Category Archives: Stem Cell Medicine


Cesca Therapeutics Forms Joint Venture with Healthbanks Biotech (USA) to Provide Immune Cell Banking and Cell Processing Services – PRNewswire

RANCHO CORDOVA, Calif., Oct. 22, 2019 /PRNewswire/ -- Cesca Therapeutics Inc.(Nasdaq: KOOL), a market leader in automated cell processing and autologous cell therapies for regenerative medicine, and ThermoGenesis, its wholly owned device subsidiary, today announced that the company has entered into a definitive joint venture agreement with HealthBanks Biotech (USA) Inc., one of the world's leading stem cell bank networks, to commercialize its proprietary cell processing platform, CAR-TXpress, for use in immune cell banking as well as for cell-basedcontract development and manufacturing services (CMO/CDMO). The joint venture will be named ImmuneCyte Life Sciences Inc. ("ImmuneCyte") and is expected to officially launch during the fourth quarter of 2019.

Under terms of the agreement, ImmuneCyte will initially be owned 80% by HealthBanks Biotech and 20% by Cesca. Cesca will contribute to ImmuneCyte exclusive rights to use ThermoGenesis' proprietary cell processing technology for the immune cell banking business and non-exclusive rights for other cell-based contract development and manufacturing services. Cesca will also contribute its clinical development assets to the joint venture, as the company has decided to discontinue these activities in order to focus exclusively on the device business.

Once operational, ImmuneCyte will be among the first immune cell banks in the U.S. to provide clients with the opportunity to bank their own healthy immune cells for future use as a resource for cell-based immunotherapies, such as dendritic cell and chimeric antigen receptor (CAR) T-cell therapies. ImmuneCyte will utilize ThermoGenesis' proprietary CAR-TXpress platform which allows for the isolation of different components from 200 ml of blood in cGMP compliant, closed system. Given that the CAR-TXpress platform can increase cell processing efficiency by up to 16-fold as compared with the traditional, labor-intensive ficoll gradient centrifugation-based cell processing method, ImmuneCyte is expected to offer customers an unparalleled competitive advantage, including an ability to store their own immune cells at a tangibly lower cost.

"The ImmuneCyte joint venture will be paramount to the execution of our strategy to become a preferred cell processing and manufacturing solution provider in the cell and gene therapy field," said Dr. Chris Xu, Chairman and Chief Executive Officer of Cesca Therapeutics. "CAR-T therapeutic research is advancing rapidly. Partnering with HealthBanks Biotech, one of the foremost stem cell bank networks, with an experienced team and an established global infrastructure, will offer customers the ability to preserve younger, healthier and uncontaminated immune cells for potential future use. By applying our proprietary CAR-TXpress technology to immune cell banking and other CDMO cellular manufacturing services, we will allow for the manufacture and production of more effective and less costly immunotherapies."

In 2017, the U.S. Food and Drug Administration (FDA) approved two CAR-T cell therapies, under breakthrough designation, for the treatment of advanced B cell leukemia and lymphomas. Both use autologous (a patient's own) immune T cells to fight cancer and have reported an over 80% response rate in the "no-option" patient group, for those who have failed both chemo- and radiation therapies. This has helped to spur massive global interest for the development of additional CAR-T immunotherapies1. By the end of September 2019, there were over 800 CAR-T cell clinical trials registered on the http://www.clinicaltrials.gov website, targeting a wide variety of blood cancers and solid tumors.

Although highly effective, several recent studies on the eligibility of patients to enroll in CAR-T clinical trials showed that as many as 30-50% of cancer patients may not be eligible to enroll or to get sufficient CAR-T cells manufactured for the therapy. Reasons may include: (1) the function of the immune system declines with age and can be negatively affected by other medical conditions, (2) most standard cancer therapies, such as chemotherapy and radiation, destroy the immune system, and (3) in many cases of advanced cancer, cancer cells will enter circulation, invade and interfere with the body's natural production of immune cells. According to a recently reported JULIE trial, a CAR-T clinical trial in relapsed or refractory diffuse large B-cell lymphoma (DLBCL), one-third of the 238 screened patients failed to be enrolled, and more than half of the 238 failed to receive the intended CAR-T therapy2,3. ImmuneCyte will offer customers the ability to preserve younger, healthier and uncontaminated immune cells, for potential future use in advanced cancer immunotherapy.

About HealthBanks Biotech (USA) Inc.HealthBanks Biotech, headquartered in Irvine, CA, is one of the leading stem cell bank networks in the world and offers services globally through its sister companies located in the United States and other regions and nations. HealthBanks Biotech is accredited by the FDA, AABB, and CAP. The HealthBanks Biotech group was originally founded in 2001 with a vision that stem cells and cell and gene therapies could transform modern medicine. HealthBanks Biotech is a subsidiary of Boyalife Group, Inc. (USA), an affiliate of Boyalife (Hong Kong) Limited, the largest stockholder of Cesca. For more information about HealthBanks Biotech (USA) Inc., pleasevisit:www.healthbanks.us.

About ImmuneCyte Life Sciences Inc.ImmuneCyte will provide clients with the opportunity to bank their own immune cells when the cells are "healthy and unaffected" as a future resource for cellular immunotherapies, such as CAR-T. ImmuneCyte utilizes a proprietary CAR-TXpress platform, a GMP compliant close-system capable of automated separating and cryopreserving different components from blood.For more information about ImmuneCyte Life Sciences Inc., pleasevisit:www.immunecyte.com.

About Cesca Therapeutics Inc.Cesca Therapeuticsdevelops, commercializes and markets a range of automated technologies for CAR-T and other cell-based therapies. Its device division, ThermoGenesis develops, commercializes and markets a full suite of solutions for automated clinical biobanking, point-of-care applications, and automation for immuno-oncology. The Company has developed a semi- automated, functionally closed CAR-TXpressplatform to streamline the manufacturing process for the emerging CAR-T immunotherapy market. For more information about Cesca and ThermoGenesis, pleasevisit: http://www.cescatherapeutics.com.

Company Contact:Wendy Samford916-858-5191ir@thermogenesis.com

Investor Contact:Paula Schwartz,Rx Communications917-322-2216pschwartz@rxir.com

References:

1. Facts About Chimeric Antigen Receptor (CAR) T-Cell Therapy, Leukemia and Lymphoma Society (2018). https://www.lls.org

2. Updated Analysis of JULIET Trial: Tisagenlecleucel in Relapsed or Refractory DLBCL (2018).

3. Eligibility Criteria for CAR-T Trials and Survival Rates in Chemorefractory DLBCL. Journal of Clinical Pathways (2018).

