Novel Strategies for Targeting the Guardian of the Genome Emerge – OncLive
As the guardian of the genome and the most frequently mutated gene in human cancer, TP53 and the p53 tumor suppressor protein it encodes make a compelling therapeutic target with the potential for broad-based activity. But p53 presents a significant challenge for investigators, and the field is littered with clinical trial failures and abandoned drug development programs.1,2
This year was shaping up to be a landmark one for this intensively researched cancer drug target, with a hotly anticipated readout from a phase 3 trial of idasanutlin, a small molecule inhibitor of the p53-regulatory protein MDM2.3,4
However, results from the phase 3 MIRROS trial in patients with relapsed/refractory acute myeloid leukemia (AML) proved yet another disappointment5 for a field that has taken more than its fair share of blows over the decades.1,2
Nevertheless, investigators continue to push the boundaries of drug development in their efforts to develop novel p53-targeting agents and potential combinatorial strategies. Several companies are pursuing drugs that reactivate mutant forms of the p53 protein, restoring its tumor-suppressive properties.
One such agent, eprenetapopt (APR-246), received a breakthrough therapy designation in January 2020 for the treatment of patients with TP53-mutant myelodysplastic syndromes (MDS).6 Promising phase 2 data for the drug were highlighted at the 2019 American Society of Hematology Annual Meeting (ASH).7
Discovered more than 4 decades ago,8 the p53 protein is best known for its role as a transcription factor. Modulating the expression of multiple important genes positions p53 as a master regulator of a range of cellular processes, the most thoroughly studied being the DNA damage response.
Levels of p53 protein are generally low; however, in response to cellular stressors such as DNA damage, p53 is activated, accumulates in the nucleus, and induces the expression of genes that contain specific response elements. Among its targets are regulators of the cell cycle, DNA repair, and apoptosis, which allow the cell to pause cycling to repair damaged DNA or induce cell death if the damage is irreparable. In this way, p53 serves as a barrier to the genomic instability that fosters cancer development, earning it the nickname guardian of the genome (FIGURE).2,9-12
The p53 protein is composed of multiple functional domains: Two transactivation domains operate together and independently to mediate the transcription of p53 target genes, a proline-rich domain is implicated in p53-mediated inhibition of cell growth and stimulation of apoptosis, and a DNA-binding domain allows p53 to bind the promoters of target genes.2
In addition, p53 contains an oligomerization domain that enables it to form a homotetramer (required for transcription factor activity), a nuclear export signal, and an unstructured C-terminal domain that is targeted by post-translational modifications that fine-tune p53s activity.2
The activity of p53 is tightly controlled by other mechanisms, most notably by 2 negative regulators, MDM2 and MDM4. MDM2 is an E3 ubiquitin ligase that tags p53 with the small molecule ubiquitin, promoting the removal of p53 from the nucleus and targeting it for degradation by the proteasome.1,2,9,11
Notably, the MDM2 gene is a transcriptional target of p53; thus, a negative feedback loop exists whereby p53 promotes the expression of its own negative regulator. MDM4 does not possess E3 ligase activity but interacts with MDM2 to promote ubiquitination of p53.2
The importance of p53 as a tumor suppressor is reflected in reports that it is mutated in approximately half of all human cancers.2,9,10,12 Its prevalence varies widely across tumor types, reaching up to 95% in high-grade serous ovarian cancer (TABLE 1).13
Somatic TP53 mutations are also extremely common in small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, and invasive breast cancer, particularly the triple-negative subtype.14
Meanwhile, germline mutations in TP53 are associated with the rare Li-Fraumeni syndrome, in which individuals have an increased risk of developing cancer over the course of their lifetime.11,12
Although many types of mutation have been identified in TP53, the vast majority occur within the DNA-binding domain, affecting p53s ability to activate its target genes and leading to a loss of tumor- suppressive function.2,12
Interestingly, unlike other tumor suppressor proteins, which are usually affected by deletion or nonsense mutations, most TP53 mutations result in a single amino acid substitution.5 These missense mutations are broadly classified into 1 of 2 types: either contact mutations that directly impede p53s ability to bind target genes DNA or structural mutations that induce a conformational change in the p53 protein that affects its function.2,10,12
Moreover, it is thought that the effect of mutant p53 on carcinogenesis may occur through more than just a passive loss of its tumor-suppressive capabilities. Mutant p53 can also affect wild-type p53 when both forms are present in the same cell. Unlike deletions or nonsense mutations, missense mutations allow the production of full-length (albeit defective) protein. This mutant p53 protein is capable of forming complexes with the wild-type protein that dampen the antitumor functions of the wild-type protein.10,14,15
The mutant form also has been shown to acquire protumorigenic functions through interaction with other proteins that play a role in various cancer hallmarks.2,10,12
Even in the absence of gene mutations, p53 function is often impaired in cancer cells. A major mechanism is through dysregulation of the MDM2 and MDM4 proteins, which are frequently overexpressed in various tumor types. Ultimately, the p53 pathway is thought to be nearly universally dysfunctional in human malignancies, making it an enticing therapeutic target.2,11
For decades, investigators have sought to harness the p53 protein in drug development, but tumor suppressor proteins are notoriously difficult to target and require unconventional therapeutic strategies. A variety of methods are under investigation today, according to a search of ClinicalTrials.gov. These include vaccines and agents with targets that affect p53 functions. One of the most prevalent strategies involves targeting MDM2 protein activity and one of the most innovative seeks to reactivate p53 regulation (TABLE 2).
