufacturing defects; the potential impact of the COVID-19 pandemic and other risks detailed from time-to-time in our ongoing current reports, quarterly filings, annual information forms, annual reports and annual filings with Canadian securities regulators and the United States Securities and Exchange Commission.

Should one or more of these risks or uncertainties materialize, or should the assumptions set out in the section entitled "Risk Factors" in our filings with Canadian securities regulators and the United States Securities and Exchange Commission underlying those forward-looking statements prove incorrect, actual results may vary materially from those described herein. These forward-looking statements are made as of the date of this press release and we do not intend, and do not assume any obligation, to update these forward-looking statements, except as required by law. We cannot assure you that such statements will prove to be accurate as actual results and future events could differ materially from those anticipated in such statements. Investors are cautioned that forward-looking statements are not guarantees of future performance and accordingly investors are cautioned not to put undue reliance on forward-looking statements due to the inherent uncertainty therein.

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Aptose Reports Results for the Fourth Quarter and Full Year 2022 - GlobeNewswire

Why Does a Leukemic Mutation Not Always Lead to the Disease? – Technology Networks

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Why do some people with a genetic mutation associated with leukemia remain healthy, while others with the same mutation develop the blood cancer? In a new study published inBlood, scientists from the USC Stem Cell laboratory of Rong Lu discovered a mechanism that linked a leukemic mutation to varying potentials for disease development a discovery which could eventually lead to a way to identify patients with the mutation who are most at risk.

To explore this paradox, first author Charles Bramlett and his colleagues labeled and tracked individual blood stem cells in mice with a mutation in a gene called TET2, which is prevalent in patients with myeloid leukemia. The scientists found that a subset of blood stem cells and their progenyknown as clonesmade an outsized contribution to the overall population of blood and immune cells. The over-contributing clones tended to produce a lot of myeloid cells including immune cells called granulocytes, which may potentially lead to myeloid leukemia.

There were also notable differences in the gene activity of the over-contributing clones, compared to the rest of the clones. The over-contributing clones showed reduced activity in several genes known to suppress the development of leukemia and other cancers. They also showed reduced activity in genes that are involved in RNA splicing, the process of removing non-coding sequences from the RNA that carries messages from the DNA to the cells protein-making machinery.

One of these RNA splicing genes, Rbm25, showed a particularly dramatic reduction in its activity in the over-contributing clones. To explore the effect of Rbm25, the scientists used CRISPR/Cas9 gene editing to manipulate the activity of Rbm25 in cells with TET2 mutations. They found that increasing Rbm25 activity slowed the cells proliferation. In contrast, reducing Rbm25 activity made the cells multiply more quickly, and also caused changes in RNA splicing of the geneBcl2l1,which regulates programmed cell death, also known as apoptosis. The natural process of apoptosis is critical for ridding the body of aberrant cells, such as pre-cancerous cells that multiply too aggressively and accumulate dangerous mutations that can lead to disease.

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In accordance with these new discoveries in mice, Rbm25 activity is also negatively correlated with white blood cell counts that mark poor survival in human patients with myeloid leukemia.

Our study suggests that a leukemia-associated genetic mutation could trigger different amounts of myeloid cell production, which may be modulated by other risk factors such as RNA splicing regulators, said Lu, an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine, and gerontology at USC, and a Leukemia & Lymphoma Society Scholar. These findings could be used to better stratify which patients are at the highest risk, and also present intriguing possibilities for developing future therapies that target aberrant RNA splicing in preleukemia phases.

Reference:Bramlett C, Eerdeng J, Jiang D, et al. RNA splicing factor Rbm25 underlies heterogeneous preleukemic clonal expansion in mice. Blood. 2023:blood.2023019620. doi:10.1182/blood.2023019620

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Why Does a Leukemic Mutation Not Always Lead to the Disease? - Technology Networks

Direct reprogramming of human fibroblasts into insulin-producing … – Nature.com

Exogenous expression of the transcription factors Pdx1, Neurog3, and MafA in human fibroblasts

We first sought to examine whether the transcription factors Neurog3, Pdx1, and MafA could induce expression of the INSULIN (INS) gene in human fibroblasts as readout of the capacity of these cells to be transformed toward a -cell fate. To deliver these factors we employed a polycistronic adenoviral vector carrying the three transgenes (Ad-NPM hereafter), which had been previously used to promote -cell reprogramming from pancreatic acinar cells19. After optimization of adenoviral transduction in fibroblasts (see Methods), abundant (>80%) cells positive for Cherry, which is also encoded by Ad-NPM, were easily observable three and seven days after viral infection (Fig.1a). Likewise, high levels of transcripts encoding the NPM factors were expressed at both time points (Fig.1b). Three days after addition of Ad-NPM we detected marginal levels of INS mRNA that were increased >10-fold by day 7 (Fig.1c). As cell culture formulations can have a major impact on gene expression events and cellular reprogramming, we tested different conditions after Ad-NPM infection. We observed that moving to RPMI-1640 and, to a lesser extent, CMRL-1066 medium and lowering the fetal calf serum concentration to 6% dramatically boosted INS gene activation, reaching values that were 0.12% those of human islets (Fig.1d and Supplementary Figure1). Under the same culture conditions, only a very marginal induction of the INS gene occurred when the N+P+M factors were delivered simultaneously via distinct adenoviruses to human fibroblasts (Supplementary Fig.2). In addition to INS, we discovered that the NPM factors also activated the hormone genes GLUCAGON (GCG) and SOMATOSTATIN (SST), albeit at lower levels than INS as indicated by decreased relative expression values (compared to the housekeeping gene TBP) (Fig.1e). The NPM factors also induced expression of genes encoding islet differentiation transcription factors including NEUROD1, INSM1, PAX4, NKX2-2, and ARX (Fig.1f).

Human fibroblasts (HFF1) were infected with a polycistronic recombinant adenovirus encoding the transcription factors Neurog3, Pdx1, MafA, and the reporter protein Cherry (Ad-NPM). Untreated parental fibroblasts were used as controls (indicated as C in graphs). a Bright field images and Cherry immunofluorescence of control fibroblasts and fibroblasts infected with Ad-NPM at day 3 and 7 post-infection. Scale bar, 100 m. b qPCR of transgenes at day 3 (n=11) and 7 (n=6) after infection with Ad-NPM. c qPCR of human INS at day 3 (n=7) and 7 (n=13) after infection with Ad-NPM. d qPCR of human INS in fibroblasts maintained in the indicated culture media (DM=DMEM; CM=CMRL; RP=RPMI) during 7 days after infection with Ad-NPM or with an adenovirus expressing B-galactosidase (B-gal) (n=310). In yellow, INS mRNA levels in isolated human islets (n=10). e, f qPCR of islet hormone genes (GCG, SST) and islet differentiation transcription factors (NEUROD1, INSM1, PAX4, NKX2-2, ARX) at day 7 post-NPM (n=815). g qPCR of the indicated fibroblast markers at day 3 (n=511) and day 7 post-NPM (n=56). In bf, expression levels are expressed relative to TBP. In g, expression is expressed relative to control fibroblasts, given the value of 1 (dotted line). Data are presented as the meanSEM for the number of samples indicated in parentheses. *P<0.05; **P<0.01; ***P<0.001, between indicated conditions using unpaired t-test (bf), or relative to control fibroblasts using one sample t-test (g).

To further establish if the NPM factors promoted cell fate conversion and not simply activated their target genes in fibroblasts, we surveyed expression of genes associated with the fibroblastic signature, including several factors involved in maintenance of the fibroblastic transcriptional network such as TWIST2, PRRX1, and LHX920. We found that these genes were downregulated as early as three days after NPM introduction. Other fibroblast markers exhibited a more delayed response but, by day 7 post-NPM, all tested genes exhibited significant down-regulation (Fig.1g). Together, these experiments validate that islet cell fate can be induced in human fibroblasts using a defined set of transcription factors.

The observed induction of the islet hormone genes GCG and SST implied that the NPM factors might not specifically endorse -cell fate in fibroblasts. Furthermore, we found that these factors did not induce NKX6-1, which encodes a -cell specific factor required for the formation of pancreatic cells during development21 and key for optimal maturation of stem cell cells in vivo22,23 (Fig.2a). These findings indicated that the NPM factors sub-optimally promoted a -cell state in human fibroblasts. In order to enhance -cell fate over other islet cell identities, we opted to add new transcription factors to the reprogramming cocktail.