SOURCE Cesca Therapeutics Inc.

http://www.cescatherapeutics.com

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Cesca Therapeutics Forms Joint Venture with Healthbanks Biotech (USA) to Provide Immune Cell Banking and Cell Processing Services - PRNewswire

Advancing patient care through innovative orthopaedics – SciTech Europa

Founded in 1958, the AO foundation is a medically guided, not-for-profit organisation led by an international group of surgeons specialised in the treatment of trauma and disorders of the musculoskeletal system. Today, the AO has a global network of over 200,000 health care professionals. Each year it offers over 830 educational events around the world, which are supported by nearly 9,000 faculty and are attended by over 58,000 participants. It has 20,000 surgeon members working in the fields of trauma, spine, craniomaxillofacial (CMF), veterinary, and reconstructive surgery.

The Mission of the AO foundation is promoting excellence in patient care and outcomes in trauma and musculoskeletal disorders. The focus of the AO clinical divisions, clinical unit, and Institutes, is on producing new concepts for improved fracture care, delivering evidence-based decision making, guaranteeing rigorous concept and product approval as well as timely and comprehensive dissemination of knowledge and expertise. The AO is made up from four clinical divisions (AOTrauma, AOSpine, AOCMF, AOVET), one clinical unit (AORecon), and four institutes the AO Research Institute Davos (ARI), AO Education Institute, AO Clinical Investigation & Documentation and AO Technical Commission (AOTK).

AO Research Institute Davos (ARI) is both the academic arm and the translational arm of the AO foundation. In its work to further the AO foundations mission (promoting excellence in patient care and outcomes in trauma and musculoskeletal disorders), ARIs purpose is to advance patient care through innovative orthopaedic research and development.

The goals of ARI include: Contribute high quality applied preclinical research and development (exploratory and translational) focused towards clinical applications/solutions; investigate and improve the performance of surgical procedures, devices and substances; foster a close relationship with the AO medical community, academic societies, and universities; and provide research environment / research mentorship / research support for AO clinicians.

Our Bone Regeneration focus area looks at bone healing in response to fracture involving a complex sequence of dynamic events, directed by numerous different cell types and growth factors. A critical factor for bone repair is the maintenance, or effective restoration, of an adequate blood supply, which is necessary to provide the damaged tissue with oxygen, nutrients and growth factors, as well as immune cells and mesenchymal stem cells required to repair the damage and induce new bone formation. Although bone generally has a high regenerative capacity, in some cases this inherent bone healing is compromised, which results in delaying healing or non-union of the bone fracture with increased health care costs and reduced quality of life issues for affected patients.

While a variety of risk factors have been identified that predispose a patient to an increased risk of developing delayed bone healing or non-union, it is currently not possible to identify specific at-risk patients at an early stage. Using in vitro, in vivo and microfluidic technologies, the aim of the Bone Regeneration Focus Area is to gain a greater understanding of the cellular interactions and mediators, including immunoregulation, underlying such impaired healing responses. By determining how cells such as immune cells, mesenchymal stem cells and endothelial cells normally interact during the repair process, and how this process is altered during impaired healing, we can then identify key mediators of the healing process. Our goal is to use tissue engineering and regenerative medicine approaches to promote bone healing, aimed at restoring bone integrity and its effective biomechanical properties.

In terms of this focus area, we aim at investigating the potential mechanisms leading to intervertebral disc (IVD) damage and evaluating novel biological treatment methods for IVD repair and regeneration. Acute and chronic damage to the IVD are major causes of low back pain. However, the factors that contribute to the loss of function of the IVD and the underlying pathophysiology are still poorly understood. We have established a whole IVD organ culture system with the ability to maintain entire discs with the endplates for several weeks under controlled nutrient and mechanical loading conditions.

Within this bioreactor, the beneficial or detrimental effects of nutrition, mechanical forces, and/or biochemical factors on disc cell viability and metabolic activity can be investigated. We have developed various defect and degeneration models, allowing us to design and evaluate appropriate biological treatment strategies. These include implantation of cells, delivery of anabolic, anti-catabolic or anti-inflammatory molecules, biomaterials or a combination thereof. Data from ex vivo models are also correlated to in vivo observations to identify molecular markers of IVD damage or degeneration.

To study the potential of new therapies for articular cartilage repair and regeneration, a bioreactor system applying multiaxial load to tissue-engineered constructs or osteo-chondral explants has been established. The bioreactor mimics the load and motion characteristics of an articulating joint. Chondral and osteochondral defect and disease models enable us to test tailored treatments under physiologically relevant mechanically loaded ex-vivo conditions. Cell- and material-based therapies as well as chondrogenic or anti-inflammatory factors are under investigation for cartilage repair and regeneration.

Biomaterials for skeletal repair can provide structural and mechanical features for the filling of defects, but also be a carrier for drugs, cells and biological factors. One of our goals is the development of 3D structures for bone, disc and cartilage tissue engineering, using tailored polymers and composites manufactured with additive manufacturing processes.

Our experience lies in the design of biocompatible, biodegradable polymers and their processing with controlled architecture and embedded biologics. A second field of research investigates the preparation of hyaluronan, a natural occurring biopolymer, based biomaterials which can be used to deliver drugs and cells. These injectable biodegradable materials have considerable potential in infection prophylaxis and tissues repair. We are also developing innovative technologies for the structuration and assembly of tissue-like matrices aiming to mimic for example, biological matrix mechanical and structural anisotropy. Additive manufacturing technologies will lead to the development of patient specific implants that can be tailor made to each individual case.

The Stem Cell focus area is particularly interested in stem cell therapies for bone and cartilage that could be applied within a clinical setting. We are increasingly investigating donor variation with the aim to predictively identify the potency of cells from individual donors. In the search for biomarkers to determine patient specific healing potential, exosomes and non-coding RNA sequences such as miRNA are increasingly being used as a diagnostic and therapeutic tool. The development of a serum-based biomarker approach would dramatically improve patient specific clinical decisions.

We also aim to investigate the role of mechanical and soluble factors in the activation of mesenchymal stem cells, and the promotion of differentiation and tissue repair. We can induce chondrogenic differentiation of human MSCs purely by mechanical stimulation and this is leading to new insights into cell behavior under loading conditions. Mechanical forces can be applied by way of rehabilitation protocols and are able to modify stem cell and immune cell function. Such studies are forming the basis of the emerging field of regenerative rehabilitation. In addition to the effect of load on direct differentiation, it is known that biomechanical stimulation can modulate the cell secretome. Investigating these changes could lead to the identification of new targets that may be present during articulation. This offers new avenues for potential clinical therapies.

