Roundtable on cGMP Stem Cell Manufacturing

Allele Biotechnology & Pharmaceuticals is hosting a cGMP Stem Cell Manufacturing Roundtable to discuss ways to accelerate stem cell-based therapies toward clinical development and commercialization. The roundtable will bring together top minds from academic settings, cGMP facilities, and biotech industries in an informal setting to explore partnerships and avenues for developing effective and marketable iPSC-derived therapies.

The meeting will be held on April 20th at The Hilton on Torrey Pines and will consist of four sessions covering (1) existing cGMP facilities, (2) manufacturing and quality systems, (3) regulatory concerns, and (4) business strategy.

Meeting highlights will be produced to summarize the presentations and discussions. For inquiries, contact info@allelebiotech.com or call 858-587-6645.

NIH Awards Allele Collaboration with Grant to Fund the Development of Cell-Based Therapy for Alzheimer’s Disease

The NIH’s National Institute on Aging has awarded Allele Biotechnology and Pharmaceuticals (“Allele”) a Phase 1 SBIR grant to develop a stem cell-based therapy for the treatment of Alzheimer’s disease. The award includes funds for consortium activity with researchers at The Scintillon Institute, whose expertise in neurodegeneration leverages Allele’s expertise in stem cell technology.

Alzheimer’s disease is the most common form of dementia, affecting over 35 million people worldwide. Currently, there is no cure for this devastating disease. Patients with Alzheimer’s disease suffer from synaptic and neuronal loss, which is thought to be caused by the presence of a chemically “sticky” protein called amyloid beta (Aβ). The aggregates of Aβ may damage synaptic integrity and/or trigger immune cell activation, ultimately causing cell death.

Successful cell-replacement therapies would need to distribute cells to damaged areas in the brain and stimulate integration of new neurons into existing cellular networks. While the idea of replacing lost neurons sounds promising, even successfully transplanted neurons would face the same toxic environment that destroyed the original neurons.

Researchers at Allele and Scintillon propose a novel way to prevent further damage from Aβ to transplanted neural stem cells. They are collaborating to genetically modify human neural stem cells to express a small (58-amino acid) peptide derived from the protein called α1-takusan, which Scintillon researchers previously discovered to harbor a protective activity against Aβ-induced toxicity (1). The researchers will then transplant the cells expressing the α1-takusan fragment into transgenic mouse models to evaluate whether these cells can ameliorate or even rescue the neurological phenotypes related to Alzheimer’s disease.

The Allele-Scintillon team hopes that transplanting these cells will mitigate synaptic and neuronal damage from Aβ, ultimately leading to a novel cell-replacement therapy for Alzheimer’s disease. This is the second SBIR grant that Allele has received from the NIH on treating Alzheimer’s by combating Aβ toxicity; the first being the creation of nanoantibodies against Aβ, which has generated multiple single-domain antibodies now in early development.

(1) Nakanishi N, Ryan SD, Zhang X, Khan A, Holland T, Cho EG, Huang X, Liao FF, Xu H, Lipton SA, Tu S (2013) Synaptic protein alpha1-takusan mitigates amyloid-beta-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci 33:14170-14183. PMCID: PMC3756761

The NIH Awards Allele with Grant for the Development of a New Antibody Therapy for Treating Alzheimer’s Disease

SAN DIEGO–(BUSINESS WIRE)–

The National Institute on Aging of the NIH has awarded a grant to Allele Biotechnology and Pharmaceuticals (“Allele”) to develop a new antibody therapy for treating Alzheimer’s disease. Alzheimer’s disease is the most common cause of dementia, but there are currently no treatments to stop or reverse its progression.

Alongside academic collaborators, scientists at Allele have revealed a strong correlation between a previously uncharacterized target gene and Alzheimer’s disease. They discovered that expression of the gene reduces beta-amyloid production and tau phosphorylation, two components of plaque formation in Alzheimer’s disease. Furthermore, high levels of this protein in the brain can counteract loss of synapses and cognitive impairments in mice.

Allele will generate a panel of antibodies that recognize this protein with the goal of employing one of these antibodies as a therapeutic drug candidate. The antibodies’ unique size and shape allow them to pass the blood-brain barrier to reach crucial regions of the brain, and each antibody can be easily modified and engineered to heighten its therapeutic potential. Researchers at Allele hope that an antibody treatment will improve the function of its target protein in the brains of Alzheimer’s patients and ultimately reduce pathogenesis of the disease.

Recombinant antibodies represent one of the most important classes of biological therapeutics: 80% of the best selling drugs on the market are antibodies; immune checkpoint therapies and CAR-T cell therapies rely on antibodies. Continuously seeking unique antibodies against high value targets is a key focus of Allele, along with its induced pluripotent stem cell (iPSC) programs and iPSC-based drug screening projects. With the support of the new NIH grant, Allele will not only move closer to finding antibody drug candidates in fighting one of the most devastating diseases, but also generate long-needed research tools for other scientists to further study Alzheimer’s disease. For example, fusion of these antibodies to fluorescent proteins such as mNeonGreen can be used to image Alzheimer’s disease-related factors in cultured neurons, astrocytes, oligodendrocytes, or “minibrain”-like organoids derived from human iPSCs.

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Allele Receives NIH Award to Fund the Development of Large-Scale Stem Cell Production

SAN DIEGO–(BUSINESS WIRE)–

The NIH’s National Heart, Lung, and Blood Institute has awarded Allele Biotechnology and Pharmaceuticals (“Allele”) a Phase 1 SBIR grant to develop a novel manufacturing system to produce stem cell-derived human tissue and cells for clinical therapy. By increasing the scale of production and reducing the cost of manufacturing, Allele is confident that this system will overcome a considerable roadblock for clinical applications of stem cells, which is to produce a sufficient amount of therapeutic material at a manageable cost.