Human fibroblasts (HFF1) were infected with Ad-NPM alone or sequentially with Ad-NPM and adenoviruses encoding the transcription factors Pax4 and Nkx2-2. Ad-Pax4 and Ad-Nkx2-2 were added three days after NPM in the two-virus conditions. In the three-virus condition, Pax4 was added three days and Nkx2-2 and six days after NPM (condition called 5TF). All cells were collected ten days after infection with Ad-NPM. a qPCR of the indicated transgenes and endogenous genes. Expression levels are calculated relative to TBP. Values represent the meanSEM (n=412). b Representative immunofluorescence images showing insulin staining (in red) using two different antibodies, one against C-PEP, in untreated fibroblasts and in fibroblasts infected with Ad-NPM alone or with 5TF. Nuclei were stained with Hoechst (in blue). Scale bar, 25 m. *P<0.05; ****P<0.0001 relative to NPM in (b) using one-way ANOVA and Tukeys multiple comparison test.

Pax4 is activated downstream of Neurog3 during development24 and has been shown to favor - over -cell specification25,26, and to contribute to maintenance of the expression of Nkx6.1 in differentiating cells27. Despite that the NPM factors induced endogenous PAX4 mRNA, the expression levels attained might not be sufficient to endorse - over -cell fate. Hence, we treated fibroblasts with an adenovirus encoding Pax4 three days after NPM (Fig.2a). This resulted in the significant enhancement of INS expression as compared to NPM alone but, unexpectedly, GCG expression was also increased (Fig.2a), indicating that ectopic Pax4 improved islet hormone gene expression without apparent impact on - versus -cell fate conversion in human fibroblasts.

As the NKX6-1 gene remained silent in response to NPM+Pax4 (Fig.2a), we tried directly adding Nkx6-1 to the NPM reprogramming cocktail. However, exogenous Nkx6-1 resulted in considerable cell death irrespective of level of expression or timing of introduction. As an alternate approach, we added exogenous Nkx2-2, which also regulates early -cell differentiation and is an upstream activator of Nkx6-1 during mouse islet development21. Treatment with an adenovirus encoding Nkx2-2 three days after NPM led to endogenous activation of NKX6-1 expression with no compromise of fibroblast viability (Fig.2a). Nkx2-2 also induced PAX6, a pan-endocrine gene required to achieve high levels of islet hormone gene expression during mouse pancreas development28,29. Remarkably, ectopic Nkx2-2 reduced NPM-induced GCG gene activation without affecting INS gene expression (Fig.2a).

During development, Pax4 and Nkx2-2 are found in -cell precursors at around the same time, and their parallel activities are thought to enable the -cell differentiation program27. Hence, we tested the effects of including both transcription factors in the reprogramming cocktail. To ensure optimal expression of each transcription factor, we treated cells with Ad-Pax4 and Ad-Nkx2.2 sequentially, at day 3 and day 6 post-NPM, respectively. Following this protocol, the blockade of GCG gene activation and the induction of the NKX6.1 and PAX6 genes seen with NPM+Nkx2.2, and the higher INS expression elicited by NPM+Pax4 relative to NPM alone were all maintained (Fig.2a). Neither Pax4 nor Nkx2-2, added alone or together, had any impact on the minimal INS gene induction shown when the N+P+M factors were delivered via separate adenoviruses to human fibroblasts (Supplementary Fig.2).

Consistent with the gene expression data, staining for insulin protein was more robust in cells reprogrammed with NPM+Pax4+Nkx2.2 than in cells reprogrammed with NPM as assessed using two different antibodies, one against human insulin and another against human C-PEP to exclude possible insulin uptake from the media (Fig.2b). We quantified the immunofluorescence images and found that 67.96.2% of cells in the culture were INS+at day 10.

From here on, we used the sequential introduction of the five transcription factors (5TF protocol, Fig.3a) to generate insulin-producing cells from human fibroblasts (reprogrammed cells will be referred as 5TF cells). At day 10, 5TF cells displayed an epithelial morphology (Fig.3b) and hadnt grown as much as untreated fibroblasts (day 10; 5TF: 441033103 cells/well; control: 23810318103 cells/well, n=18). This decreased cell number was likely due to diminished proliferation, which was evident as soon as one day following Ad-NPM infection (Fig.3c). The capacity of cells to reduce the MTT compound, in contrast, was comparable to that of fibroblasts, indicating that viability was not compromised (Fig.3d).

a Scheme of the reprogramming protocol 5TF (NPM+Pax4+Nkx2.2) showing the sequence of addition of adenoviruses encoding the indicated transcription factor/s. Duration of incubation with each adenovirus is represented with a line. Cells were studied at days 10-11 after initial addition of Ad-NPM. b Representative bright field image of parental fibroblasts and 5TF reprogrammed fibroblasts at day 10. Scale bar, 75 m. c Cell proliferation measured by BrdU incorporation and d cell viability measured by MTT assay for n=3 independent reprogramming experiments. Bars represent values relative to control fibroblasts (given the value of 1, represented by a dotted line). Note that day 4 values are before Pax4 introduction. e, f qPCR of islet/-cell transcription factor and -cell function genes in untreated control fibroblasts (C, n=522), in fibroblasts infected with Ad-NPM alone (n=322) or with 5TF (n=522). Expression levels were calculated relative to TBP. qPCR of the indicated endogenous genes (g) and transgenes (h) at day 21 after initiation of reprogramming (n=913, from 7 reprogramming experiments). Transcript levels are expressed relative to levels in cells at day 10 of the reprogramming protocol (given the value of 1, shown with a dotted line). Data are meanSEM for the number of n indicated in parentheses. *P<0.05, **P<0.01, ***P<0.001 compared to control fibroblasts (c, d), or between indicated bars using unpaired t-test (e, f), or compared to day 10 5TF cells (g, h) using one-sample t-test.

Next we studied expression of selected differentiation transcription factor genes at days 10-11 of the protocol. All genes tested, except PAX4, were more expressed in 5TF relative to NPM (NEUROD1, INSM1, HNF1B, MAFB, PDX1, NEUROG3, NKX2.2) (Fig.3e). Likewise, several genes (PCSK1, KCNJ11, GLP1R, NCAM1) that are linked to -cell function were increased in 5TF cells as compared to NPM cells (Fig.3f). Remarkably, some genes were induced de novo by 5TF (ABCC8, GIPR) (Fig.3f). In line with a loss of GCG activation, the pro-convertase gene PCSK2, which is expressed at higher levels in than in cells30, was reduced by 5TF as compared to NPM (Fig.3f). These results support that sequential introduction of Pax4 and Nkx2-2 after NPM endorses the -cell differentiation program in human fibroblasts. -cell gene activation was sustained for at least twenty-one days after initiation of the protocol despite reduced expression of the reprogramming factor transgenes (Fig.3g, h). Furthermore, expression of several of the tested genes increased with time in culture including NKX6-1, PCSK1, KCNJ11, ABCC8 and CHGB among others (Fig.3g), suggestive of permanent cell lineage conversion.

Glucose-induced insulin secretion by cells is mediated by cellular glucose metabolism, closure of ATP-dependent potassium channels, membrane depolarization and opening of voltage-dependent calcium channels, resulting in an increase in cytosolic Ca2+ that triggers insulin exocytosis. We investigated whether 5TF cells increased intracellular Ca2+ in response to glucose and membrane depolarization elicited by high potassium. We found that 65% of the cells exhibited a response to glucose, high potassium, or both, whilst 35% of cells were unresponsive to either stimulus (Fig.4a and Supplementary Video1). Parental fibroblasts not engineered for 5TF expression were unresponsive to these stimuli (Fig.4b and Supplementary Video2). Among responsive cells, approximately half responded to both glucose and high potassium and half responded only to potassium (Fig.4a). We observed heterogeneity in the amplitude and kinetics of responses among individual cells (Fig.4c). Next, we performed static incubation assays to study GSIS and found that 5TF cells released similar amounts of human insulin at low (2mM) and high (20mM) glucose concentrations (Fig.4d). Thus, even though 5TF cells increased their intracellular calcium in response to glucose and membrane depolarization, they secreted insulin in a constitutive manner.

5TF cells were loaded with the calcium indicator Fluo-4-AM at day 10 of the reprogramming protocol. Single-cell imaging to detect cytosolic calcium was performed in the following sequence: low glucose (2mM, G2), high glucose (20mM, G20) and membrane depolarization with KCl (30mM). a Quantification of the frequency of cells (n=200, from six independent reprogramming experiments) that responded to glucose, membrane depolarization elicited by high potassium or both. Representative measurements of dynamic Fluo-4 fluorescence for (b) six fibroblasts and (c) four 5TF cells. d In vitro insulin secretion by 5TF cells. ELISA determination of secreted human insulin by control fibroblasts (n=413) and 5TF cells (n=16) under non-stimulatory conditions (glucose 2mM) and under stimulatory conditions (glucose 20mM). Data are meanSEM and correspond to six independent reprogramming experiments, 24 biological replicates per experiment.