The Musculoskeletal Infection team focusses their research activities on Fracture-Related Infection (FRI), with goals to optimise antibiotic prophylaxis, reduce the burden of therapeutic interventions, and study the impact of co-administered medication on infection. Our studies include preclinical in vitro and in vivo studies, as well as an increasing focus on observational studies in human patients.

In collaboration with ARI colleagues in the preclinical testing facility, we now have models that can mimic an open fracture, with a chronology and fixation that more accurately reflects clinical reality. Further advancements in our animal models in the past year include the controlled delivery of antimicrobials via the use of programmable, implantable pumps to more precisely control antibiotic dosing. In addition, we have investigated in more detail the use of anti-inflammatory medication in our animal studies and found it can have a major impact on treatment outcome, and so will be a focus for future studies with clear relevance for trauma patients. The preclinical evaluation of novel anti-infective interventions under Good Laboratory Practice (GLP) conditions has also continued in the past year, with two novel antimicrobial intervention studies performed in this space in the past year.

On the in vitro side, we have begun to develop an in vitro model for Staphylococcus aureus infection that has the potential to include human immune system cell-lines. This can not only reduce future animal studies but will also allow us to test interventions in a human-specific system. The antibiotic loaded hydrogel that has been in testing in ARI for several years, has now also been tested against MRSA biofilms and continues to be superior to aqueous solutions of antibiotics. In patient samples, we have made our first preparations for a study on the impact of antibiotic therapy on the human gut and skin microbiome. This is an under explored area of immense potential for bone health and will be a multi-year investigation with expert collaborations internationally.

A Fracture-Related Infection (FRI) consensus meeting in Davos in December 2016 achieved consensus on the fundamental features of FRI, and a proposal for defining the presence of FRI was reached. The establishment of this definition offers the opportunity to standardise preclinical research, improves the reporting of clinical studies and finally of course also aids in the decision-making during daily clinical practice. In the following 18 months, the expert group shifted attention to the next phase, validating the diagnostic criteria and develop treatment principles for FRI and a consensus on diagnosis and treatment principles for FRI.

In reflecting the greater complexity of this question, and to engage with other professional organisations, the group has grown to include external partners. Joining the ARI, AOTrauma and the AOTK Anti-Infection task force (AITF), is the European Bone and Joint Infection Society (EBJIS), the Orthopaedic Trauma Association (OTA), and the Pro-Implant Foundation, as well as a broadened panel of experts with extensive clinical experience in FRI. A first meeting of the expert group took place in Zrich in February. Prior to the meeting, the group was asked to review and consider the published literature on FRI, within nine specific concepts that were then presented for discussion in dedicated sessions during the meeting. The meeting engaged 35 experts and key opinion leaders in the field of FRI. Recommendations were developed on diagnosis and treatment of FRI. These guiding principles will be made available through scientific publications and an AO Bone Infection App.

Internal fracture fixation existed but only in individual hospitals and not globally, that is where ARI and AO came in and rolled this out globally and invented many new additions to this. ARI invented compression plates, minimal invasive surgery for trauma (plates, screws, nails etc.), locking plates for fractures close to articulating joints and for osteoporotic patients.

Currently tissue engineering and regenerative medicine (TERM) is in the research stage of its life cycle and has not really translated into routine surgical practice in orthopaedics. The combination of cells and biomaterials however has great potential in repair. The main issues are again regulatory, and the best way forward would be to develop techniques that can be applied in a single surgery within the operation room. Anything beyond this window and outside the operation room will take a significant amount of time to get approval and will likely not be surgeon friendly and obviously will be very costly.

TERM has its biggest potential in orthopaedics in the areas of cartilage repair (delaying classic orthopaedics), disc regeneration (back pain being one of the largest problems globally) and in bone this could be in large bone defects, but not a major area in fracture repair, where appropriate mechanical stimulation can be used to drive the repair to optimum levels and speed (which is also in the research stage). TERM has also potential in tendon and ligament repair.

Imaging and biomarkers for diagnostics and therapy (Theranostics) will be important in early detection of diseases or complications and then to prevent further development of the disease, delaying the time until classic orthopaedics is required. This may go beyond stopping the disease and towards tissue regeneration. The earlier the detection, the more potential for TERM.

The main challenges for a researcher are in translation and the fact that large companies today exist in a more complex regulatory environment, which means they are inclined to be very risk averse. This means in practice they need to see evidence of benefits or proof-of-concept in a clinical setting. The researchers in turn need to have greater awareness of these regulatory issues relating to medical development and CE approved manufacturers, than in the past. The increasingly complex regulatory environment of course has a greater impact on small companies and spin-offs, and can be seen as having a dampening effect on innovation development. Incremental innovations or solutions to niche problems will struggle to get the funding needed to carry them through the regulatory approval process. Researchers do benefit from this too, since in an environment in which companies are inclined to be more risk averse, they place a higher premium on solutions or concepts that have been through a rigorous clinical testing process. In orthopedics, we are approaching an innovation plateau with metals, and new technologies (such as tissue engineering, which is showing good results in research at present) still need to kick in to date little has translated to the patient in this field. 3D printing may have a place in spine or craniomaxillofacial areas, but offers little benefits to trauma in the most common areas for fracture repair. Surgeons who promote patient specific implants (PSI) in joint replacement have little proof that this offers clear improvements compared to current well-tested and proven joint replacement implants. The seamless integration of digitisation and robotic help into the patient treatment work-flow is another area to grow to help the surgeons in their daily practice.

Prof R. Geoff Richards

Director

AO Research Institute Davos

geoff.richards@aofoundation.org

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Advancing patient care through innovative orthopaedics - SciTech Europa

Phenotypic Screening Advances in Technologies and Techniques – Technology Networks

Phenotypic screening is gaining new momentum in drug discovery with the hope that this approach will improve the success rate of drug approval.1 In this article we look at some of the latest screening tools and their applications.

This is illustrated by their recent study with Dr Ayman Zen where the team developed a high-content imaging screen using the endothelial tube formation assay, miniaturized to a 384-well plate format. Screening with an annotated chemical library of 1,280 bioactive small molecules identified a retinoid agonist, Tazarotene, that enhanced in vitro angiogenesis and wound healing in vivo. This high content screen identified an already FDA-approved small molecule that could be potentially exploited in regenerative medicine.3

Immuno-oncology: Pushing the Frontier of Discovery Through Advanced High Throughput Flow Cytometry

Immuno-oncology encompasses a number of approaches with one common thread: they harness the bodys own immune system against cancer.