Among the earliest and most promising approaches to treating tumors without TP53 mutations was the attempt to block the interaction between p53 and its negative regulator MDM2. Targeting protein-protein interactions also holds challenges, but investigators identified a hydrophobic groove on the surface of MDM2 that offered a binding foothold.1,2
The early 2000s saw the emergence of the nutlins, named after the Roche facility in Nutley, New Jersey, where they were discovered.1 The first to advance to clinical trials, RG7112, showed promise in phase 1 studies but was limited by the development of significant gastrointestinal (GI) and hematologic toxicities.1,2,9
Idasanutlin is a more potent and selective nutlin analogue based on a different chemical scaffold.1,3,9 Data from phase 1/2 studies suggested that idasanutlin had clinical activity alone and in combination with other drugs in patients with AML,3 a cancer type in which p53 dysfunction is highly prevalent despite a comparatively low rate of TP53 mutations (5%-8% of newly diagnosed patients; 30%-40% of therapy-related AML).16
Idasanutlin advanced to the phase 3 MIRROS trial, in which it was evaluated in combination with cytarabine compared with cytarabine alone in patients with relapsed/ refractory AML fit for intensive salvage therapy (NCT02545283). However, the MIRROS study was terminated due to futility based on efficacy results at a planned interim analysis, according to an update posted in May 2020 on ClinicalTrials.gov.4
The results of this analysis were presented at the virtual 25th European Hematology Association Congress in June 2020. A total of 447 patients were randomized 2:1 to receive idasanutlin 300 mg (or placebo) twice daily plus cytarabine 1 g/m2 once daily on days 1 to 5 of a single 28-day induction cycle. Responders could follow this with up to 2 optional consolidation cycles of once-daily idasanutlin 300 mg plus cytarabine 1 g/m2.
The study failed to meet its primary end point of improved overall survival (OS); median OS was 8.3 months in the idasanu-tlin arm and 9.1 months for placebo (HR, 1.08; 95% CI, 0.81-1.45; P = .58). Overall response rate (ORR) was 38.8% versus 22.0% (OR, 2.25; 95% CI, 1.36-3.72), and complete response (CR) was achieved in 20.3% and 17.1% of patients, respectively (OR, 1.23; 95% CI, 0.70-2.18).
The most common adverse events (AEs) were GI toxicities, and there were similar rates of grade 3 to 5 AEs in the 2 arms; most commonly, febrile neutropenia, thrombocytopenia, and anemia.5
Several other clinical trials of idasanutlin are ongoing, including a phase 1b study in which idasanutlin is being tested in combination with the BCL-2 inhibitor venetoclax (Venclexta)a combination that has shown potent synergy in preclinical trials in elderly patients with relapsed/ refractory AML who are ineligible for chemotherapy (NCT02670044).
Among 49 patients, there was a 41% anti-leukemic response rate, a measure that encompasses the rates of CR, CR with incomplete platelet count recovery, CR with incomplete hematologic recovery, partial response (PR), and morphologic leukemia- free state. Median duration of response (DOR) was 4.9 months, and median OS was 4.4 months. The most common AEs were diarrhea and nausea, and grade 3 or 4 AEs included febrile neutropenia, neutropenia, and thrombocytopenia.17
Although some companies have suffered setbacks with MDM2 inhibitors, others are persevering; several new agents in this class have entered clinical trials.1 KRT-232 (AMG 232) was originally developed by Amgen, but Kartos Therapeutics has taken over development. The results of a first-in- human clinical trial were recently published (NCT01723020). A total of 107 patients with various advanced solid tumors or multiple myeloma were enrolled, most of whom had received 3 or more prior lines of therapy.
During dose escalation (n = 39), KRT-232 was administered at doses of 15, 30, 60, 120, 240, 300, 360, and 480 mg. There were 3 dose-limiting toxicities (DLTs): grade 3 neutropenia and grade 3 and 4 thrombocytopenia. The highest tolerated dose, 240 mg, was evaluated in dose expansion (n = 68). The most common treatment-related AEs (TRAEs) in the dose-expansion group were diarrhea, nausea, vomiting, fatigue, decreased appetite, and thrombocytopenia, mostly grade 1 or 2 in severity.