The differentiation and functionality of many cell types vary dramatically between three-dimensional (3D) and two-dimensional (2D) monolayer cultures, the former being closer to the natural 3D microenvironment of cells in a living organism. Thus, we generated spheroids of 5TF cells (1200-1800 cells/spheroid; average diameter of 12827m) one day after the introduction of Nkx2-2 and maintained them in culture for three additional days (Fig.5a). At the time of collection, insulin-positive staining was easily identified but glucagon and somatostatin staining was undetectable (Fig.5b and Supplementary Fig.3). While INS transcript levels were nearly 2-fold higher in 5TF cell spheroids compared to 5TF cells kept in monolayer, other -cell marker genes, such as the prohormone convertase PCSK1 and the ATP-sensitive potassium channel subunits KCNJ11 and ABCC8, showed a higher response (4 to 5-fold) to 3D culture (Fig.5c). Thus, cell aggregation during the last stage of reprogramming (note that total length of the protocol was not changed) conferred improved activation of genes associated to -cell function. Despite increased gene activation, -cell gene expression in 5TF cell spheroids remained lower than in human islets, with differences ranging widely among examined genes (Fig.5c).

a Schematic representation of the modified 5TF protocol (5TF-3D): cells were moved from 2D to 3D culture during the last three days (days 710) of the protocol. Representative bright field image of 5TF cell spheroids. Scale bar, 100 m. b Representative immunofluorescence image showing insulin staining in red and nuclei in blue (marked with Hoechst) of a 5TF cell spheroid at the end of the reprogramming protocol. Scale bar is 50 m. c qPCR of the indicated genes in 5TF cell spheroids. Transcript levels are expressed as fold relative to levels in 5TF cells maintained in 2D culture throughout the 10-day protocol (given the value of 1, dotted line). Data are meanSEM for n=412. *P<0.05, **P<0.01, ***P<0.001 relative to 2D culture using one-sample t-test. Fold-change differences in expression levels between human islets and 3D-5TF reprogrammed cells are shown in the upper yellow box. d Heat map of differentially expressed genes between parental fibroblasts (C) and 5TF cell spheroids (n=3 reprogramming experiments). e GSEA plots on indicated gene sets and pathways. f Dot plots showing the enrichment analysis on Gene Ontology (GO) and KEGG categories of differentially expressed genes (gained in red, lost in blue) between fibroblasts (C) and 5TF cells. The X-axis represents the adjusted p value, the size of the dot represents the number of enriched genes (count) and the color intensity of the dots represents the percentage of hits in each category. g GSEA plot on -cell disallowed genes. h Relative expression levels of -cell disallowed genes repressed in 5TF cell spheroids as compared to fibroblasts (given the value of 1) based on RNA-seq data normalized expression values. Data are meanSEM (n=3). Insets show mRNA expression of the indicated genes in untreated control fibroblasts (n=5), 5TF cell spheroids (n=6) and human islets (n=5) as assessed by qPCR. Expression levels were calculated relative to TBP. Data are meanSEM. *P<0.05, **P<0.01 relative to control fibroblasts using unpaired t-test.

To obtain a more comprehensive understanding of thecell identity switch induced by the 5TF-3D reprogramming protocol, we performed RNA-sequencing of 5TF cell spheroids and parental fibroblasts. A total of 2806 genes (1186 upregulated, 1620 downregulated) were differentially expressed between both cell populations (adjusted p-value <0.05 and fold-change (FC)>2) (Fig.5d and Supplementary Data1). Gene set enrichment analysis (GSEA) showed that pancreas/-cell and peptide hormone metabolism gene sets were enriched in 5TF cells (Fig.5e). Biological functions associated with gained genes included epithelium development, synaptic signaling, ion transport, calcium sensing and secretion (Fig.5f). Among the upregulated genes related to stimulus-secretion coupling, there were synaptotagmins (SYT1,2,3,6,13,17), syntaxins (SYN2 SYN3), calcium sensors (SCG2) and SNARE protein complexes (VAMP1). Correlating with our previous results, cell cycle and mitotic function genes were enriched among repressed genes (Fig.5e, f). Additionally, GSEA demonstrated that 5TF cells had a lower expression of the gene set associated with the epithelial-mesenchymal transition (Fig.5e). In agreement, functions including cytoskeleton organization and cellular migration were overrepresented among lost genes (Fig.5f). Interestingly, GSEA also revealed that the -cell disallowed gene set, which includes genes that are selectively suppressed in cells and believed to be detrimental for cell function31,32,33, was reduced in 5TF cells (Fig.5g). A total of 23 previously recognized -cell disallowed were significantly downregulated in 5TF cells (Fig.5h). By using qPCR, we confirmed the repression of three of these genes -OAT, LDHA, and SMAD3- which are regarded as part of the core disallowed unit33. Of note, the levels of these genes in 5TF cells matched those of human islets (Fig.5h). Collectively, these results show that 5TF-3D reprogramming promotes a change in the fibroblast transcriptome, including selective gene activation along with specific gene repression events, enabling a change in cell identity from fibroblast towards a -cell fate.

Consistent with gene activation events identified in prior gene expression analyses, immunofluorescence staining showed the presence of the mature -cell markers PCSK1, NCAM1, and KCNJ11 (Kir6.2) in many insulin-positive 5TF cells. PTPRN (IA2) was also expressed albeit more sporadically in insulin-positive 5TF cells (Fig.6a). Using conventional electron microscopy, we looked for the existence of secretory granules and discovered that most cells contained multiple spherical electron-dense prototypical secretory vesicles (Fig.6b). These vesicles showed a high degree of morphological heterogeneity, presumably as consequence of their degree of maturation and/or loading. Although they did not have the appearance of typical insulin-containing granules from primary cells, which are characterized by a clear halo surrounding a dark polygonal dense core34, some of the vesicles exhibited a gray or less electron dense halo and looked like the granules described in immature insulin-positive cells generated in early stem cell differentiation protocols35,36.

a Representative confocal images of 5TF cell spheroids immunostained with the indicated antibodies. Scale bar, 10 m. b Conventional transmission electron microscopy showing a representative image of a 5TF cell spheroid. Prototypical electron dense secretory vesicles (asterisks) are observed dispersed in the cytoplasm. Well-preserved mitochondria (mit), endoplasmic reticulum (ER), Golgi membranes (G) and lipid droplets (LD) are also observed. Inset shows a detail of a secretory vesicle with an average diameter of 450nm. N, nucleus. Scale bars are 200nm (inset) and 500nm. c In vitro glucose-induced insulin secretion by 5TF cell spheroids (n=14, from 8 reprogramming experiments). Secretion by control spheroids composed of parental fibroblasts (n=5) is also shown. d Glucose stimulation Index (ratio between insulin secreted at 20mM glucose vs. 2mM glucose) of 5TF cells maintained in 2D or in 3D (spheroid) cultures (n=1618, from 8 to 10 reprogramming experiments). e Glucose dose curve of insulin secretion by 5TF cell spheroids (n=412, 5 reprogramming experiments). Data are presented as the meanSEM for the number of n indicated in parentheses. *P<0.05; ***P<0.001 between the indicated conditions using unpaired t-test (c), one sample t-test (d) or one-way ANOVA (e).

We next performed static incubation GSIS assays. 5TF cell spheroids exhibited significant insulin secretory response to glucose (fold 20mM/2mM: 2.020.18) as compared to 2D cultures (fold 20mM/2mM: 1.080.15) (Fig.6c, d). To establish the glucose threshold for stimulation of insulin secretion, 5TF cell spheroids were subjected to either 2,5,11 or 20mM glucose. Between 2mM and 11mM/20mM glucose, 5TF spheroids showed a 2.3-fold increase in insulin production on average (Fig.6e). In contrast, although there was some variability, they did not show a statistically significant increase in insulin secretion between 2mM and 5mM glucose (Fig.6e). These observations indicate that 5TF cell spheroids are stimulated at higher glucose threshold; it is interesting to note that human islets have a glucose threshold at 3mM and a maximal response at 15mM37.

The 5TF-3D protocol was repeated on an additional HFF line and produced results that were comparable (Supplementary Fig.4) proving the reproducibility of the reprogramming protocol.