Download this article to learn how advanced throughput flow cytometry overcomes these challenges to drive forward innovation in the immuno-oncology field.

Ebner is currently working in collaboration with recent Nobel-Prize winner Peter Ratcliffe, alongside scientists at Edinburgh University and MIT, to model hypoxia in glioblastoma. Hypoxia is a problem with some glioblastomas as it protects cells from radiotherapy treatment. Our aim is to use Peters expertise to help us set up an assay that mimics real tumor hypoxia. Then if we can identify small compounds that alter that hypoxic condition we can make the glioma cells more susceptible to either radiotherapy or temozolomide or some other treatment combination.

The labs main readout is high-content imaging, using fluorescent microscopy that can take many thousands of pictures. This approach utilizes different labels and harnesses software that automates the image analysis. The image analysis is set by the biologists but then it's applied across the entire screen. Its lower throughput than plate-based readout, but you get a lot more information out of the images, says Ebner. Increasingly, high content imaging is moving towards using AI and deep learning where you're trying to draw out even more information than the primary phenotype that you were looking at.

Indeed, a recent study using CRISPR-Cas9 mutagenesis showed that the proteins targeted by many cancer drugs currently in clinical development are non-essential for tumor growth, despite evidence to the contrary from previous studies using RNAi and small molecule inhibitors.4 In addition, the efficacy of the drugs tested was unaffected when CRISPR was used to knockout its assumed target suggesting that many are eliciting their anticancer activity through off-target effects.

The other benefit of CRISPR is that its extremely flexible, says Pettitt. This means you can expand the range of cell line models, for example, that you can screen in. The key reason why RNAi was such a popular technology, and now CRISPR is, is that you can basically knock out a gene by synthesizing just a short piece of RNA, he explains. CRISPR guides are very easy to synthesize, you can do it in a very high throughput setting, and you can design customized libraries to knock out every gene in the genome or a particular set of genes. As long as you can get the CRISPR machinery into your cells, it works very reliably.

The classic CRISPR (CRISPR-Cas9) system comprises a nuclease called Cas9 which you can program with a short RNA (20 nucleotides). The RNA will direct the nuclease to a certain site in the genome that matches and the nuclease will cleave the genome at that point. Repair of that double-strand break results in small insertions and deletions that result in knock out of a gene. But theres now more evolved applications of the technology emerging.

I think it's possible to be very creative with CRISPR in a way that it isnt with RNAi, says Pettitt. With RNAi you can really only shut genes off, but with CRISPR as well as making random mutations to knock out genes - you can also precisely edit genes if you provide a template region with a mutation with it. This can be incorporated into the target site for CRISPR so you can introduce the specific mutation youre interested in.

One such example is the problem with BRCA1 mutations: its important to be able to functionally classify whether these mutations are benign or pathogenic. A recent study used CRISPR to test 96.5% of all possible single-nucleotide variants (SNVs) in exons that encode functionally critical domains of BRCA1 and found over 400 non-functional missense SNVs were identified, as well as around 300 SNVs that disrupt expression. This knowledge will immediately aid clinical interpretation of BRCA1 genetic test results.5 In another study,6 Pettitt and colleagues used genome-wide CRISPR-Cas9 mutagenesis screens to identify the mutated forms of PARP that cause in vitro and in vivo PARP inhibitor resistance, and found that these mutations are also tolerated in cells with a pathogenic BRCA1 mutation resulting in a different profile of sensitivity to chemotherapy drugs compared with other types of PARP inhibitor resistance.

You couldnt screen at that level of detail using RNAi, where you design custom CRISPR that targets many different regions of the same gene and you can figure out which domains of the protein are important for your phenotype of interest, says Pettitt.

There are other evolutions of CRISPR now being developed as screens. For example, if you mutate the nuclease activity of Cas9, it still retains its ability to localize to the target site, so you can fuse Cas9 to transcriptional activators or repressors, and screen for transcriptional repression with CRISPR, as well as knock-out screens, says Pettitt. Theres also a whole range of CRISPR tools being developed that will edit bases by causing missense mutations rather than insertions or deletions, or causing methylation of DNA, or bringing in fluorescent proteins so you can visualize where the DNA sequences in the cells are. Its a measure of how flexible and useful CRISPR is in comparison to RNAi.

So will CRISPR be the one technology that everyone turns to for phenotypic screening in future? Im a firm believer that no technology answers every question, says Ebner. CRISPR is amazing, its use as a therapeutic or biologic is the stuff of science fiction. But as a tool for target identification, it comes with one important caveat. CRISPR knockout means exactly that it removes the potential protein that would otherwise be in the mix. Thats very different from a small compound inhibiting a protein that is still able to form a complex or that is just not active. Its the perfect example of a brilliant technology that is transformative, but it's not perfect. No technology is perfect.

References

1. Zheng W, Thorne N and McKew JC. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today 2013; 18: 1067-1073.

2. Horvath P, Aulner N, Bickle M, et al. Screening out irrelevant cell-based models of disease. Nat Rev Drug Discov. 2016 Nov;15(11):751-769. doi: 10.1038/nrd.2016.175. Epub 2016 Sep 12.

3. Al Haj Zen A, Nawrot DA, Howarth A, et al. The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing. Mol Ther. 2016 Oct;24(10):1745-1759. doi: 10.1038/mt.2016.153.

4.Lin et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translat Med. 2019; 11: (509). doi: 10.1126/scitranslmed.aaw8412

5.Findlay GM, Daza RM, Martin B et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct; 562(7726): 217222. doi: 10.1038/s41586-018-0461-z

6.Pettitt et al. Genome-wide and high-density CRISPRCas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun. 2018 May 10;9(1):1849. doi: 10.1038/s41467-018-03917-2.

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Phenotypic Screening Advances in Technologies and Techniques - Technology Networks

Worlds first cell atlas of developing liver created by Cambridge scientists – Cambridge Independent

The worlds first cell atlas of the human developmental liver has been created, giving fresh insight into how the blood and immune systems develop in the foetus.

A high-resolution resource, it will aid our understanding of normal development and efforts to tackle diseases that can form during development, such as leukaemia and immune disorders.

The cell atlas maps how the cellular landscape within the developing liver changes between the first and second trimesters of pregnancy, including how stem cell from the liver seed other tissues, supporting the high demand for oxygen required for growth.

Researchers from the Wellcome Sanger Institute in Hinxton, the Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Newcastle University and their collaborators created the atlas by using single cell technology to analyse 140,000 liver cells and 74,000 skin, kidney and yolk sac cells.

In adults, it is bone marrow that is primarily responsible for the creation of blood and immune cells in a process called haematopoiesis.