Per central evaluation, 4% of patients had unconfirmed PRs (including patients with well-differentiated liposarcoma, squamous cell carcinoma, and breast cancer), whereas most patients experienced stable disease (SD).18 KRT-232 also recently showed limited clinical activity in a phase 1 clinical trial in patients with relapsed/refractory AML (NCT02016729).19
Ascentage Pharma is developing another MDM2 antagonist, APG-115, and a phase 1 study in patients with advanced solid tumors has been completed (NCT02935907). Among 28 patients, who had received a median of 4 prior lines of therapy and were treated with doses ranging from 10 to 300 mg for 21 days of 28-day cycles, 6 patients experienced SD after 2 cycles. The most common AEs included fatigue, nausea, vomiting, diarrhea, decreased appetite, dehydration, neutropenia, leukopenia, pain in extremity, and thrombocytopenia.20
None of the MDM2 inhibitors under evaluation block MDM4 activity, and tumors overexpressing this protein would likely be resistant to these drugs. A dual inhibitor of both MDM2 and MDM4 is therefore desirable, and Aileron Therapeutics has a first-in-class drug, ALRN-6924, in clinical trials. In p53, a helical region binds to both MDM2 and MDM4, and ALRN-6924 is a stapled peptide, locked in a helical conformation that mimics this region.21,22 It is being evaluated in several ongoing phase 1 clinical trials.
Aileron is also exploring ALRN-6924 as a chemoprotectant. It is anticipated that ALRN-6924 will arrest the cell cycle in normal cells that express wild-type p53, but not in cancer cells with a TP53 mutation. Thus, treatment should limit the off-target toxicity of DNA-damaging chemotherapies that target rapidly proliferating cells.23
One of the most exciting strategies for targeting cells that have TP53 mutations is reactivation of the mutant protein. The most widely investigated drugs are PRIMA-1 (p53 reactivation and induction of massive apoptosis) and its methylated derivative, eprenetapopt.
Both are prodrugs that are converted into an active metabolite, methylene quinuclidinone, which binds covalently to thiol groups in the core of the mutant p53 protein and causes it to undergo a conformational change, restoring wild-type activity.9,12
Eprenetapopt is more potent and has improved membrane permeability compared with PRIMA-1, and it has become the focus of ongoing clinical trials.2,12 It demonstrated anticancer activity and had a favorable safety profile in a range of preclinical cancer models, which led to the commencement of early-stage clinical testing.2,12 In a first-in-human study, eprenetapopt was reported to be safe and showed some activity in patients with hematologic malignancies (NCT00900614).24
Patients with TP53-mutant MDS have a particularly poor prognosis, and new treatment options are needed.25 In a phase 1/2 study (NCT03072043), eprenetapopt was evaluated in combination with the hypomethylating agent azacitidine in patients with TP53-mutant higher-risk MDS or oligoblastic ( 30% blasts) AML.26
Phase 1b results demonstrated that eprenetapopt treatment led to transcriptional activation of p53 target genes. Additionally, patients experienced predominantly grade 1 or 2 AEs, and there were no DLTs. Among 11 evaluable patients, there were 9 CRs and 2 bone marrow CRs.26
Results from the phase 2 portion of the trial were presented at the 2019 ASH meeting. A total of 49 patients had been enrolled and treated with the recommended phase 2 dose of 4500 mg administered intravenously on days 1 to 4 in combination with azacitidine 75 mg/m2 for 7 days (days 4-10 or days 4-5 and 8-12) in 28-day cycles. The median age of patients was 66 years, and most patients had MDS, all higher risk.
The ORR was 87%, including a 53% CR rate and 18% bone marrow CR with hematologic improvement. An additional 4 patients had SD, and just 2 had progressive disease. Median DOR was 6.5 months.
Having TP53 as the sole gene mutation was predictive of a higher CR rate (69% vs 25%; P = .006), and there was a nonsignificant trend toward higher ORR in these patients (93% vs 75%; P = .17). In the overall cohort, the median OS was 11.6 months. The 18 patients who discontinued study treatment to proceed to stem cell transplant had better median OS than those who did not (16.1 months vs 9.2 months). TRAEs included nausea, vomiting, dizziness, constipation, neuropathy, leukopenia, and thrombocytopenia.7
Based on these findings, the FDA granted fast track and orphan drug designations to eprenetapopt for MDS treatment.6 A phase 3 clinical trial of eprenetapopt in combination with azacitidine in patients with TP53mutated MDS is ongoing (NCT03745716),7 and Aprea Therapeutics recently reported that enrollment was complete, with topline results expected in late 2020.27
Interim results of a French trial were also presented at the 2019 ASH meeting. Fifty-three patients (34 with MDS and 19 with AML, all higher risk and harboring TP53 mutations) were treated with 4500 mg of eprenetapopt on days 1 to 4 and azacitidine 75 mg/m2 on days 4 to 10 of 28-day cyclesAmong 16 patients evaluable for response, The ORR was 75%, including 56% CR and 19% bone marrow CR or SD with hematologic improvement. Common TRAEs were febrile neutropenia and neurological toxicities, the latter including ataxia, cognitive impairment, acute confusion, isolated dizziness, and facial paresthesia.28
Eprenetapopt also demonstrated activity in combination with carboplatin and pegylated liposomal doxorubicin in patients with high-grade serous ovarian cancer, a cancer type with a high prevalence of TP53 mutations, in the phase 1/2 PiSARRO trial (NCT02098343).29
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Novel Strategies for Targeting the Guardian of the Genome Emerge - OncLive
Lab-Grown Mini-Lungs Mimic the Real Thing Right Down to Covid Infection – Duke Today
DURHAM, N.C. -- A team of Duke University researchers has developed a lab-grown living lung model that mimics the tiny air sacs of the lungs where coronavirus infection and serious lung damage take place. This advance has enabled them to watch the battle between the SARS-CoV-2 coronavirus and lung cells at the finest molecular scale.