Finally, we studied the stability of reprogramming in vivo. With this aim, we transplanted 300 5TF cell spheroids (10001200 cells/spheroid) into the anterior chamber of the eye (ACE) of non-diabetic immune-deficient NOD scid gamma (NSG) mice (Fig.7a). The ACE allows fast engraftment38 and in vivo imaging39. Ten days following transplantation, we used two-photon microscopy to evaluate in vivo graft re-vascularization and confirmed the presence of functioning vessels in the grafts (Fig.7b). Additionally, by observing the long-term tracer CFDAs fluorescence, we confirmed that the transplanted cells were alive (Fig.7b). To assess the maintenance of insulin expression in vivo, we harvested the eye grafts at day 10 for RNA extraction and immunostaining. Human INS mRNA was readily detectable and levels, calculated relative to human TBP, were comparable to those in 5TF cell clusters prior to transplantation (Fig.7c). In agreement, abundant HLA+(human cell marker) cells that stained for insulin were detected in the eye grafts by immunofluorescence staining (43.52.8% INS+HLA+/totalHLA+, n=5) (Fig.7d, e and Supplementary Fig.5). We observed positive staining for the reprogramming transcription factors in 2030% of the INS+cells (Supplementary Figure6). Although we were unable to discriminate between the two, high transgene expression found by qPCR analysis in eye grafts (Supplementary Fig.6) indicated that the staining represented virally encoded exogenous protein rather than endogenous protein. Since adenoviral vectors do not normally integrate into the host DNA, we speculate that the cessation of cell division induced by reprogramming may explain persistent transgene expression in 5TF cells. In fact, similar findings were reported in reprogrammed human duct-derived insulin-producing cells9. We were able to identify INS+cells in 4 (of 5) grafts harvested one month after transplantation even though their number was reduced relative to day 10 grafts (Supplementary Fig.7). The proportion of INS+HLA+ cells in 30-day grafts was more heterogeneous than in 10-day grafts, and in 3 (of 5) grafts, it was comparable or even higher than that of 10-day grafts, demonstrating the maintenance of reprogramming (Supplementary Fig.7).

a Schematic illustration and image showing 5TF cell spheroids transplanted into the anterior chamber of the eye (ACE) of a normoglycemic NSG mouse. b Vascularization of 5TF cell grafts ten days following transplantation into the ACE. Representative in vivo image depicting functional vessels (RITC-dextran, red) and viable 5TF cells (CFDA, green). Scale bar, 100 m. c qPCR of INS and TBP transcripts in eyes of non-transplanted mice (nt, n=3) and mice transplanted with either control fibroblast spheroids (C, n=3) or 5TF cell spheroids (n=5) collected ten days post-transplantation. INS gene expression in 5TF cell spheroids prior to transplantation is depicted in the blue bar (n=6). INS gene expression is calculated relative to TBP. Expression of TBP relative to mouse Tbp is shown to prove the presence of human cells in eyes receiving control and 5TF spheroids. Data are presented as meanSEM. d Representative immunofluorescence images showing HLA staining in red and insulin staining in green in 5TF cell grafts ten days post-transplantation. Scale bar, 25 m. e Percentage of cells doubly positive for insulin and HLA (relative to total HLA+cells) in 5TF cell grafts at day 10 following transplantation. Each dot corresponds to one eye graft (n=5). f ELISA determination of human insulin in the aqueous humor in un-transplanted mice (n=7), in mice transplanted with either 300 fibroblast spheroids (n=14) or 300 5TF cell spheroids (n=17) at day 10 post-transplantation and in mice transplanted with 150200 human islets (n=4) at day 1215 post-transplantation. Data are presented as meanSEM for the number of n indicated in parentheses. ***P<0.001; ***P<0.0001 between indicated samples using unpaired t-test.

To study if 5TF cells secreted insulin in vivo, we first measured the presence of human insulin by ELISA in the aqueous humor of the transplanted eyes. Human insulin was readily detectable in eyes carrying 5TF cell grafts (17 of 17, ranging from 76 to 1103 pmol/L) whilst no insulin was detected in eyes transplanted with parental fibroblast clusters or in non-transplanted mice (Fig.7f). For comparison, eyes containing 300 5TF spheroids showed on average approximately 20-fold lower levels of human insulin than eyes containing 150200 human islets (Fig.7f). Due to space limitations in the ACE, we transplanted a larger number of spheroids (35005000) into the omentum of normoglycemic NSG mice in order to detect circulating human insulin in host animals. We measured low amounts of human insulin in the plasma of most transplanted mice, and these levels increased in 6 (of 10) mice after receiving an intraperitoneal glucose injection on day 30 post-transplantation (3.60.9 vs 13.93.7pmol/L, p=0.014) (Supplementary Fig.8). Transplants were repeated in other locations yielding similar results (Supplementary Table2). As observed in the ACE grafts, a low number of INS+cells were identified in omentum grafts harvested at 30 days post-transplantation (Supplementary Fig.8). These findings show that, despite restricted survival, reprogramming is maintained and 5TF cells maintain the capacity to release insulin in an in vivo setting.

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From mutation to arrhythmia: Desmosomal protein breakdown as an … – Science Daily

Mutations in genes that form the desmosome are the most common cause of the cardiac disease arrhythmogenic cardiomyopathy (ACM), which affects one in 2000 to 5000 people worldwide. Researchers from the group of Eva van Rooij now discovered how a mutation in the desmosomal gene plakophilin-2 leads to ACM. They found that the structural and functional changes in ACM hearts caused by a plakophilin-2 mutation are the result of increased desmosomal protein degradation. The results of this study, published in Science Translational Medicine on March 22nd 2023, further our understanding of ACM and could contribute to the development of new therapies for this disease.

ACM is a progressive and inheritable cardiac disease for which currently no treatments exist to halt its progression. Although patients initially do not experience any symptoms, they are at a higher risk of arrhythmias and resulting sudden cardiac arrest. As the disease progresses, patches of fibrotic and fat tissue form in the heart which can lead to heart failure. At this stage, patients require a heart transplantation as treatment.

Plakophilin-2

Over 50% of all ACM cases are caused by a mutation in one of the desmosomal genes, which together form complex protein structures known as desmosomes. Desmosomes form "bridges" between individual heart muscle cells, allowing the cells to contract in a coordinated manner. Most of the desmosomal mutations that cause ACM occur in a gene called plakophilin-2. Nevertheless, very little is known on how mutations in this gene lead to the disease. To change this, the Van Rooij lab first studied human heart samples from ACM patients carrying mutations in the plakophilin-2 gene. "We saw lower levels of all desmosomal proteins and disorganized desmosomal proteins in fibrotic areas of the ACM hearts," says Jenny (Hoyee) Tsui, first author on the paper. Tsui: "In addition, cultured 3D heart muscle tissue originating from a patient with a plakophilin-2 mutation, was unable to continue beating at higher pacing rates, which resembles arrhythmias seen in the clinic."

ACM in mice

The researchers then used a genetic tool called CRISPR/Cas9 to introduce the human plakophilin-2 mutation in mice to mimic ACM. This allowed them to study progression of the disease in more detail. They observed that old ACM mice carrying this mutation had lower levels of desmosomal proteins and heart relaxation issues, similar to ACM patients. Strikingly, the researchers discovered that the mutation lowered levels of desmosomal proteins even in young, healthy mice of which the heart contracted normally. From this they concluded that a loss of desmosomal proteins could underlie the onset of ACM caused by a plakophilin-2 mutation.

Protein degradation

The researchers then moved on to explain the loss of desmosomal proteins. For this they studied both RNA and protein levels in their ACM mice. "The levels of desmosomal proteins were lower in our ACM mice compared to healthy control mice. However, the RNA levels of these genes were unchanged. We discovered that these surprising findings are the result of increased protein degradation in ACM hearts," explains Sebastiaan van Kampen, co-first author of the paper. Tsui adds: "When we treated our ACM mice with a drug that prevents protein degradation, the levels of desmosomal proteins were restored. More importantly, the restored levels of desmosomal proteins improved calcium handling of heart muscle cells, which is vital for their normal function."

Towards new therapies

The results of this study, published in Science Translational Medicine, raise new insights into ACM development and indicate that protein degradation could be an interesting target for future therapies. "Protein degradation occurs in every cell of our body and is crucial for the function of these cells. To overcome side-effects of future therapies we will need to develop drugs that prevent degradation of desmosomal proteins in heart muscle cells specifically," explains Eva van Rooij, group leader at the Hubrecht Institute and last author of the study. More research is thus needed to realize this. In the future, these new specific drugs could potentially be used to halt the onset and prevent progression of ACM.

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From mutation to arrhythmia: Desmosomal protein breakdown as an ... - Science Daily

Link named oncology division director Washington University … – Washington University School of Medicine in St. Louis

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Leukemia specialist is leader in research, patient care

Daniel Link, MD, has been named director of the Division of Oncology at Washington University School of Medicine in St. Louis.