In early embryonic life, the yolk sac and liver play a key role in creating these cells, which then seed peripheral tissues such as skin, kidney and ultimately bone marrow.

But until now, the precise process of how blood and immune systems develop in humans has been unknown.

Isolating cells from the developing liver, the researchers were able to identify them by what genes they were expressing and discover what the cells looked like.

They tagged haematopoietic cells in sections of developmental liver using heavy metal markers in order to map them to their location.

Prof Muzlifah Haniffa, a senior author of the study from Newcastle University and senior clinical fellow at the Wellcome Sanger Institute, said: Until now research in this area has been a little bit like blindfolded people studying an elephant, with each describing just a small part of it.

This is the first time that anyone has described the whole picture, how the blood and immune systems develop in such detail. Its been an extraordinary, multidisciplinary effort that is now available as a tool for the whole scientific community.

The scientists learned that during foetal development, mother haematopoietic stem cells stay in the liver. But the liver alone cannot supply enough red blood cells, so the next generation daughter cells called progenitor cells travel to other tissues, maturing in places such as the skin. Thee, they develop into red blood cells to help meet the high demand for oxygen in the developing foetus.

Dr Elisa Laurenti, a senior author from the Wellcome MRC Cambridge Stem Cell Institute and the Department of Haematology at the University of Cambridge, said: We knew that as adults age our immune system changes. This study shows how the livers ability to make blood and immune cells changes in a very short space of time, even between seven and 17 weeks post-conception.

If we can understand what makes the stem cells in the liver so good at making red blood cells, it will have important implications for regenerative medicine.

The study, published in Nature, also involved the mapping of genes involved in immune deficiencies to reveal which cells were expressing them.

It is known that gene mutations can lead to immune disorders such as leukaemia.

A better understanding of the development of healthy liver functions could aid our understanding of how to treat such conditions.

The work is part of the ambitious effort to create the first complete Human Cell Atlas.

Dr Katrina Gold, genetics and molecular sciences portfolio manager at Wellcome, said: Our immune system is vital in helping to protect us from disease, yet we know very little about how immune cells develop and behave in the early embryo. This study is hugely important, laying a critical foundation for future research that could help improve our understanding of disorders linked to the early immune system, such as childhood leukaemias.

The Human Cell Atlas has the potential to transform our understanding of health and disease and were excited to see these first discoveries from our Wellcome-funded multidisciplinary team of scientists.

Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute, University of Cambridge and co-chair of the Human Cell Atlas organising committee, said: The first comprehensive cellular map of the developmental liver is another milestone for the Human

Cell Atlas initiative.

The data is now freely available for anyone to use and will be a great resource to better understand healthy cellular development and disease-causing genetic mutations.

Read more

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AstraZeneca and Cancer Research UK launch joint Functional Genomics Centre in Cambridge

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Worlds first cell atlas of developing liver created by Cambridge scientists - Cambridge Independent

Cesca Therapeutics Forms Joint Venture with Healthbanks Biotech (USA) to Provide Immune Cell Banking and Cell Processing Services – BioSpace

ImmuneCyte to Begin Operations in Fourth Quarter of 2019

RANCHO CORDOVA, Calif., Oct. 22, 2019 /PRNewswire/ -- Cesca Therapeutics Inc. (Nasdaq: KOOL), a market leader in automated cell processing and autologous cell therapies for regenerative medicine, and ThermoGenesis, its wholly owned device subsidiary, today announced that the company has entered into a definitive joint venture agreement with HealthBanks Biotech (USA) Inc., one of the world's leading stem cell bank networks, to commercialize its proprietary cell processing platform, CAR-TXpress, for use in immune cell banking as well as for cell-based contract development and manufacturing services (CMO/CDMO). The joint venture will be named ImmuneCyte Life Sciences Inc. ("ImmuneCyte") and is expected to officially launch during the fourth quarter of 2019.

Under terms of the agreement, ImmuneCyte will initially be owned 80% by HealthBanks Biotech and 20% by Cesca. Cesca will contribute to ImmuneCyte exclusive rights to use ThermoGenesis' proprietary cell processing technology for the immune cell banking business and non-exclusive rights for other cell-based contract development and manufacturing services. Cesca will also contribute its clinical development assets to the joint venture, as the company has decided to discontinue these activities in order to focus exclusively on the device business.

Once operational, ImmuneCyte will be among the first immune cell banks in the U.S. to provide clients with the opportunity to bank their own healthy immune cells for future use as a resource for cell-based immunotherapies, such as dendritic cell and chimeric antigen receptor (CAR) T-cell therapies. ImmuneCyte will utilize ThermoGenesis' proprietary CAR-TXpress platform which allows for the isolation of different components from 200 ml of blood in cGMP compliant, closed system. Given that the CAR-TXpress platform can increase cell processing efficiency by up to 16-fold as compared with the traditional, labor-intensive ficoll gradient centrifugation-based cell processing method, ImmuneCyte is expected to offer customers an unparalleled competitive advantage, including an ability to store their own immune cells at a tangibly lower cost.

"The ImmuneCyte joint venture will be paramount to the execution of our strategy to become a preferred cell processing and manufacturing solution provider in the cell and gene therapy field," said Dr. Chris Xu, Chairman and Chief Executive Officer of Cesca Therapeutics. "CAR-T therapeutic research is advancing rapidly. Partnering with HealthBanks Biotech, one of the foremost stem cell bank networks, with an experienced team and an established global infrastructure, will offer customers the ability to preserve younger, healthier and uncontaminated immune cells for potential future use. By applying our proprietary CAR-TXpress technology to immune cell banking and other CDMO cellular manufacturing services, we will allow for the manufacture and production of more effective and less costly immunotherapies."

In 2017, the U.S. Food and Drug Administration (FDA) approved two CAR-T cell therapies, under breakthrough designation, for the treatment of advanced B cell leukemia and lymphomas. Both use autologous (a patient's own) immune T cells to fight cancer and have reported an over 80% response rate in the "no-option" patient group, for those who have failed both chemo- and radiation therapies. This has helped to spur massive global interest for the development of additional CAR-T immunotherapies1. By the end of September 2019, there were over 800 CAR-T cell clinical trials registered on the http://www.clinicaltrials.gov website, targeting a wide variety of blood cancers and solid tumors.