The virus damages the delicate, balloon-like air sacs, known as alveoli, leading to pneumonia and acute respiratory distress, the leading cause of death in Covid-19 patients. But scientists have been hampered in Covid-19 studies by the lack of experimental models that mimic human lung tissues.
Now, a team led by Duke cell biologist Purushothama Rao Tata has developed a model using lung organoids, also dubbed mini-lungs in a dish. The organoids are grown from alveolar epithelial type-2 cells (AT2s) which are the stem cells that repair the deepest portions of the lungs where SARS-CoV-2 attacks.
Earlier research at Duke had shown that just one AT2 cell, isolated into tiny dishes, could multiply to produce millions of cells that assemble themselves into balloon-like organoids that look just like alveoli. However, the soup in which the cells were grown contained complex ingredients such as serum from cows that is not completely defined.
Tatas group took on the big challenge of predicting and testing many combinations of chemically pure factors that would do the job just as well, a problem that required close co-operation with Dukes shared computing cluster.
The result is a purely human organoid without any helper cells. Mini-lungs grown in tiny wells will enable high throughput science, in which hundreds of experiments can be run simultaneously to screen for new drug candidates or to identify self-defense chemicals produced by lung cells in response to infection.
This is a versatile model system that allows us to study not only SARS-CoV-2, but any respiratory virus that targets these cells, including influenza, Tata said. A paper describing the development of the mini-lungs and some early experiments with coronavirus infection appeared early online Oct. 21 in the journal Cell Stem Cell.
In using mini-lungs to study SARS-CoV-2 infection, Tatas team collaborated with virology colleagues at Duke and the University of North Carolina in Chapel Hill. To safely handle these deadly viruses, the researchers utilized state-of-the art biosafety level 3 facilities at Duke and UNC-CH to infect lung organoids. The researchers watched the gene activity and chemical signals that are produced by the lung cells after infection.
This is a major breakthrough for the field because we were using cells that didnt have purified cultures, said Ralph Baric, a co-author on the paper who is a distinguished professor of epidemiology, microbiology and immunology at UNC and world authority on coronaviruses. The Duke mini-lungs are 100 percent human with no supporting cells that could confuse findings. This is incredibly elegant work to figure out how to purify and grow AT2 cells in culture in pure form, Baric said.
Barics lab is capable of changing any nucleotide of the Covid-19 viruss genetic code at will, so it produced a glowing version that would reveal where it went in the mini-lungs, confirming that it did indeed home in on the crucial ACE2 cell surface receptor, leading to infection.
When infected with the virus, the organoids were shown to launch an inflammatory response mediated by interferons. The researchers have also witnessed the cytokine storm of immune molecules the lungs launch in response to the virus.
It was thought cytokine storm happened due to the large influx of immune cells, but we can see it also happens in the lung stem cells themselves, Tata said.
Tatas lab found the cells produced interferons and experienced self-destructive cell death, just as samples from Covid-19 patients have shown. The signal for cell suicide was sometimes triggered in uninfected neighboring lung cells as well, as the cells struggled to get ahead of the virus. The researchers also compared the gene activity patterns between the mini-lungs and samples from six severe Covid-19 patients and found they agreed with striking similarity.
Weve only been able to see this from autopsies until now, Tata said. Now we have a way to figure out how to energize the cells to fight against this deadly virus.
In another series of experiments, mini-lungs treated with low doses of interferons before infection were able to slow viral copying. But suppressing interferon activity before infection led to increased viral replication.
Tata, who is a part of Dukes regenerative medicine initiative, Regeneration Next, said his lab was working on growing the mini lungs in mid-2019 and had achieved a working model just as the coronavirus pandemic emerged. He said his group will be working with both academic and industry partners to use these cells for cell-based therapies and eventually to try to grow a complete lung for transplantation.
Baric said his lab will probably be using the mini-lungs to better understand a new strain of SARS-CoV-2 called D614G that has become the dominant version of the virus. This strain, which emerged in Italy, has a spike protein that is apparently more efficient at recognizing the ACE2 receptor on lung cells, making it even more infectious.