Daniel C. Link, MD, a highly regarded physician-scientist who treats patients with leukemia and also conducts innovative research aimed at developing better treatments for the blood cancer, has been named director of the Division of Oncology in the Department of Medicine at Washington University School of Medicine in St. Louis.

In addition, Link, who also is the Alan A. and Edith L. Wolff Distinguished Professor of Medicine, is deputy director of Siteman Cancer Center, based at Barnes-Jewish Hospital and Washington University School of Medicine.

Link will continue the work of John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine, who has led the Division of Oncology since 1997 and served as Sitemans first deputy director. DiPersio, a world-renowned physician-scientist specializing in the treatment of leukemia with immunotherapies and stem cell transplants, is stepping down from these leadership roles to return to full-time patient care and research to improve strategies for stem cell transplantation, treat graft-versus-host disease and develop novel types of CAR-T cell therapies for blood cancers.

Dr. Link is exceptionally qualified to take on this new role, said Victoria J. Fraser, MD, the Adolphus Busch Professor of Medicine and head of the Department of Medicine. He is an outstanding physician-scientist with tremendous leadership skills and was chosen for this position after an extensive national search. He is a national leader in leukemia research and is an exceptional mentor for fellows, postdoctoral scholars and junior faculty, many of whom have gone on to leadership positions in the field. I also want to recognize and extend my sincere gratitude to Dr. DiPersio for his exceptional leadership as the inaugural oncology division director for 25 years and his outstanding contributions as the deputy director of Siteman Cancer Center.

Link, also a professor of pathology & immunology, is a world leader in understanding hematopoiesis, the process by which different types of blood cells are formed. He has made key advances in the field of stem cell transplantation for the treatment of blood cancers. As the principal investigator of a prestigious Specialized Program of Research Excellence (SPORE) in Leukemia, an estimated $23 million grant, Link leads efforts aimed at boosting translational research and moving promising investigational treatments developed at Washington University into clinical trials. Such grants, funded by the National Institutes of Health (NIH), are highly competitive and a cornerstone of the National Cancer Institutes (NCIs) efforts to support collaborative, interdisciplinary translational cancer research. Link also has served as co-leader of the Hematopoiesis Development and Malignancy Program at Siteman Cancer Center since 2005.

Over the past 10 years, Link has helped to develop the hematopoietic malignancy program at Washington University into one of the top such programs in the country. Link has served as a mentor to 46 pre- or postdoctoral trainees, many of whom have established independent laboratories at Washington University and elsewhere. His commitment to mentoring and developing the next generation of scientists has been recognized with the universitys Outstanding Faculty Mentor Award and the Distinguished Faculty Award for Graduate Student Teaching. In 2015, he received the School of Medicine Alumni Faculty Achievement Award.

Link earned his bachelors degree from the University of Wisconsin-Milwaukee and his medical degree from the University of Wisconsin-Madison. He completed his residency in medicine at what was then Barnes Hospital and a fellowship in hematology-oncology at Washington University School of Medicine. He joined the faculty in 1993 and has remained at the School of Medicine for his entire career.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Childrens hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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Biologics Outsourcing Market : Latest Research Reveals Key Trends for Business Growth| Lonza Group AG, Wuxi Bi – openPR

Biologics Outsourcing Market

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Market Segmentation

The global biologics outsourcing market has been analyzed on the basis of product type, source, application, end-use, and region. Based on the product type, the market is segmented into antibodies, recombinant proteins, vaccines, and others. Among these, antibodies segment is estimated to hold a prominent share in the market. Based on source, the market is segmented into human, microbial, and others. The microbial segment is projected to exhibit a considerable growth during the forecast period.Based on application, the market is segmented into stem cell research, vaccine and therapeutics development, blood & blood-related products development, cellular and gene therapy products development, and others. Stem cell research segment is estimated to hold a prominent share in the market. Based on end-user, the market covers the analysis of therapeutics & diagnostics, and research. Geographically, the market is analyzed into North America, Western Europe, Eastern Europe, Asia Pacific, Latin America, and Middle East & Africa.

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Market Structure and Competition Landscape

The global biologics outsourcing market is characterized by the presence of significant number of players. Some of the prominent players operating in the market include Lonza Group AG, Wuxi Biologics (Cayman) Inc., Boehringer Ingelheim International GmbH, Samsung Biologics Co. Ltd., Thermo Fisher Scientific Inc., Wuxi Biologics (Cayman) Inc., Genescript Biotech Corp., and others. Growing focus on biologics and increasing R&D spending on biologics drugs by these industry players are expected to drive the market. Some of the key developments in the global biologics outsourcing market include:In January 2022, Samsung Biologics agreed to pay US$ 2.3 billion for Biogen s 50% stake in Samsung Bioepis, a joint venture between the two companies. This is aimed to improve Samsung Bioepis biosimilar development capabilities and future performance in new drug development.In March 2021, WuXi acquired a single-use biologics production plant in Hangzhou, China, from Pfizer Inc.