Although highly effective, several recent studies on the eligibility of patients to enroll in CAR-T clinical trials showed that as many as 30-50% of cancer patients may not be eligible to enroll or to get sufficient CAR-T cells manufactured for the therapy. Reasons may include: (1) the function of the immune system declines with age and can be negatively affected by other medical conditions, (2) most standard cancer therapies, such as chemotherapy and radiation, destroy the immune system, and (3) in many cases of advanced cancer, cancer cells will enter circulation, invade and interfere with the body's natural production of immune cells. According to a recently reported JULIE trial, a CAR-T clinical trial in relapsed or refractory diffuse large B-cell lymphoma (DLBCL), one-third of the 238 screened patients failed to be enrolled, and more than half of the 238 failed to receive the intended CAR-T therapy2,3. ImmuneCyte will offer customers the ability to preserve younger, healthier and uncontaminated immune cells, for potential future use in advanced cancer immunotherapy.

About HealthBanks Biotech (USA) Inc.HealthBanks Biotech, headquartered in Irvine, CA, is one of the leading stem cell bank networks in the world and offers services globally through its sister companies located in the United States and other regions and nations. HealthBanks Biotech is accredited by the FDA, AABB, and CAP. The HealthBanks Biotech group was originally founded in 2001 with a vision that stem cells and cell and gene therapies could transform modern medicine. HealthBanks Biotech is a subsidiary of Boyalife Group, Inc. (USA), an affiliate of Boyalife (Hong Kong) Limited, the largest stockholder of Cesca. For more information about HealthBanks Biotech (USA) Inc., please visit: http://www.healthbanks.us.

About ImmuneCyte Life Sciences Inc.ImmuneCyte will provide clients with the opportunity to bank their own immune cells when the cells are "healthy and unaffected" as a future resource for cellular immunotherapies, such as CAR-T. ImmuneCyte utilizes a proprietary CAR-TXpress platform, a GMP compliant close-system capable of automated separating and cryopreserving different components from blood. For more information about ImmuneCyte Life Sciences Inc., please visit: http://www.immunecyte.com.

About Cesca Therapeutics Inc.Cesca Therapeutics develops, commercializes and markets a range of automated technologies for CAR-T and other cell-based therapies. Its device division, ThermoGenesis develops, commercializes and markets a full suite of solutions for automated clinical biobanking, point-of-care applications, and automation for immuno-oncology. The Company has developed a semi- automated, functionally closed CAR-TXpress platform to streamline the manufacturing process for the emerging CAR-T immunotherapy market. For more information about Cesca and ThermoGenesis, please visit: http://www.cescatherapeutics.com.

Company Contact:Wendy Samford916-858-5191ir@thermogenesis.com

Investor Contact:Paula Schwartz, Rx Communications917-322-2216pschwartz@rxir.com

References:

1. Facts About Chimeric Antigen Receptor (CAR) T-Cell Therapy, Leukemia and Lymphoma Society (2018). https://www.lls.org

2. Updated Analysis of JULIET Trial: Tisagenlecleucel in Relapsed or Refractory DLBCL (2018).

3. Eligibility Criteria for CAR-T Trials and Survival Rates in Chemorefractory DLBCL. Journal of Clinical Pathways (2018).

View original content:http://www.prnewswire.com/news-releases/cesca-therapeutics-forms-joint-venture-with-healthbanks-biotech-usa-to-provide-immune-cell-banking-and-cell-processing-services-300942618.html

SOURCE Cesca Therapeutics Inc.

Company Codes: NASDAQ-SMALL:KOOL

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Cesca Therapeutics Forms Joint Venture with Healthbanks Biotech (USA) to Provide Immune Cell Banking and Cell Processing Services - BioSpace

Engineered cell-based therapy as a new treatment strategy for type 1 diabetes – Medical News Bulletin

Cell-based therapy for type 1 diabetes is a new treatment strategy that is showing promising results. Type 1 diabetes is a chronic disease that can develop early in life. The disease involves the destruction of pancreatic beta cells by the bodys auto-immune response resulting in insufficient insulin production to regulate blood glucose. If left untreated, this condition can lead to serious long-term effects such as neuropathy, retinopathy, and renal failure. Insulin therapy is the current standard of care treatment of type 1 diabetes. However, insulin therapy cannot fully prevent the long-term complications associated with type 1 diabetes.

Organoids are tiny, three-dimensional tissue cultures that are derived from stem cells. Organoids can be created to replicate the complexity of an organ or they can be crafted to express selected aspects of an organ such as producing only certain types of cells.

Researchers have created organoids that differentiate into insulin-producing pancreatic cells. These modified insulin-producing cells successfully regulated blood glucose levels when implanted in diabetic mice.

The cluster of cells in the pancreas that produce insulin is known as islets. Islet cell transplantation is a powerful tool to treat type 1 diabetes. Many studies have shown how this cell therapy could be effective in the treatment of diabetes if long-term control of glucose levels can be achieved.

Researchers have faced challenges in this treatment strategy due to loss of islet cells after the transplantation. The loss of cells occurs mainly because of inflammation of the transplant site and revascularization of cells that disrupts blood and oxygen supply leading to cell death. Scientists are looking for new strategies that can prevent the loss of islet cells and improve clinical islet transplantation outcomes.

Amniotic epithelial cells are stem cells that have a high proliferative capacity, self-renewal ability, multilineage differentiation, ease of access, and are safe for transplantation. During the last few years, human amniotic epithelial cells have been of great interest to researchers working on regenerative medicine.

In a new study recently published in Nature Communications, researchers from Geneva, Switzerland, engineered viable and functional insulin-producing organoids by combining human amniotic epithelial cells and dissociated islet cells. The researchers tested if inclusion of human amniotic epithelial cells enhanced the engraftment and viability of islet cells and determined if this cell-therapy for type 1 diabetes was successful in mouse models. Various tests such as insulin expression, insulin secretion, and stability under hypoxic conditions were used to test the viability of the organoids.

The organoids composed of human amniotic epithelial cells and islet cells did not experience any islet loss post transplantation. The researchers observed a clear protective effect of amniotic epithelial cells on islet cells in conditions of hypoxia. In addition, the organoids maintained responsiveness to glucose and showed significant protection from cell death.

The researchers found that islet organoids enriched with human amniotic epithelial cells resulted in mass engraftment of insulin producing beta cells thus improving function of these cells. Compared with islet cell organoids not combined with amniotic epithelial cells, the organoids with islet cells and amniotic epithelial cell combination normalized the blood glucose levels in diabetic mice. This suggests that there was adequate blood glucose regulation achieved by these engineered organoids.

These findings show that combining islet cells with human amniotic epithelial cells markedly improves their functionality and viability of islet cells. It also helps in the successful engraftment of islet cells. This cell therapy for type 1 diabetes has the potential to be the next treatment strategy for this condition.

