SBIR and Business issues

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


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


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.


Generation of Human Stem Cells under Good Manufacturing Practice: Facility Update

cGMP Facility on Nancy Ridge Dr.

Allele’s New cGMP Facility on Nancy Ridge Dr.

Last year Allele dedicated a new building space for cleanroom operations to provide a cell banking service for personalized medicine. This facility will be the center of current Good Manufacturing Practice (cGMP) production of human induced pluripotent stem cells (iPSCs) using Allele’s proprietary synthetic mRNA platform. Over the past three months, progress to get the facility up and running has been substantial. Our facility includes four main modules: the reception area and doctors’ offices, a Fibroblast Isolation and Maintenance room, a Reprogramming and iPSC Maintenance room, and a Quality Control room. Air handling, which is a major component of the environmental control system, has been installed and validated. Equipment such as biosafety cabinets, incubators, and refrigerators have been installed and qualified, as well as equipment for performing essential quality control steps. To standardize personnel-related steps of cGMP processing, we have prepared rigorous SOPs and have extensively trained individual manufacturing operators. Overall, we are enthusiastic about the facility’s progress and are committed to delivering the best possible service as the industry leader in iPSC banking.


iPSC roomCells


cGMP Compliance: What Does It Mean for Your Cell Lines?

As the promise for cell-based therapy grows, the interest in making clinically relevant cell lines has skyrocketed for industrial and academic researchers alike. For translation into human therapies, cell-based products must be made following current Good Manufacturing Practice (cGMP). Many groups have already claimed to generate cell lines that are “cGMP-compliant,” “cGMP-ready,” or “certifiable under cGMP.” But what does it take to be truly cGMP-compliant, and what practices can you introduce in your lab to comply with cGMP standards?

A common misconception in the United States is that a facility is granted a ‘cGMP license’ from the government to manufacture cGMP-grade products. Rather, the Food and Drug Administration (FDA) evaluates the manufacturing process for each product to determine if it is compliant with cGMP standards. The primary concern when it comes to deriving cell-based products for therapies is making sure that the product is derived in a safe and reproducible manner. To ensure maximum quality assurance, researchers should

• choose reliable, xenogeneic-free raw materials,
• establish and monitor a clean environment,
• qualify all equipment and software,
• remove variation in laboratory procedures by creating detailed Standard Operating Procedures (SOPs) and by providing rigid process validation at each step.

Nevertheless, even establishing robust quality assurance does not imply that the process is scalable for commercial production. In the world of biologics, “the product is the process.” A requisite step to ensure a smooth transition to cGMP practice is to ensure that the process of manufacturing is not altered due to changes in production scale. For example, depending on the therapy, millions or billions of cells may be required for a single patient. Therefore, it is in the best interest of the researchers to develop a scalable method at the beginning to avoid revamping the entire process (e.g., changing from adherent cells to suspension). Along these lines, the quality control (QC) requirements of cell-based products should be carefully considered and not have to include difficult-to-assay tests. For example, some cell lines have been qualified as cGMP-compliant upon conversion from research-grade conditions to cGMP quality standards. Rigorous tests were performed on the converted lines to ensure that the cells were free of contamination. Even though strict measures were carried out to ensure cGMP compliancy, deriving cell lines in this manner makes scalability and reproducibility a challenge. Ideally, the entire process of deriving cell products for clinical use should be performed under cGMP conditions: from the acquisition of human tissue to the manufacturing, testing, and storage of derivative cell products.

Another important consideration when instituting cGMP-compliance is documentation. Each process must be described with rigorous SOPs, the training of individual manufacturing operators must be well-documented, and the entire established process must be validated and well noted. Failure to document—in the eyes of the FDA—is often equated with failure to perform the underlying activity. It is equally important to remain ‘current.’ The FDA expects manufacturing processes to stay up-to-date with current regulations, even as policies change.

For an academic lab, closely aligning with cGMP standards can ensure that the resulting cell lines are comparable to other truly cGMP-produced products used during clinical trials. It is in the best interest of academic researchers to establish rigorous SOPs and use qualified reagents and equipment, even if it is not possible to carry out all steps in a certified cleanroom. Whenever possible, it is advisable to acquire truly cGMP cell lines from appropriate sources for preclinical projects; if prohibited by costs or other reasons, it is recommended to use a protocol that is as close to cGMP as possible.

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