This research was performed with support from the Chan Zuckerberg Foundation, the U.S. National Institutes of Health (UC6-AI058607, AI132178, AI149644, R00HL127181, R01HL146557, R01HL153375, R21GM1311279, F30HL143911, DK065988), Duke University and United Therapeutics Corporation.
CITATION: Human Lung Alveolospheres Provide Insights Into SARS-Cov-2 Mediated Interferon Responses and Pneumocyte Dysfunction, Hiroaki Katsura*, Vishwaraj Sontake*, Aleksandra Tata*, Yoshihiko Kobayashi*, Caitlin E. Edwards*, Brook E. Heaton, Arvind Konkimalla, Takanori Asakura, Yu Mikami, Ethan J. Fritch, Patty J. Lee, Nicholas S. Heaton, Richard C. Boucher, Scott H. Randell, Ralph S. Baric, Purushothama Rao Tata.* indicates co-first authors. Cell Stem Cell, early online Oct. 21, 2020. DOI: 10.1016/j.stem.2020.10.005
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Lab-Grown Mini-Lungs Mimic the Real Thing Right Down to Covid Infection - Duke Today
Neural Stem Cell Market Research Report on Opportunities, Drivers and Threats Outlook, Covid-19 Impact by 2026 | Futuristic Reports – The Think…
An innovative research study has been offered by Futuristic Reports, offering a comprehensive analysis of the Global Neural Stem Cell Market where users can get an advantage from the comprehensive market research report with all the essential useful information. This is the newest report, covering the existing COVID-19 impact on the Neural Stem Cell market. It has fetched along with numerous changes in market conditions. This segment also provides the Neural Stem Cell scope of different applications and types that can potentially influence the future market. The comprehensive statistics are based on current trends and historical milestones.
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Impact of COVID-19 on Neural Stem Cell Market
The report also contains the effect of the ongoing worldwide pandemic, i.e., COVID-19, on the Neural Stem Cell Market and what the future holds for it. It offers an analysis of the impacts of the epidemic on the international market. The epidemic has immediately interrupted the requirement and supply series. The Neural Stem Cell report also assesses the economic effect on firms and economic demands. Futuristic Reports has accumulated advice from several delegates of this Neural Stem Cell business and has engaged from the secondary and primary research to extend the customers with strategies and data to combat industry struggles throughout and after the COVID-19 pandemic.
Some of the key players operating in this market include:
(STEMCELL Technologies, R&D Systems, Thermo Fisher Scientific, Neuralstem, ReNeuron Limited, Asterias Biotherapeutics, NeuroGeneration, Axol Bio, NeuroNova AB, Lonza, StemCells)
Based on Product Type, Neural Stem Cell market report displays the production, profits, cost, and market segment and growth rate of each type, covers:
Type 1 Type 2 Type 3 Type 4 Type 5
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Medical care Hospital Laboratory
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The report offers a comprehensive assessment of the progression and other Neural Stem Cell market features in significant regions, including South Korea, Taiwan, North America, Europe, Canada, Germany, France, Southeast Asia, Mexico, and Brazil, Pacific, and Latin America. U.S., U.K., Italy, Russia, China, Japan, etc.
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Stem Cell Therapies Market 2020 Revenue, Opportunity, Forecast and Value Chain 2028 – PharmiWeb.com
Future Market Insights (FMI) presents its new, comprehensive study on the global Stem Cell Therapies market spanning from 2020-2030. Researches at FMI have no left no stone unturned in bestowing readers a comprehensive view of the market, by studying the drivers, trends, challenges, and restraints. Backed by historical data and projected data, the report breaks down the vast study into numerous geographies and end-use segments, among others to condense the research.
Analysts at FMI have employed in-depth analysis to offer a lucid understanding of the market and the factors shaping its growth trajectory. Ranging from macro socio-economic factors to micro geography-specific trends, the research has taken into consideration every facet that is likely to play a vital role in the growth of the market in the years to come. Presenting a plethora of valuable information, the report will serve as an effective tool, guiding the market players in making fruitful decisions in the forthcoming years.
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Impact of COVID-19 on Stem Cell Therapies Market
The unforeseen outbreak of COVID-19, which swiftly metamorphosed into the pandemic of unexpected proportions, has shifted the worlds focus towards the healthcare sector. National governments are closely working with healthcare institutions and pharmaceutical companies to provide effective treatment to patients suffering with the infection. As a result, there has been a reorientation of medical priorities across healthcare institutions with treatment for COVID-19 patients being the utmost priority. This is sure to impact the growth of the Stem Cell Therapies market through the pandemic period.
FMIs report includes a dedicated section expounding both the short-term and long-term impact of the pandemic on the Stem Cell Therapies market. The study is shaped to bolster stakeholders in making the right decisions to mitigate challenges and leverage opportunities through the pandemic.
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Stem Cell Therapies Market: Segmentation
To simply the gargantuan study, the report is segregated on the basis of different segments.
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The aforementioned segments are studied with respect to each individual region, considering the region-specific trends, drivers and restraints.
