Allele Receives Tissue Bank License for Manufacturing and Distribution of cGMP-compliant iPSCs

Allele Biotechnology & Pharmaceuticals has received a Tissue Bank License from the California Department of Public Health, making it the world’s first establishment to collect tissue for the manufacture and banking of induced pluripotent stem cells (iPSCs) for commercial applications.

Allele’s cGMP facility is dedicated to the generation, banking, and differentiation of iPSCs for therapeutic use and drug discovery. All tissues and cells are processed in a state-of-the-art cleanroom to satisfy FDA requirements for Phase III clinical trials and commercial production. The cleanroom’s modular space and adaptable design allow different areas to be dedicated to the manufacture of various iPSC-derived cells.

The first tissues were processed in August 2017 when the cGMP manufacturing suite officially opened after a 2-year construction and remodeling effort and nearly a decade of iPSC reprogramming research and optimization. The iPSCs generation process is fully cGMP- and GTP-compliant, beginning with the onsite collection of tissue from donors or clients by a physician. All cGMP manufacturing personnel have undergone extensive training with strict qualification and documentation measures to ensure successful reprogramming of cells in an ISO-5 environment. Once generated, iPSCs are banked and can be distributed or differentiated for transplantation into patients. The entire process is validated and performed under the umbrella of a 21 CFR-compliant quality system.

Generation of iPSCs is based on Allele’s proprietary mRNA-only protocol which was designed and optimized expressly for cGMP production. The methods were developed to produce iPSCs that are free from genomic integration of plasmid DNA, viruses, and feeder cells. According to CEO and the lead scientist behind the technology, Dr. Jiwu Wang, “The powerful mRNA technology developed by Allele’s researchers made it much easier for cells to enter clinical trials down the road and we expect multiple patent issuances shortly.”

The cGMP facility has a dedicated mRNA production area for the manufacture of cGMP-compliant mRNAs. In addition to supporting iPSC reprogramming efforts, cGMP mRNA will support ongoing internal development programs to generate iPSC derived cells. Current efforts are focused on the development of pancreatic beta cells, neurons, oligodendrocytes and their progenitor cells, hepatocytes, muscle cells, and mesenchymal cells.

Established in 1999, Allele Biotechnology has a mission to further therapeutic innovation by providing cutting edge technologies and clinical grade solutions to partners working in collaborative and creative ways to support preclinical studies and clinical trials in the stem cell therapy arena.

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.

Allele-iPSC News Translate: iPS clinical research encounters a problem. Doctors say “the problem is not caused by iPSCs”

Kobe City Medical Center General Hospital and Riken Research Institute announced and reported to the Japanese government that a patient who had received allogeneic iPSC-derived cells developed an “epi retinal membrane”, which they subsequently removed by operation. Dr. Masayo Takahashi at Riken says “the problem is caused by the transplantation procedure, but not by iPSCs. This will not affect future clinical research that uses iPSCs.”

The laws that govern regenerative medicine in Japan mandates that the deaths and hospitalizations that occur during treatment need to be reported to the government as “serious harmful effects”. This is the first such report involving iPSC clinical research.

The problem occurred to a man in his 70s, who is at the risk of blindness due to “wet age-related macular degeneration”. Last June, he received a transplantation of the solution containing allogeneic iPSC-derived retinal pigment epithelium (RPE) in his left eyes. Last October, the epi retinal membrane and swelling started to develop and the membrane was removed on January 15.

The possibility exists that the solution leaked from the needle hole during the transplantation, and the leaked cells might have formed the membrane. The transplanted cells inside the retina are stable and there has been no decline in his eyesight.

Dr. Takahashi says “although this event qualifies as a serious harmful event, the patient’s condition has not worsened and there has been no rejection of transplanted cells”. Dr. Yasuo Kurimoto, a surgeon who performed the operation, says “the procedure was the problem. We would like to improve the method, in order to make iPSC therapy a common treatment.”

The current clinical trial targets patients with wet age-related macular degeneration and is run by the Kobe City Hospital, Riken, Osaka-University Hospital, and Kyoto-University CiRA (Dr. Shinya Yamanaka). Between last March and October, five patients have received the transplantation.

Original News Credits: https://www.kobe-np.co.jp/news/iryou/201801/0010902012.shtml

Tags: AMD, eye disease, iPSC, Japan iPSC, RPE, stem cells, Takanishi, Yamanaka

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

Allele Publication Explains cGMP Generation of Induced Pluripotent Stem Cells

The discovery that adult somatic cells can be reprogrammed to pluripotent stem cells has given the biomedical community a powerful platform for personalized medicine. However, the translation of cell therapies from bench to bedside holds a significant challenge. Realizing the clinical potential for stem cells requires their production under current Good Manufacturing Practice (cGMP) regulations enforced by the FDA. A new protocol (http://onlinelibrary.wiley.com/doi/10.1002/cpsc.18/abstract) published by scientists at Allele and detailed in this quarter’s issue of Current Protocols in Stem Cell Biology, reveals key conditions required for converting adult fibroblasts to induced pluripotent stem cells (iPSCs) under cGMP regulations.¹

The patent-pending protocol is an update to a previous protocol that describes how to reprogram fibroblasts to iPSCs using mRNA. “The system of using mRNA to reprogram fibroblasts presents itself as a very favorable candidate for generating iPSCs for cell therapy” according to the senior author of the paper and CEO of Allele, Dr. Jiwu Wang, “our company is committed to developing stem cell based therapies using this protocol and through the establishment of our own stem cell GMP facilities here in California”. mRNA transfection is “footprint free”, meaning no insertions or alterations have been made to the genome. Transfection of mRNA is also “cleanup free,” because mRNA transcripts are supplied to the cells in the culture medium only for the time required to induce pluripotency. Furthermore, genomic analyses of iPSCs reprogrammed using mRNA indicate that this method of conversion is unlikely to introduce problematic mutations.²

The new version of the protocol describes reprogramming technology that utilizes all cGMP-certified reagents and vessels, meaning that every material is manufactured under guidelines that allow for ancillary use in manufacturing processes related to cell therapy. All materials described in the protocol – from cell medium and components to the coating for tissue culture plates – were meticulously evaluated at every step of generating and storing iPSCs. For truly cGMP produced cell lines, all processes should take place in certified cleanrooms with qualified equipment and thoroughly trained operators.

Establishing a cGMP process for any product intended for human use is a daunting undertaking. Unlike drugs and small-molecule pharmaceuticals, stem cells are living entities whose production cannot be chemically synthesized. Therefore, special considerations must be made – particularly for making individual cell lines – to help assure the highest safety and quality of downstream stem cell products. Adhering to cGMP regulations infuses high quality into the design and manufacturing process at every step. Through rigorous testing, researchers at Allele have identified critical parameters for generating iPSCs from fibroblasts that are cGMP-compliant, and are optimistic that the methods described in this recent publication will serve as a launch pad for the development of future cell products and therapies.

1. Ni Y, Zhao Y, Warren L, Higginbotham J, Wang J. cGMP Generation of Human Induced Pluripotent Stem Cells with Messenger RNA. Current Protocols in Stem Cell Biology,2016; 39:4A.6.1-4A.6.25.
2. Bhutani K, Nazor KL, Williams R, et al. Whole-genome mutational burden analysis of three pluripotency induction methods. Nature communications. 2016;7:10536.

Allele GMP CRO and Cell Therapy

Tags: Allele Therapeutics, CA company, CIRM, GMP, iPSC, stem cell therapy