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Table of Content

Chapter One: Market Introduction1.1. Scope of Study1.2. Problem Statement1.3. Market SegmentationChapter Two: Assumptions and AcronymsChapter Three: Executive Summary3.1. Global Market in20223.2. Analyst Insights & Recommendations3.3. Growth Opportunities and Key Strategies3.4. Supply-side and Demand-side TrendsChapter Four: Research MethodologyChapter Five: Analysis of COVID-19 Impact and Road AheadChapter Six: Market Indicators and Background6.1. Macro-Economic Factors6.2. Forecasting FactorsRobust assessment of various factors including industrial performance, industry players expenditures, and economic conditions among others6.3. Supply Chain & Value Chain Analysis6.4. Industry SWOT Analysis6.5. PESTLE Analysis6.6. Porter s Five Forces AnalysisChapter Seven: Rules & RegulationsChapter Eight: Global and Regional Market Dynamics8.1. Drivers8.2. Restraints8.3. Trends8.4. OpportunitiesChapter Nine: Global Biologics Outsourcing Market: Key Investment Analysis9.1. By Leading Biologics Companies9.2. Technological Assessment9.3. By Region9.4. M&A ActivitiesRobust assessment of major investments made by various industry players along with key technological assessment, and key end-use sectorChapter Ten: Global Biologics Outsourcing Market: Service Cost Analysis10.1. By Service Type10.1.1. Antibody Production Service10.1.2. Custom Monoclonal Antibody Production Service10.1.3. Custom Polyclonal Antibody Production Service10.1.4. Protein Production Service10.1.5. Gene Editing ServiceChapter Eleven: Global Biologics Outsourcing Market: Biological Development Phase Analysis11.1. Discovery11.2. Pre-Clinical11.3. Clinical11.4. CommercializationChapter Twelve: Parent Market Overview12.1. Global Life Sciences Market12.2. Global Healthcare MarketChapter Thirteen: Segmental Analysis13.1. Global Biologics Outsourcing Market by Product Type13.1.1. Segment Overview13.1.1.1. Antibodies13.1.1.1.1. Monoclonal Antibody13.1.1.1.2. Antibody Drug Conjugates13.1.1.1.3. Others (Polyclonal Antibodies etc. )13.1.1.2. Recombinant proteins13.1.1.3. Vaccines13.1.1.4. Others (Fusion Proteins, etc. )13.2. Global Biologics Outsourcing Market by Source13.2.1. Segment Overview13.2.1.1. Human13.2.1.2. Microbial13.2.1.3. Others (Transgenic Animals such as Avian, Insects, etc. )13.3. Global Biologics Outsourcing Market by Application13.3.1. Segment Overview13.3.1.1. Stem Cell Research13.3.1.2. Vaccine and Therapeutics Development13.3.1.3. Blood & Blood-Related Products Development13.3.1.4. Cellular and Gene Therapy Products Development13.3.1.5. Others (Tissue & Tissue Related Products Development)13.4. Global Biologics Outsourcing Market by End Use13.4.1. Segment Overview13.4.1.1. Therapeutics and Diagnostics13.4.1.2. Research13.5. Global Biologics Outsourcing Market by Region13.5.1. North America13.5.2. Latin America13.5.3. Western Europe13.5.4. Eastern Europe13.5.5. Asia Pacific13.5.6. Middle East & AfricaChapter Fourteen: Regional Analysis14.1. North America Biologics Outsourcing Market Analysis and Forecast2019-202814.1.1. Market Overview14.1.2. North America Biologics Outsourcing Market by Product Type14.1.3. North America Biologics Outsourcing Market by Source14.1.4. North America Biologics Outsourcing Market by Application14.1.5. North America Biologics Outsourcing Market by End Use14.1.6. North America Biologics Outsourcing Market by Country14.1.6.1. US14.1.6.2. Canada14.2. Latin America Biologics Outsourcing Market Analysis and Forecast2019-202814.2.1. Market Overview14.2.2. Latin America Biologics Outsourcing Market by Product Type14.2.3. Latin America Biologics Outsourcing Market by Source14.2.4. Latin America Biologics Outsourcing Market by Application14.2.5. Latin America Biologics Outsourcing Market by End Use14.2.6. Latin America Biologics Outsourcing Market by Country14.2.6.1. Brazil14.2.6.2. Mexico14.2.6.3. Rest of Latin America14.3. Western Europe Biologics Outsourcing Market Analysis and Forecast2019-202814.3.1. Market Overview14.3.2. Western Europe Biologics Outsourcing Market by Product Type14.3.3. Western Europe Biologics Outsourcing Market by Source14.3.4. Western Europe Biologics Outsourcing Market by Application14.3.5. Western Europe Biologics Outsourcing Market by End Use14.3.6. Western Europe Biologics Outsourcing Market by Country14.3.6.1. Germany14.3.6.2. UK14.3.6.3. France14.3.6.4. Spain14.3.6.5. Italy14.3.6.6. Benelux14.3.6.7. Nordic14.3.6.8. Rest of Western Europe14.4. Eastern Europe Biologics Outsourcing Market Analysis and Forecast2019-202814.4.1. Market Overview14.4.2. Eastern Europe Biologics Outsourcing Market by Product Type14.4.3. Eastern Europe Biologics Outsourcing Market by Source14.4.4. Eastern Europe Biologics Outsourcing Market by Application14.4.5. Eastern Europe Biologics Outsourcing Market by End Use14.4.6. Eastern Europe Biologics Outsourcing Market by Country14.4.6.1. Russia14.4.6.2. Poland14.4.6.3. Rest of Eastern Europe14.5. Asia Pacific Biologics Outsourcing Market Analysis and Forecast2019-202814.5.1. Market Overview14.5.2. Asia Pacific Biologics Outsourcing Market by Product Type14.5.3. Asia Pacific Biologics Outsourcing Market by Source14.5.4. Asia Pacific Biologics Outsourcing Market by Application14.5.5. Asia Pacific Biologics Outsourcing Market by End Use14.5.6. Asia Pacific Biologics Outsourcing Market by Country14.5.6.1. China14.5.6.2. Japan14.5.6.3. India14.5.6.4. South Korea14.5.6.5. Australia14.5.6.6. ASEAN14.5.6.7. Rest of Asia-Pacific14.6. Middle East & Africa Biologics Outsourcing Market Analysis and Forecast2019-202814.6.1. Market Overview14.6.2. Middle East & Africa Biologics Outsourcing Market by Product Type14.6.3. Middle East & Africa Biologics Outsourcing Market by Source14.6.4. Middle East & Africa Biologics Outsourcing Market by Application14.6.5. Middle East & Africa Biologics Outsourcing Market by End Use14.6.6. Middle East & Africa Biologics Outsourcing Market by Country14.6.6.1. GCC14.6.6.2. South Africa14.6.6.3. Turkey14.6.6.4. Rest of the Middle East & AfricaChapter Fifteen: Competitive Landscape15.1. Competition Dashboard15.1.1. Global and Regional Market Share Analysis15.1.2. Market Structure15.2. Competitive Benchmarking15.3. Key Strategy Analysis15.4. Company Profiles15.4.1. Lonza Group AG15.4.1.1. Company Overview15.4.1.2. Product/Service Offerings15.4.1.3. Key Financials15.4.1.4. Recent Developments15.4.2. Wuxi Biologics (Cayman) Inc.15.4.2.1. Company Overview15.4.2.2. Product/Service Offerings15.4.2.3. Financials15.4.2.4. Recent Developments15.4.3. Boehringer Ingelheim International GmbH15.4.3.1. Company Overview15.4.3.2. Product/Service Offerings15.4.3.3. Financials15.4.3.4. Recent Developments15.4.4. Abzena Ltd.15.4.4.1. Company Overview15.4.4.2. Product/Service Offerings15.4.4.3. Financials15.4.4.4. Recent Developments15.4.5. GL Biochem Corp.15.4.5.1. Company Overview15.4.5.2. Product/Service Offerings15.4.5.3. Financials15.4.5.4. Recent Developments15.4.6. Catalent, Inc.15.4.6.1. Company Overview15.4.6.2. Product/Service Offerings15.4.6.3. Financials15.4.6.4. Recent Developments15.4.7. Samsung Biologics Co. Ltd.15.4.7.1. Company Overview15.4.7.2. Product/Service Offerings15.4.7.3. Financials15.4.7.4. Recent Developments15.4.8. ThermoFisher Scientific Inc.15.4.8.1. Company Overview15.4.8.2. Product/Service Offerings15.4.8.3. Financials15.4.8.4. Recent Developments15.4.9. Syngene International Ltd.15.4.9.1. Company Overview15.4.9.2. Product/Service Offerings15.4.9.3. Financials15.4.9.4. Recent Developments15.4.10. Rentschler Biopharma SE15.4.10.1. Company Overview15.4.10.2. Product/Service Offerings15.4.10.3. Financials15.4.10.4. Recent Developments15.4.11. Abbvie Inc.15.4.11.1. Company Overview15.4.11.2. Product/Service Offerings15.4.11.3. Financials15.4.11.4. Recent Developments15.4.12. Genscript Biotech Corp.15.4.12.1. Company Overview15.4.12.2. Product/Service Offerings15.4.12.3. Financials15.4.12.4. Recent Developments*List of companies is not exhaustiveChapter Sixteen: Disclaimer

Direct ContactJessica Joyal+1(213)338-8279 | +1(877)376-9989sales@themarketinsights.com

About us.Delivering foresights along with statistical analysis of the operational business industry impacts has been our foremost priority. With the constant developments in the research & development industry, we have always challenged the conventional research methodologies and discovered new research tactics to evolve the growing B2B requirements.

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Biologics Outsourcing Market : Latest Research Reveals Key Trends for Business Growth| Lonza Group AG, Wuxi Bi - openPR

Gene therapy: Everything you need to know about the DNA … – Livescience.com

Gene therapy has been headline news in recent years, in part due to the rapid development of biotechnology that enables doctors to administer such treatments. Broadly, gene therapies are techniques used to treat or prevent disease by tweaking the content or expression of cells' DNA, often by replacing faulty genes with functional ones.

The term "gene therapy" sometimes appears alongside misinformation about mRNA vaccines, which include the Pfizer and Moderna COVID-19 vaccines. These vaccines contain mRNA, a genetic cousin of DNA, that prompts cells to make the coronavirus "spike protein." The vaccines don't alter cells' DNA, and after making the spike, cells break down most of the mRNA. Other COVID-19 shots include the viral vector vaccines made by AstraZeneca and Johnson & Johnson, which deliver DNA into cells to make them build spike proteins. The cells that make spike proteins, using instructions from either mRNA or viral vector vaccines, serve as target practice for the immune system, so they don't stick around long. That's very, very different from gene therapy, which aims to change cells' function for the long-term.

Let's take a dive into what gene therapy actually is, addressing some common questions along the way.

DNA is a molecule that stores genetic information, and genes are pieces of genetic information that cells use to make a particular product, such as a protein. DNA is located inside the nucleus of a cell, where it's packaged into chromosomes, and also inside mitochondria, the "power plant" organelles located outside the nucleus.

Although there are mitochondrial diseases that could someday be cured with gene therapy, currently, the term gene therapy refers to treatments that target nuclear genes the genes on the 23 pairs of chromosomes inside the nucleus.

Classically, gene therapy has referred to the process of either "knocking out" a dysfunctional gene or adding a copy of a working gene to the nucleus in order to improve cell function. Gene therapy is currently directed at diseases stemming from a problem with just one gene, or at most a few genes, rather than those that involve many genes.

However, the field of gene therapy is now expanding to include strategies that don't all fall into the classic categories of knocking out bad genes or adding good genes. For example, researchers at Sangamo Therapeutics are developing genetic techniques for treating Parkinson, Alzheimer and Huntington diseases that work by ramping up or suppressing the activity of specific genes.

While the treatments may add genes to body cells, knock out genes or act in some way to change the function of genes, each gene therapy is directed to the cells of particular body tissues. Thus, when scientists and doctors talk about what gene therapy does to DNA, they are not talking about all of the DNA in the body, but only some of it.

Gene therapy can be either ex vivo or in vivo.