At the core of translating this potentially game-changing technology into medically-beneficial applications is the use of induced pluripotent stem cells (iPSCs), which hold unprecedented promise of providing any type of immune-matched cells of unlimited quantity. Allele has already developed a patented method of reprogramming somatic cells into iPSCs, secured industrial licensees using this technology, and initiated cGMP procedures for clinical applications.

Further moving iPSCs into commercially viable clinical cell therapies still requires overcoming one major barrier: the prohibitive cost of manufacturing iPSC-derived cells, mostly due to the need of expensive clinical-grade growth factors and cytokines. For example, the estimated cost of the growth factors and cytokines needed to produce a typical transfusion of platelets is $87,252.

Ultimately, Allele’s goal is to create clinical-grade iPSCs and control their differentiation into specific cell types at a scale large enough to satisfy the clinical demand. “We have been diligently working on removing the use of protein factors through our own proprietary protocols to generate many clinically-relevant cell types, including beta cells, mesenchymal stem cells, neural progenitor cells, oligodendrocytes, liver, and heart cells,” said Dr. Jiwu Wang, Allele’s CEO and the Principle Investigator of the new NIH grant. “By developing a recombinant protein-independent, real-time adjusted culture system under this project, we are confident that—as many groundbreaking technologies such as genome sequencing have done—the manufacturing process will mature and the costs will come down to eventually benefit everybody.”

Allele’s plan gained trust from the NIH scientific review panel, which gave it a near-perfect score. With this funding, Allele’s researchers will move even faster towards the goal of bringing iPSC products to clinical applications. Successful efforts will also likely provide a vehicle for genome-editing technologies such as CRISPR to be delivered into patients.

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Stem Cell Therapies: What’s Approved, What Isn’t, and Why Not?

With acceptance of stem cell therapies growing, so have controversies surrounding regulations.

Desperate to heal sports injuries, top professional athletes have been known to pay tens of thousands of dollars for experimental stem cell treatments that many used to find controversial. But now, stem cell therapies have become more mainstream and are no longer limited to professional athletes. Stem cell clinics offer both medical and non-medical treatments with claims of improving aesthetics and quality of life.

One recent study found over 400 websites – with the largest portion in the United States – advertising stem cell-based therapies (1); another found over 570 U.S. clinics offering stem cell interventions (2), giving more evidence that the market for stem cell therapies in the U.S. is growing at an accelerated rate. Yet these therapies are too often based on unfounded claims and lack proper clinical trials or authorized regulation. Despite what some clinics claim, very few stem cell treatments are currently available that are actually approved by the Food and Drug Administration (FDA). Hematopoietic stem cells harvested from bone marrow are routinely used in transplant procedures to treat patients with cancer or other blood or immune system disorders. Banking of umbilical cord blood is FDA-regulated and its use is approved for certain indications. Otherwise, consumers should be wary of claims by stem cell clinics implying FDA-approval.

So why aren’t more FDA-approved stem cell therapies available?

The FDA has strict regulations on using stem cell products in humans. In most cases, stem cell-based products are categorized the same way as pharmaceutical drugs. Therefore, each new therapy must go through a rigorous process including pre-clinical animal trials, phased clinical studies, and pre-market review by the FDA prior to offering the treatment in the clinic.

And with stringent regulatory requirements comes prohibitive costs. Research animals, Phase I-III clinical trials, and the regulatory demands for good manufacturing practice (GMP) labs result in an extraordinarily costly process that may hinder the progress of new therapies. The cost of developing a new drug has even been estimated to reach billions of dollars.

Nevertheless, a complete lack of regulation of stem cell therapies – as is seen in many of the stem cell clinics springing up worldwide – is clearly problematic. Alarmingly, many clinics advertise claims related to medical diseases for which there is no scientific consensus that supports their safety or efficacy. Premature commercialization of unproven therapies not only puts patients at risk, but also jeopardizes the credibility of still-developing stem cell products.

One of the most exciting outlooks for stem cell therapy is the prospect of using one’s own stem cells for personalized medicine. Should the development of an autologous stem cell product really be regulated the same way as a pharmaceutical drug, which is aimed at treating huge populations of people? If not, how should stem cell products be regulated?

In an effort to make the transition of novel stem cell products to the clinic more seamless, some countries have made significant changes in regulations. For instance, in 2014, Japan broke out a separate regulatory system for stem cell products that softened legislation dramatically to require only limited safety and efficacy data. Some argue that countries with softer regulations and less stringent safety and efficacy milestones, such as Japan, have poised themselves to become the likely pioneers in the field of regenerative medicine.

Regulatory frameworks for the clinical application of stem cell products are still evolving in most countries, including the U.S. In March, the Reliable and Effective Growth for Regenerative health Options that improve Wellness (REGROW) Act was introduced to congress. This change in legislation would remove some of the regulatory hurdles that hinder the progress of biologic therapies.

Regardless, the FDA needs to establish a more reasonable regulatory system that can evaluate the safety and efficacy of stem cell products in a more efficient manner.

1.  Berger, I., et al., Global Distribution of Businesses Marketing Stem Cell-Based Interventions. Cell Stem Cell, 2016. 19(2): p. 158-62.

2.  Turner, L. and P. Knoepfler, Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell, 2016. 19(2): p. 154-7.