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Stem Cell Therapies Market: Competition Analysis
The study bestows valuable insights into the competitive landscape of the global Stem Cell Therapies market, by studying numerous players, their growth strategies, and key developments. The report dwells deep and studies different facets such as product launches, production methodologies, and steps adopted by players to make processes cost-effective, among others, are expected to influence their individual standpoint. Understanding the prevailing trends and strategies on the supply-side empowers players to foster their plan of action accordingly to progress on a remunerative path. Key players covered in the research include
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Stem Cell Therapies Market 2020 Revenue, Opportunity, Forecast and Value Chain 2028 - PharmiWeb.com
Baby Gets Early Stem Cell Transplant to Treat Rare Disease Thanks to Newborn Screening – University of Michigan Health System News
At birth, Minette looked perfectly healthy, and her parents took their 7 pound, 9- ounce, brown-eyed baby girl home thinking all was well.
But her newborn screening test revealed something different.
The results indicated Minette had a rare lysosomal storage disease known as mucopolysaccharidosis type I, or MPS-1. Babies usually dont show any symptoms at birth, but the condition is progressively debilitating, eventually causing permanent damage to mental development, organ function and physical abilities.
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And at nine days old in January, 2019, after a series of tests run by the newborn screen follow up team in pediatric genetics at Michigan Medicine C.S. Mott Childrens Hospital, Minette was officially diagnosed with MPS-1.
There were no signs of this disease during pregnancy or after her birth, says her mother Samantha Mejia, of West Bloomfield, Mich.
It was so important that we identified it early so she could get treatment that would give her a better chance of living a more normal life.
MPS-1 means the body is missing or does not have enough of an enzyme needed to break down long chains of sugar molecules (glycosaminoglycans) within structures called lysosomes. Lysosomes are essentially the bodys recycling centers large molecules go in and come out small enough so the body can use them.
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When these molecules cant be broken down, they build up in the cell, causing many organs and tissues of the body to become enlarged, damaged and unable to work properly. Some children may develop mild to moderate mental impairment or learning difficulties, respiratory problems, sleep apnea and heart disease.
In severe cases like Minettes, children stop developing between ages 2-4, which is followed by progressive mental decline including loss of physical abilities and language skills.
MPS-1 was added to the Michigan newborn screen in August, 2017 just a little more than a year before Minette was born joining a list of more than 50 disorders that can now be detected through a simple blood test after birth.
Prior to being added to the newborn screen, many children were often diagnosed between ages one-and-a-half and three years old because they start losing developmental milestones or begin showing certain facial features as a result of glycosaminoglycans storage, such as thickened nostrils, lips or ears.
The clinical diagnosis of MPS-1 is often delayed because the symptoms tend to be non-specific early on. Newborn screening is crucial for making an early diagnosis and initiating treatment, which significantly alters the long term outcomes for patients, says Rachel Fisher, pediatric genetic counselor at Mott and a lysosomal storage disorder newborn screen coordinator for the state of Michigan.
Because of Minettes early diagnosis, her Mott care teams could quickly take next steps for treatment. She started enzyme therapy within six weeks, and at three months of age underwent four days of chemotherapy before ultimately getting a hematopoietic stem cell transplant to help replace the enzyme her body was missing.
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Baby Gets Early Stem Cell Transplant to Treat Rare Disease Thanks to Newborn Screening - University of Michigan Health System News
Stem Cell and Regenerative Therapy Market Report to Describe Major Companies and Their Strategies (2019-2024) – PRnews Leader
Theglobal stem cell and regenerative medicines marketshould grow from $21.8 billion in 2019 to reach $55.0 billion by 2024 at a compound annual growth rate (CAGR) of 20.4% for the period of 2019-2024.
Report Scope:
The scope of this report is broad and covers various type of product available in the stem cell and regenerative medicines market and potential application sectors across various industries. The current report offers a detailed analysis of the stem cell and regenerative medicines market.
The report highlights the current and future market potential of stem cell and regenerative medicines and provides a detailed analysis of the competitive environment, recent development, merger and acquisition, drivers, restraints, and technology background in the market. The report also covers market projections through 2024.
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The report details market shares of stem cell and regenerative medicines based on products, application, and geography. Based on product the market is segmented into therapeutic products, cell banking, tools and reagents. The therapeutics products segments include cell therapy, tissue engineering and gene therapy. By application, the market is segmented into oncology, cardiovascular disorders, dermatology, orthopedic applications, central nervous system disorders, diabetes, others
The market is segmented by geography into the following regions: North America, Europe, Asia-Pacific, South America, and the Middle East and Africa. The report presents detailed analyses of major countries such as the U.S., Canada, Mexico, Germany, the U.K. France, Japan, China and India. For market estimates, data is provided for 2018 as the base year, with forecasts for 2019 through 2024. Estimated values are based on product manufacturers total revenues. Projected and forecasted revenue values are in constant U.S. dollars, unadjusted for inflation.