Ex vivo gene therapy means that cells are removed from the body, treated and then returned to the body. This is the approach used to treat genetic diseases of blood cells, because bone marrow can be harvested from the patient, stem cells from that bone marrow can be treated with gene therapy for instance, to supply a gene that is missing or not working correctly and the transformed cells can be infused back into the patient.

In vivo gene therapy means that the gene therapy itself is injected or infused into the person. This can be through injection directly to the anatomic site where the gene therapy is needed (a common example being the retina of the eye), or it can mean injection or infusion of a genetic payload that must travel to the body tissues where it is needed.

In both ex vivo and in vivo gene therapy, the genetic payload is packaged within a container, called a vector, before being delivered into cells or the body. One such vector is adeno-associated virus (AAV). This is a group of viruses that exist in nature but have had their regular genes removed and replaced with a genetic payload, turning them into gene therapy vectors.

AAV has been used to deliver gene therapy for many years, because it has a good safety record. It is much less likely to cause a dangerous immune response than other viruses that were used as vectors several decades ago, when gene therapy was just getting started. Additionally, packaging genetic payloads within AAV carriers allows for injected or infused gene therapy to travel to particular body tissues where it is needed. This is because there are many types of AAV, and certain types are attracted to certain tissues or organs. So, if a genetic payload needs to reach liver cells, for example, it can be packaged into a type of AAV that likes to go to the liver.

In the early days of gene therapy, which began in 1989, researchers used retroviruses as vectors. These viruses delivered a genetic payload directly into the nuclear chromosomes of the patient. However, there was concern that such integration of new DNA into chromosomes might cause changes leading to cancer (opens in new tab), so the strategy was initially abandoned. (More recently, scientist have successfully used retroviruses in experimental gene therapies without causing cancer; for example, a retrovirus-based therapy was used to treat infants with "bubble boy disease.")

After moving away from retroviruses, researchers turned to adenoviruses, which offered the advantage of delivering the genetic payload as an episome a piece of DNA that functions as a gene inside the nucleus but remains a separate entity from the chromosomes. The risk for cancer was extremely low with this innovation, but adenovirus vectors turned out to stimulate the immune system in very powerful ways. In 1999, an immune reaction from adenovirus-carrying gene therapy led to the death of 18-year-old Jesse Gelsinger, (opens in new tab) who'd volunteered for a clinical trial.

Gelsinger's death shocked the gene therapy community, stalling the field for several years, but the current gene therapies that have emerged over the years based on AAV are not dangerous. However, they tend to be expensive and the success rate varies, so they typically are used as a last resort for a growing number of genetic diseases.

Gene therapy can treat certain blood diseases, such as hemophilia A, hemophilia B, sickle cell disease, and as of 2022, beta thalassemia (opens in new tab). What these diseases have in common is that the problem comes down to just one gene. This made beta thalassemia and sickle cell disease low-hanging fruits for ex vivo gene therapies that involve removing and modifying bone marrow stem cells, whereas hemophilia A and hemophilia B are treated with in vivo gene therapies that target liver cells. That said, other treatments exist for these blood diseases, so gene therapy is more of a last resort.

Numerous enzyme deficiency disorders also come down to one bad gene that needs to be replaced. Cerebral adrenoleukodystrophy, which causes fatty acids to accumulate in the brain, is one such disorder that can be treated with gene therapy, according to Boston Children's Hospital (opens in new tab). CAR T-cell therapy, which is approved for certain cancers, involves removing and modifying a patient's immune cells and is known as a "cell-based gene therapy." (opens in new tab)

Gene therapy has also been useful in treating hereditary retinal diseases (opens in new tab), for which other treatments have not been useful.

Another group of targets for gene therapy are diseases of the nervous system.

"We are at a remarkable time in the neurosciences, where treatments for genetic forms of neurological disorders are being developed," Dr. Merit Cudkowicz (opens in new tab), the chief of neurologyat Massachusetts General Hospital and a professor at Harvard Medical School, told Live Science.

For example, gene therapies are being developed to treat a pair of genetic diseases called Tay-Sachs disease and Sandhoff disease. Both conditions result from organelles called lysosomes filling up with fat-like molecules called gangliosides. The effects of these diseases (opens in new tab) include delay in reaching developmental milestones, loss of previously acquired skills, stiffness, blindness, weakness and lack of coordination with eventual paralysis. Children born with Tay-Sachs disease and Sandhoff disease generally dont make it past 2 to 5 years of age.

"There has been no routine antenatal or neonatal test for Tay-Sachs and Sandhoff, because there has been no available treatment whatsoever," said Dr. Jagdeep Walia (opens in new tab), a clinical geneticist and head of the Division of Medical Genetics within the Department of Pediatrics and the Kingston Health Sciences Centre and Queen's University in Ontario, Canada. Walia is developing a gene therapy aimed at replacing the gene for Hex A, the enzyme that is deficient in these children. So far, the treatment has shown good efficacy and safety in animal models, but it still needs to be tested in human patients.

The future looks hopeful when it comes to gene therapy overall, on account of new technological developments, including CRISPR gene editing. This is an extremely powerful technique for cutting out parts of DNA molecules and even pasting new parts in analogous to what you do with text in word processing applications. CRISPR is not the first method that scientists have used to edit DNA, but it is far more versatile that other techniques. It is not yet quite ready for in vivo chromosomal manipulation, but it is advancing exponentially.

Perhaps even closer to the horizon is the prospect of delivering larger genetic payloads into cells. One big drawback of the AAV vector is that each virus particle can carry just a small amount of DNA, but recent research has revealed that a different type of virus, called cytomegalovirus, can be adapted to carry gene therapies (opens in new tab) with a much bigger payload than AAV. Not only might this some day expand gene therapy to more diseases requiring larger genes than AAV can carry, but it also could enable more than one gene to be delivered in a single therapy.

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Down syndrome research : 5 advancements over the year – Labiotech.eu

It was in 1959 when an extra chromosome on the 21st pair in the human cell was discovered by French geneticist Jerome Jean Louis Marie Lejeune. This was followed by research in the discipline of cytogenetics the study of chromosomes. This chromosomal aberration which affects around one in 1000 live births worldwide, is called trisomy 21 or Down syndrome named after the British physician who characterized the condition.

Following the discovery, the first mouse model with Down syndrome was created in 1974 which brought about guidelines for studying other chromosomal abnormalities.

Soon enough, prenatal diagnostic measures like amniocentesis were introduced to detect a fetus with Down syndrome.

Over the years, therapies have been focused on individual physical and intellectual needs, and to battle comorbidities like heart defects and hypothyroidism. Early intervention programs are offered to young children with Down syndrome where they engage with professionals who aid in providing speech and physical therapy, among other assistance.

Although amino acid supplements have been prescribed to people with cognitive disorders as a result of the condition to influence brain activity, recent clinical trials demonstrated adverse side effects. As studies have involved only a few participants, drugs to treat symptoms of dementia in Down syndrome have not proven to be efficacious yet.

However, news drug trials are attempting to fight symptoms, and assistive devices like special pencils to make writing easier, touch screen gadgets and large-letter keyboards have been developed to enhance learning in children.

As we observe World Down Syndrome Day on March 21, here are some of the latest advancements in Down syndrome research.

Although the triplication of chromosome 21 (T21) is an established fact, very little has been known about its effect on transcription in the nucleus of cells.

However, a study conducted by researchers at the Massachusetts Institute of Technology (MIT) in the U.S., has shed light on the interplay between T21 and transcriptome, which is the sequence of messenger RNA molecules.

It was found that, unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit chromosomal introversion characterized by more genetic interaction within each chromosome rather than among them and changes in chromatin accessibility a factor that influences the regulation of gene transcription. The research findings have indicated a link between Down syndrome and senescence (associated with aging), affecting neurodevelopment.

The treatment of the T21-harboring NPCs with senolytic drugs, which selectively clear senescent cells, alleviated some of the biological dysfunctions associated with Down syndrome, according to Fady Riad, CEO of consulting firm Centurion Life Sciences.

Riad expressed that senolytics like dasatinib and quercetin might be potential therapeutic options for patients since they may alleviate cellular and molecular dysfunction in NPCs.

The Spanish Hospital del Mar Medical Research Institute is conducting a phase 1b clinical trial to test the safety and efficacy of a new treatment to improve cognitive function in people with Down syndrome.

As studies have shown that people with Down syndrome have a hyperactivated CB1 cannabinoid receptor, the drug candidate is based on the modulation of the receptor with specific inhibitors which has proven to be effective on animal models. The French biotech Aelis Farma developed AF0217, a molecule that counteracts the hyperactivity of CB1 cannabinoid in the brain.