The researchers express the need to further explore the use of these organoids to include more favorable implantation sites and expanding to the use of stem cells that are an unlimited source of insulin.

Written by Preeti Paul, M.Sc.

Reference: Fanny Lebreton et al., Insulin producing organoids engineered from islet and amniotic epithelial cells to treat diabetes. Nature Communications 10, Article number: 4491 (2019)

Image bySteve BuissinnefromPixabay

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WindMIL Therapeutics and University of California, Irvine Announce Collaboration to Collect Bone Marrow from Patients with Gliomas to Develop Marrow…

BALTIMOREand PHILADELPHIA and IRVINE, Calif., Oct. 15, 2019 (GLOBE NEWSWIRE) -- WindMIL Therapeutics and the University of California, Irvine (UCI) today announced that the first patients have been identified in an investigator-sponsored study for the collection of bone marrow from patients with gliomas. The study will evaluate generating marrow infiltrating lymphocytes (MILs) for these patients through WindMILs proprietary cellular activation and expansion process. The study is being conducted at UCI.

Patients suffering with glioblastoma are in great need of new, promising treatments that might advance the current standard of care, said Daniela A. Bota, MD, PhD, director of theUCI Health Comprehensive Brain Tumor Program,seniorassociate dean for clinical research, UCI School of Medicine and clinical director, UCI Sue & Bill Gross Stem Cell ResearchCenter. The University of California, Irvine is excited toplay a key role in research that may lead to a clinical trial that enlists the immune system in novel ways to fight this terrible disease.

Gliomas are the most common of the malignant brain tumors. Glioblastoma, the most common glioma, has a five-year survival of less than 5 percent. Additional treatment options are urgently needed for these patients. Adoptive immunotherapy is a possible approach for gliomas and the use of MILs, a cell therapy that is naturally tumor-specific, is one such treatment option.

The bone marrow is a unique niche in the immune system to which antigen-experienced memory T cells traffic and are then maintained. WindMIL has developed a proprietary process to select, activate and expand these memory T cells into MILs. Because memory T cells in bone marrow occur as a result of the immune systems recognition of tumor antigens, MILs are specifically suited for adoptive cellular immunotherapy and are able to directly eradicate or facilitate eradication of each patients unique cancer. WindMIL is currently studying MILs in multiple myeloma, non-small cell lung cancer and squamous cell carcinoma of the head and neck, and plans to expand into other solid tumors.

WindMIL is looking forward to working with the University of California, Irvine on this exciting project and is optimistic that MILs may offer the potential to help patients with these hard-to-treat diseases, said Monil Shah, PharmD, MBA, Chief Development Officer at WindMIL.

About WindMIL Therapeutics

WindMIL Therapeutics is a clinical-stage company developing a novel class of autologous cell therapies based on marrow infiltrating lymphocytes (MILs) for cancer immunotherapy. As the leader in cellular therapeutics emanating from bone marrow, WindMIL translates novel insights in bone marrow immunology into potentially life-saving cancer immunotherapeutics for patients. WindMIL believes that Cell Source Matters and the companys proprietary process to extract, activate and expand these cells offers unique immunotherapeutic advantages, including inherent poly-antigen specificity, high cytotoxic potential and long persistence. For more information, please visit: http://www.windmiltx.com.

About UCI Health

UCI Healthcomprises the clinical enterprise of the University of California, Irvine. Patients can access UCI Health at primary and specialty care offices across Orange County and at its main campus, UCI Medical Center in Orange, California. The 417-bed acute care hospital provides tertiary and quaternary care, ambulatory and specialty medical clinics and behavioral health and rehabilitation services. UCI Medical Center features Orange Countys only National Cancer Institute-designated comprehensive cancer center, high-risk perinatal/neonatal program and American College of Surgeons-verified Level I adult and Level II pediatric trauma center and regional burn center. UCI Health serves a region of nearly 4 million people in Orange County, western Riverside County and southeast Los Angeles County. Follow us onFacebookandTwitter.

About the University of California, Irvine

Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 222 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visitwww.uci.edu.

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Cell therapy startup raises $16 million to fund its quest for the Holy Grail in regenerative medicine – Endpoints News

In 2006, Shinya Yamanaka shook stem cell research with his discovery that mature cells can be converted into stem cells, relieving a longstanding political-ethical blockage and throwing open medical research on everything from curbing eye degeneration to organ printing.

But that process still has pitfalls, including in risk and scalability, and some researchers are exploring another way first hinted at years ago: new technology to convert mature cells directly into other mature cells without the complex and time-consuming process of first making them into stem cells.

One of those companies, Mogrify, just raised $16 million in Series A financing to bring its overall funding to over $20 million since its February launch. Led by CEO Darrin Disley, the funding will help expand their new base in Cambridge to a 60-strong staff and push forward their direct-conversion approach to cell therapy through research and licensing. Investors include Parkwalk Advisors and Ahren Innovation Capital.

They list potential applications as treatments for musculoskeletal and auto-immune disorders, cancer immunotherapy, and therapies for ocular and respiratory diseases. For example, you could use it regenerate cartilage in arthritis patients.

If you could take a cell from one part of the body and turn it into any other cell at any other stage of development for another part of the body, you effectively have the Holy Grail of regenerative medicine, Disley told Labiotech.eu in April.

Mogrifys advantage over the Yamanaka method called induced pluripotent stem cells (iPS), is that in theory it can be more scalable and avoid the problems associated with iPS. These include instabilities arising from the induced immature state and an increased risk of cancer if any pluripotent cells remain in the body.

The concept behind Mogrify actually predates, by nearly 19 years, Yamanakas discovery, which fast won him the 2012 Nobel Prize in Medicine. A 2017 Nature study on transdifferentiation, as the process is called, of fibroblasts into cardiac tissue traced the idea to a 1987 findingthat a master gene regulator could convert mice fibroblasts into skeletal muscle.

The problem though, according to Mogrify, is that most current efforts rely on an exhausting guess-and-check process. With hundreds of cell types and an even greater number of transcription factors the program that recodes the cell finding the right factor for the right cell can be like a custodian with a jangling, unmarked key ring trying to get into a building with thousands of locks.

Mogrifys key tech is a computer model they say can predict the right combination. The scientists behind the platform published a 2016 study in Nature applying the model to 173 human cell types and 134 tissues.

Before Mogrify, Disley led the Cambridge-based gene-editing company Horizon Discovery.

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Cell therapy startup raises $16 million to fund its quest for the Holy Grail in regenerative medicine - Endpoints News

Some cases of SIDS may have this genetic cause – Futurity: Research News

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New research links a genetic anomaly and some forms of SIDS, or sudden infant death syndrome, which claims the lives of more than 3,000 infants a year.