Report Includes:
28 data tables An overview of global markets for stem cell and regenerative medicines Analyses of global market trends, with data from 2018, estimates for 2019, and projections of compound annual growth rates (CAGRs) through 2024 Details of historic background and description of embryonic and adult stem cells Information on stem cell banking and stem cell research A look at the growing research & development activities in regenerative medicine Coverage of ethical issues in stem cell research & regulatory constraints on biopharmaceuticals Comprehensive company profiles of key players in the market, including Aldagen Inc., Caladrius Biosciences Inc., Daiichi Sankyo Co. Ltd., Gamida Cell Ltd. and Novartis AG
Summary
The global market for stem cell and regenerative medicines was valued at REDACTED billion in 2018. The market is expected to grow at a compound annual growth rate (CAGR) of REDACTED to reach approximately REDACTED billion by 2024. Growth of the global market is attributed to the factors such as growingprevalence of cancer, technological advancement in product, growing adoption of novel therapeuticssuch as cell therapy, gene therapy in treatment of chronic diseases and increasing investment fromprivate players in cell-based therapies.
In the global market, North America held the highest market share in 2018. The Asia-Pacific region is anticipated to grow at the highest CAGR during the forecast period. The growing government funding for regenerative medicines in research institutes along with the growing number of clinical trials based on cell-based therapy and investment in R&D activities is expected to supplement the growth of the stem cell and regenerative market in Asia-Pacific region during the forecast period.
Reasons for Doing This Study
Global stem cell and regenerative medicines market comprises of various products for novel therapeutics that are adopted across various applications. New advancement and product launches have influenced the stem cell and regenerative medicines market and it is expected to grow in the near future. The biopharmaceutical companies are investing significantly in cell-based therapeutics. The government organizations are funding research and development activities related to stem cell research. These factors are impacting the stem cell and regenerative medicines market positively and augmenting the demand of stem cell and regenerative therapy among different application segments. The market is impacted through adoption of stem cell therapy. The key players in the market are investing in development of innovative products. The stem cell therapy market is likely to grow during the forecast period owing to growing investment from private companies, increasing in regulatory approval of stem cell-based therapeutics for treatment of chronic diseases and growth in commercial applications of regenerative medicine.
Products based on stem cells do not yet form an established market, but unlike some other potential applications of bioscience, stem cell technology has already produced many significant products in important therapeutic areas. The potential scope of the stem cell market is now becoming clear, and it is appropriate to review the technology, see its current practical applications, evaluate the participating companies and look to its future.
The report provides the reader with a background on stem cell and regenerative therapy, analyzes the current factors influencing the market, provides decision-makers the tools that inform decisions about expansion and penetration in this market.
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Stem Cell and Regenerative Therapy Market Report to Describe Major Companies and Their Strategies (2019-2024) - PRnews Leader
Catalent and BrainStorm Cell Therapeutics Announce Partnership for the Manufacture of Mesenchymal Stem Cell Platform Therapy NurOwn – GlobeNewswire
October 22, 2020 09:00 ET | Source: BrainStorm Cell Therapeutics Inc.; Catalent
SOMERSET, N.J. and NEW YORK, Oct. 22, 2020 (GLOBE NEWSWIRE) -- Catalent (NYSE: CTLT), the leading global provider of advanced delivery technologies, development, and manufacturing solutions for drugs, biologics, cell and gene therapies, and consumer health products, and BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, today announced an agreement for the manufacture of NurOwn, BrainStorms autologous cellular therapy being investigated for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease or motor neuron disease.
NurOwn induces mesenchymal stem cells (MSCs) to secrete high levels of neurotrophic factors (NTFs) known to promote the survival of neurons and neuroprotection. The therapy has received Fast Track status from the U.S. FDA for ALS and has also been granted Orphan Drug Status for ALS by both the FDA and the European Medicines Agency. BrainStorm is currently completing a 200-patient, double-blind, placebo-controlled, repeat-dosing NurOwn Phase 3 study in the U.S.
As part of its commitment, Catalent will undertake the transfer of the manufacturing process to, and provide future CGMP clinical supply of NurOwn from, its new, 32,000 square-foot cell therapy manufacturing facility in Houston, Texas. On completion of the clinical trials and in anticipation of potential approval of NurOwn, the companies will look to extend the partnership to include commercial supply from the Houston facility.
We are proud to have a partner in Catalent whose excellence in manufacturing quality therapies will support commercial supply of NurOwn, said Chaim Lebovits, Chief Executive Officer of BrainStorm Cell Therapeutics. We know that ALS patients are in urgent need of a new treatment option. If NurOwn is successful in the current clinical trials, this agreement will be integral to ensuring rapid access for patients.
Manja Boerman, Ph.D., President, Catalent Cell & Gene Therapy, said, Our experience in cell therapy development, and the manufacturing capabilities that our newly constructed, state-of-the-art facility in Houston offers, position us to best support BrainStorm, with its leading therapeutic candidate for ALS treatment. We look forward to partnering with BrainStorm and providing our stem cell manufacturing expertise as we work to optimize production and streamline the products path towards commercial launch.