With funding from the European Union (EU), the team at the Spanish Hospital del Mar Medical Research had previously conducted a trial phase for AF0217, which was approved by the Spanish Agency for Medicines and Health Products (AEMPS), after having demonstrated that the molecule is well-tolerated.

Lead researcher Rafael de la Torre commented that this was of particular importance for the acceptance of treatment by the families of people with Down syndrome.

Phase 1b trials have recruited 45 patients with Down syndrome aged between 18 and 35.

According to Riad: This development is part of a wave of growing interest in the therapeutic potential of modulating the endocannabinoid system.

People with Down syndrome are often at the risk of being diagnosed with Alzheimers disease (AD), with a 90% lifetime incidence of AD. This is because amyloid plaques protein clumps that collect between neurons and disrupt cell function, an indicator of Alzheimers are often found in individuals in their 40s with Down syndrome, because of excessive amyloid plaque formation due to the extra copy of the APP gene encoding the amyloid precursor protein found on chromosome 21.

To battle Alzheimers, Swiss biotech AC Immune developed a vaccine candidate that inhibits plaque formation in the brain. The ACI-24.060 vaccine is designed to elicit an antibody response by the patients own immune system against pathological species of amyloid beta, according to Andrea Pfeifer, CEO of AC Immune. The mechanism is similar to that of Leqembi, an FDA-approved drug for the treatment of AD.

The vaccine, which is being studied in the ongoing phase 1/2 ABATE trial in Alzheimers disease, will be administered to the first individual from a Down syndrome cohort soon. This followshavingsuccessfully completed an early stage clinical trial which demonstrated its safety and immunogenicity in people with Down syndrome.

Pfeifer said: The lack of treatment options to address amyloid pathology in Down syndrome is unacceptable, as people living with Down syndrome represent the largest population with early onset Alzheimers disease. The individuals themselves together with their families are searching for therapies to help improve their quality of life and, as our first clinical study has shown, are willing to participate actively in the development of a solution.

An effective vaccine could potentially offer a means of prevention or reduction of disease severity and have a major impact on the lives of people living with Down syndrome, said Pfeiffer, who added that after an initial priming phase in the first year, the vaccine could be dosed annually or bi-annually as a booster to ensure that adequate antibody levels are maintained.

Pfeiffer expressed that the research will further raise the profile of the unmet medical need for individuals with Down syndrome and managing Alzheimers disease from which they almost invariably suffer.

Researchers at the University of Arizona have developed a drug that could slow the progression of AD in people with Down syndrome.

The drug, which decreases levels of DYRK1A an enzyme kinase which is excessively produced due to the overexpression of the DYRK1A gene in patients with AD has exhibited its effectiveness at suppressing AD symptoms, confirming their therapeutic potential in animal models.

Previously, DYRK1A inhibitor drugs have proven efficacy in mice models with AD, while the enzyme has been studied in Drosophila (fruit fly) with genetically engineered AD phenotypes, which showed that the overexpression of the DYRK1A gene led to photoreceptor neuron degeneration, decreased locomotion, sleep and memory loss.

According to Riad, the results are encouraging as the study focuses on an unmet medical need and paves the way for human clinical trials, however, there is the challenge of proving the drugs efficacy in human clinical trials, despite its success in preclinical studies.

A new research has confirmed a correlation between the secretion of gonadotropin-releasing hormone (GnRH), which is responsible for regulating the sex hormones and is produced in the neurons in the brain, and cognitive processes in Down syndrome. Moreover, the study showed that GnRH therapies could be given to patients with Down syndrome to boost brain connectivity.

The research conducted by a team at University of Lille in France, was initially studied in mice models with Down syndrome. It was observed that the mice had deficiencies of GnRH and an imbalance in a network of microRNAs, particularly around the trisomic regions; which affects neuronal activity, olfaction, and cognition.

The mice were then treated with cell therapy and chemogenetic interventions to produce GnRH, which showed promising results where they developed cognitive abilities similar to those of healthy mice.

This research led the team to partner with researchers at University of Lausanne in Switzerland, where trials were conducted on patients with Down syndrome. Patients were given GnRH replacement therapy drug Lutrelef every 2 hours for 6 months a therapy which is used to treat GnRH-deficient conditions like Kallmann syndrome, a condition that delays or prevents puberty. The success of the results was demonstrated by improved cognitive performance in patients.

More large-scale trials are needed but this is encouraging because GnRH replacement therapies have long been studied in humans and their safety profile is very well understood which means that an eventual path to regulatory approval will be rather straightforward, said Riad.

New technologies related to Down Syndrome research

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Down syndrome research : 5 advancements over the year - Labiotech.eu

COPHy 2023: Durability associated with multi-target therapies is … – Ophthalmology Times Europe

Antonio Campos, MD, PhD, made a presentation at the Congress on Controversies in Ophthalmology. He discusses his position on a discussion titled Durability Associated with Multi-target Therapies is Superior to anti-VEGF Mono-target Therapy in AMD with David Hutton, Executive Editor,Ophthalmology Times.

Editors note: This transcript has been edited for clarity

Hello, I'm David Hutton of Ophthalmology Times. The 14th annual Congress on controversies in Ophthalmology is being held this year in Lisbon, Portugal. At the event physicians present the pros and cons on a number of topics. Dr. Antonio Campos defended the negative position on a discussion titled Durability Associated with Multi-target Therapies is Superior to anti-VEGF Mono-target Therapy in AMD. Thanks for joining us today. Tell us about your discussion.

This is related mainly with the new faricimab versus aflibercept. And we know that angiopoietin-2 is not elevated in several cases of AMD, and 42% of the patients in the TENAYA and LUCERNE studies didn't have actually angiopoietin-2 levels elevated. Besides, there's another blocker of angiopoietin-2 that was used in ONYX trial of nesvacumab that didn't prove to be effective. And one should expect that in diabetic retinopathy studies and the recent BALATON and communal studies of retinal vein occlusion, where angiopoietin-2 is really elevated that the dual-action blocking angiopoietin-2 should have better results. But actually, that didn't prove to be right. So we must not forget that faricimab has a higher dosage than aflibercept [inaudible]. Well, the completion of the study was not perfect, and probably dosage and bioavailability will respond for most of the differences. According to my position, regulatory authorities, such as FDA and MA in Europe, also pointed out that it's not proven that there is an effective dual blocking mechanism in those medicines.

*Anat Loewenstein presented the affirmative position on this topic.

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COPHy 2023: Durability associated with multi-target therapies is ... - Ophthalmology Times Europe

Here’s Why Axolotls Are Disappearing – Green Matters

By Eva Hagan

Mar. 24 2023, Published 1:36 p.m. ET

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The carnivorous salamander native to the lakes of Mexico, the axolotl (pronounced AX-oh-lot-ul), is facing extinction primarily due to human development, habitat loss, droughts, wastewater disposal, and climate change, per National Geographic.

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According to Reuters, axolotls once swam all throughout Xochimilco's canals, however, polluted water due to urban sprawl and the increase in non-native species competition has led the population to decrease.

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Although the axolotl is often bred in labs and captivity, they continue to decline in the canals of Mexico City, their only remaining natural habitat.

According to Vox, axolotl habitat destruction started as early as the Spanish invasion during colonization, where the growth and development of Mexico City sent chemicals and sewage into local waterways, changing ecosystems forever. Since then, fertilizers, pollution, chemicals, etc. have only increased, as well as the introduction of non-native species that outcompete native species like axolotls.

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Axolotls have been popular in the aquarium and pet trade since the 19th century, traveling from Mexico to all over Europe.

The axolotl has been studied for its impressive ability to regrow tissues in the skin, muscles, heart, brain, etc., and its capacity to resist cancerous tissues. Because of its unique abilities, the axolotl was even considered in legends as Xototl, the Aztec god of fire and lightning, disguised as a salamander.

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Axolotls live anywhere from 10 to 15 years and differ from other salamanders and amphibians because they seem to stay young forever, a marvel called neoteny, where they keep their baby traits and physical features their whole life.

However, although they remain cute, they are carnivorous and feed on crustaceans, mollusks, eggs, and fish, per National Geographic.

A research article published in 2016 by the Department of Stem Cell and Regenerative Biology at Harvard University found that axolotls are able to regrow parts of their brain after injury, growing diverse sets of neurons.

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Their ability to do this, along with regrowing entire parts of their body with not so much as a scar, is deemed a superpower in the scientific world. According to an interview between the Boston Museum of Science and Fallon Durant, an axolotl researcher, scientists are studying axolotls to determine what parts of their DNA help them regenerate, and resist things like cancer. If this can be understood and replicated, it could be a game changer for human therapeutics.

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Here's Why Axolotls Are Disappearing - Green Matters