The research, published in Nature Communications, focuses on mitochondrial tri-functional protein deficiency, a potentially fatal cardiac metabolic disorder caused by a genetic mutation in the gene HADHA.

Newborns with this genetic anomaly cant metabolize the lipids found in milk, and die suddenly of cardiac arrest when they are a couple months old. Lipids are a category of molecules that include fats, cholesterol, and fatty acids.

There are multiple causes for sudden infant death syndrome, says Hannele Ruohola-Baker, professor of biochemistry at the University of Washington School of Medicine, who is also associate director of the Medicine Institute for Stem Cell and Regenerative Medicine.

There are some causes which are environmental. But what were studying here is really a genetic cause of SIDS. In this particular case, it involves defect in the enzyme that breaks down fat.

Lead author Jason Miklas, who earned his PhD at the University of Washington and is now a postdoctoral fellow at Stanford University, says he first came up with the idea while researching heart disease and noticed a small research study that had examined children who couldnt process fats and who had cardiac disease that was not readily explained.

So he and Ruohola-Baker started looking into why heart cells, grown to mimic infant cells, died in the petri dish where they were growing.

If a child has a mutation, depending on the mutation the first few months of life can be very scary as the child may die suddenly, Miklas says. An autopsy wouldnt necessarily pick up why the child passed but we think it might be due to the infants heart stopping to beat.

Were no longer just trying to treat the symptoms of the disease, Miklas says. Were trying to find ways to treat the root problem. Its very gratifying to see that we can make real progress in the lab toward interventions that could one day make their way to the clinic.

In MTP deficiency, the heart cells of affected infants dont convert fats into nutrients properly, resulting in a build-up of unprocessed fatty material that can disrupt heart functions. More technically, the breakdown occurs when enzymes fail to complete a process known as fatty acid oxidation. It is possible to screen for the genetic markers of MTP deficiency; but effective treatments remain a ways off.

Ruohola-Baker says the latest laboratory discovery is a big step towards finding ways to overcome SIDS.

There is no cure for this, she says. But there is now hope, because weve found a new aspect of this disease that will innovate generations of novel small molecules and designed proteins, which might help these patients in the future.

One drug the group is focusing on is Elamipretide, used to stimulate hearts and organs that have oxygen deficiency, but barely considered for helping infant hearts, until now. In addition, prospective parents can undergo screening to see if there is a chance that they could have a child who might carry the mutation.

Ruohola-Baker has a personal interest in the research: one of her friends in Finland, her home country, had a baby who died of SIDS.

It was absolutely devastating for that couple, she says. Since then, Ive been very interested in the causes for sudden infant death syndrome. Its very exciting to think that our work may contribute to future treatments, and help for the heartbreak for the parents who find their children have these mutations.

The National Institutes of Health, the Academy of Finland, Finnish Foundation for Cardiovascular Research. Wellstone Muscular Dystrophy Cooperative Research Center, Natural Sciences and Engineering Research of Canada, an Alexander Graham Bell Graduate Scholarship, and the National Science Foundation funded the work.

Source: University of Washington

Original Study DOI: 10.1038/s41467-019-12482-1

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More Studies Needed to Assess Effects of Cord Blood Transplants in CP, Review Finds – Cerebral Palsy News Today

More controlled clinical studies are needed to investigate the effects of umbilical cord blood transplants as a form of treatment for cerebral palsy (CP) and other diseases, according to a recent literature review.

The study, Systematic review of controlled clinical studies using umbilical cord blood for regenerative therapy: Identifying barriers to assessing efficacy, was published in Cytotherapy.

There has been an increasing use of umbilical cord blood (UCB) for different therapeutic purposes in regenerative medicine in recent years.

Cord blood is a long-known source of different cell types, including stem cells a type of cell capable of promoting the repair of damaged tissues. These cells represent a promising treatment for numerous conditions, including cerebral palsy. However, the usefulness of UCB transplants for new indications, including for the treatment of CP, type 1 diabetes, liver diseases, and congestive heart failure, is still unclear.

Clinical studies have been conducted in many different countries and have described cord blood therapy for a broad array of indications, the researchers said. However, these studies are often heterogeneous in nature, and study designs are variable and describe outcomes using a range of measures at various time-points.

In addition, many of these studies lacked a proper control group, which made estimations of therapeutic efficacy impossible for these new indications, they said.

In this review study, the researchers focused on summarizing the main findings of controlled clinical studies investigating the usefulness of UCB for CP, type 1 diabetes, and nine other new indications.

Literature searches in two online databases Medline and Embase yielded a total of 360 potentially relevant studies published between June 2016 and April 2018. After further screenings, a total of 16 controlled studies four on CP, three on type 1 diabetes, and nine on other medical conditions were selected for inclusion in this review.

Three of the four studies performed in CP, involving 247 children with the disease, were based on the use of allogeneic cells that is, UCB cells that had been obtained from a matching donor.

Only one of the studies investigated the effect of banked UCB cells that had been collected from the children at birth and then re-transplanted back to them at some point a procedure called autologous treatment.

Six months after treatment, children with CP who received allogeneic cells had a significant improvement in gross motor function, as measured by the Gross Motor Performance Measure (GMPM) and by the Gross Motor Function Measure (GMFM), compared with those who did not receive UCB cells (controls).

Mental and motor function scores at other time points were highly variable between studies.

The one study in which children received autologous treatment also reported a significant improvement in the participants GMFM scores after one year, compared with controls. This positive effect on motor function was proportional to the number of cells these children had received, known as a dose-dependent effect.

Although studies of cerebral palsy appear promising, the use of different scoring systems at varied time points following transplantation limits our ability to determine whether the intervention is beneficial, particularly at later time points beyond 12 months, the researchers said.

Of the three studies that focused on patients with type 1 diabetes, one evaluated the effects of allogeneic treatment, and two the effects of autologous treatment. All three failed to detect any positive effects of the therapy on daily insulin requirements, or on glycated hemoglobin A1c (HbA1c) the fraction of hemoglobin that is bound to glucose, or sugar, in the blood compared with controls.

Only one of the remaining nine controlled studies, which focused on investigating the effects of UCB cells in adults with optic nerve hypoplasia, reported a positive effect of treatment.

More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size, the researchers said.

Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven, they concluded.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells cells that make up the lining of blood vessels found in the umbilical cord of newborns.

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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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More Studies Needed to Assess Effects of Cord Blood Transplants in CP, Review Finds - Cerebral Palsy News Today