About Catalent Cell & Gene Therapy
With deep experience in viral vector scale-up and production, Catalent Cell & Gene Therapy is a full-service partner for adeno-associated virus (AAV) and lentiviral vectors, and CAR-T immunotherapies. When it acquired MaSTherCell, Catalent added expertise in autologous and allogeneic cell therapy development and manufacturing to position it as a premier technology, development and manufacturing partner for innovators across the entire field of advanced biotherapeutics. Catalent has a global cell and gene therapy network of dedicated, large-scale clinical and commercial manufacturing facilities, and fill-finish and packaging capabilities located in both the U.S. and Europe. An experienced partner, Catalent Cell & Gene Therapy has worked with industry leaders across 70+ clinical and commercial programs.
About Catalent
Catalent is the leading global provider of advanced delivery technologies, development, and manufacturing solutions for drugs, biologics, cell and gene therapies, and consumer health products. With over 85 years serving the industry, Catalent has proven expertise in bringing more customer products to market faster, enhancing product performance and ensuring reliable global clinical and commercial product supply. Catalent employs approximately 14,000 people, including around 2,400 scientists and technicians, at more than 45 facilities, and in fiscal year 2020 generated over $3 billion in annual revenue. Catalent is headquartered in Somerset, New Jersey. For more information, visit http://www.catalent.com
More products. Better treatments. Reliably supplied.
About NurOwn
NurOwn (autologous MSC-NTF) cells represent a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors. Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. BrainStorm has fully enrolled a Phase 3 pivotal trial of autologous MSC-NTF cells for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm also received U.S. FDA acceptance to initiate a Phase 2 open-label multicenter trial in progressive MS and enrollment began in March 2019.
About BrainStorm Cell Therapeutics Inc.
BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has fully enrolled a Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at six U.S. sites supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). The pivotal study is intended to support a filing for U.S. FDA approval of autologous MSC-NTF cells in ALS. BrainStorm also recently received U.S. FDA clearance to initiate a Phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The Phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) completed enrollment inAugust 2020. For more information, visit the company's website at http://www.brainstorm-cell.com.
Safe-Harbor Statement
Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation,; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.
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Catalent and BrainStorm Cell Therapeutics Announce Partnership for the Manufacture of Mesenchymal Stem Cell Platform Therapy NurOwn - GlobeNewswire
Be Biopharma debuts with $52M to advance engineered B-cell therapies – FierceBiotech
You may have heard of T cells, but Aleks Radovic-Moreno, Ph.D., Be Biopharmas co-founder, president and director, is betting on B cells as the future of cell therapies.
Our mission is to develop what we see as a new class of cell medicines that have a broad new pharmacology, he said of B cells potential. We think it's a big new white space that's enabled by the rich biology of these cells.
The Cambridge, Massachusetts-based company is capitalizingearly on research by scientists at the University of Washington School of Medicine. With a $52 million series A round in the bank, it'smaking a beeline for the clinic.
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Why the enthusiasm around B cells? The wayRadovic-Moreno sees it, they'rethe cellular gadget, if you will, that's really good at making large amounts of protein, and they also traffic to where you want them to go."
When we think about it from a drug development standpoint, now you have a system that can make a protein that you want in high quantities in places where you want it to be made, he added.
B cells may also be useful for targeting specific tissues and modulating microenvironments, or [talking] to the cells that are nearby, he said.
One of the biggest challenges to bringing Be Bio to fruition was making the products themselves. Theyre harder to engineer than other cell types thanksto their intrinsic biology, Radovic-Moreno said. Theyre also hard to make correctly and in large quantities, challenges the company only recently overcame.
Those two are the final two bottlenecks that were preventing B cells from being a viable stem cell therapy modality, he said.
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The applications of B cells include everything from autoimmune diseases to cancer and monogenic disorders, which are caused by variation in a single gene. B-cell therapy could eliminate the need for patients with monogenic disorders who are missing proteins to get biweekly four-hour infusions.
And that's not all. It couldalso eliminate the need for bone marrow transplants in these patients, as well asthe need for a pre-therapy round of chemotherapy, otherwise known as conditioning. For cancer patients who need conditioningahead of a stem cell treatment, the regimencan be deadly up to 10% of the time.
That's extraordinary if you think about a therapy killing patients 10% of the time, Radovic-Moreno said.
Beyond pushing Be'spipeline toward the clinic, the new fundingfrom Atlas Venture, RA Capital Management, Alta Partners, Longwood Fund and other investorswill bankroll potential partnerships and build out the company's team.
The most important thing is to build a great company, hire the best people. We want to be the best B-cell engineers in the world and in history, Radovic-Moreno said. We want to fully capitalize on the timing of this, given that it's a very kind of unusual place to be in this time and age of biotech, where you're sitting right in front of this massive blue wave, big blue ocean of possibilities so big.
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Be Biopharma debuts with $52M to advance engineered B-cell therapies - FierceBiotech