iPSCs and other stem cells

Allele Biotechnology & Pharmaceuticals Forming Cell Banking Business for Personalized Medicine

Allele to Generate Human iPS Cells under Good Manufacturing Practice for Private Individuals for Potential Therapeutic Use and Future diagnostics; Cell Banking Scientific Advisory Board formed

October 06, 2015 11:25 AM Eastern Daylight Time
SAN DIEGO–(BUSINESS WIRE)–Allele Biotechnology & Pharmaceuticals, Inc. (“Allele”), a leader in the development of specialized cells for regenerative medicine and pharmaceutical drug discovery, today announced plans to form a commercial business for the banking of human induced pluripotent stem cells (iPSCs) by private individuals.

Allele is pleased to have Drs. Mahendra Rao and Joseph Paulauskis as the first members of its Scientific Advisory Board (SAB) for iPSC banking and cGMP production. Dr. Rao is a world-renowned scientist in the fields of stem cells and medicine, having served as the VP of Regenerative Medicine at Invitrogen, founding Director of the NIH Center for Regenerative Medicine, Chair of the Biological Response Modifiers Committee (BRMAC, now CTAGT) of the FDA, and he is currently Chief Strategy Officer at Q Therapeutics. Dr. Paulauskis is the Chief Operating Officer of Paradigm Dx as well as the Vice-President of Research and Biobanking for the International Genomics Consortium, and has previously held senior positions in pharmacogenomics at Pfizer. Allele plans to make additional appointments to the SAB as individuals with world-class experience and expertise are identified.

Human iPSCs are cells that can be grown to virtually infinite numbers and can become any cell in the human body, features which hold great promise for therapies that can alleviate or cure human disease. Allele’s business model recognizes that an individual can have their own cells ready for future therapeutic use via the generation and storage of iPSCs from that individual’s skin cells. While this is similar to what is done with newborn cord blood, iPSCs can be generated from humans of any age. The banking of human iPSCs for potential future therapeutic use is a relatively new industry with unprecedented potential, and Allele is benefitting from expert opinions internally and from current and future SAB members, ensuring a solid scientific and ethical foundation for this business.

In addition to serving its customers, Allele’s iPSC bank will be an unparalleled resource for biomedical research. Proper consent and privacy guardianship will allow thousands of iPSC lines with accompanying sequence database and health information to be made available from the bank to scientists and clinicians. Currently, iPSC banks are funded by government agencies at multi-million dollar costs per project; Allele’s model does not rely on tax dollars and provides potentially a larger bank of iPSCs of higher quality to aid research and treatment efforts. To this end, NIH Director Dr. Francis Collins recently announced the implementation of the Precision Medicine Initiative (PMI), the goal of which is for health care professionals to have the resources to take into account individual differences in genes, environments, and lifestyles that contribute to disease when providing treatments in the new era.

“We are happy to have the guidance from world leading experts in stem cells, biobanking, and cell therapy fields such as Drs. Rao and Paulauskis”, said Jiwu Wang Ph.D., President and CEO of Allele. “We believe that setting the bar high will be ultimately beneficial to future customers, fellow researchers, industry partners, and regulatory agencies alike. We are happy to see the recent release by the International Society for Stem Cell Research of a draft of ‘Guidelines for the Clinical Translation of Stem Cells’, whose principals we plan to follow closely. We also intend to obtain certification by the cord blood banking association AABB, if possible, and abide by other regulatory rules as they become public, such as the “Stem Cell Clinical Research Management (tentative)” by the Health Commission of China, if and when we move to operate under that jurisdiction”.

Towards the establishment of this business effort, Allele has recently purchased an 18,000 square-foot facility, located near its headquarters in San Diego, California. This new facility will be the center of cGMP-production of human iPSCs using Allele’s proprietary synthetic mRNA platform, a technology that generates cells with neither the random integration of foreign DNA nor the use of viruses or virus-based elements, drawbacks common to other technologies for making hiPSCs; thus, the “footprint-free” cells generated by Allele’s synthetic mRNA platform are optimally suited for therapeutic use, and Allele’s technology has been licensed for clinical trials by companies such as Ocata Therapeutics (formerly ACT). This effort received strong support from Yuan Capital and Yifang Ventures.

About Allele Biotechnology & Pharmaceuticals, Inc.

Allele Biotechnology and Pharmaceuticals, Inc. is a private, San Diego-based company that explores the mechanisms of biological processes to develop technologies and products for biomedical researchers. Allele utilizes proprietary non-integrating cellular reprogramming methods to generate human and non-human primate iPS cells, GMP-grade human iPS cells and their derivatives, and differentiated cell types. With additional expertise in genome modification and cell-based sensors/reporters, Allele provides advanced cell-based assays for drug discovery. Allele also has developed a wide variety of reagents including superior fluorescent proteins and camelid antibodies. The company has also been a leader in the RNAi field with its patents in Pol III promoter-driven siRNA, shRNA, and miRNA.

Allele Biotechnology & Pharmaceuticals, Inc.
Matthew A. Singer, Ph. D.
Director of Business Development and Strategic Alliances
+1 858-587-6645, ext. 1

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Press Release: Allele Biotechnology & Pharmaceuticals Closes Purchase of cGMP Facility for Production of Clinical-Grade Cells for Cell Therapy Applications

SAN DIEGO–(BUSINESS WIRE)–Allele Biotechnology & Pharmaceuticals, Inc. (“Allele”), a leader in the development of specialized cells for pharmaceutical drug discovery and regenerative medicine, today announced that it has closed the purchase of a new facility intended for its cGMP (current good manufacturing practices) production of clinical-grade cells for cell therapy applications.

The 18,000 square-foot facility, located near the main headquarters of Allele in San Diego, California, will be the center of production of human induced pluripotent stem cells (hiPSCs) using Allele’s proprietary synthetic mRNA platform, a technology that generates hiPSCs with neither the random integration of foreign DNA nor the use of whole virus or virus-based elements, drawbacks that are common to other technologies for making hiPSCs. Such “footprint-free” cells will be produced by Allele for industrial and academic partnerships, as well as Allele’s own efforts in the area of cellular therapeutics.

hiPSCs, as cells that have the potential to become any cell in the human body, hold great promise for therapies that can alleviate or cure human disease. Towards this end, Allele has recently made a number of advances regarding the differentiation of hiPSCs towards cells of specific lineages, such as neural progenitor cells, neurons, astrocytes, mesenchymal stem cells, cardiomyocytes, skeletal muscle cells, hepatocytes, and adipocytes, including brown fat cells. These cells would also be produced in the cGMP facility when intended for specific therapies.

“This dedicated facility will help us to realize a number of our visions in bringing the benefits of pluripotent stem cells to society,” said Jiwu Wang, Ph.D., President and CEO of Allele. “The first step in helping people in need with all the stem cell technologies developed in labs is to clear a path to move them from bench to bedside, which requires high-quality, controlled production that can be monitored by the FDA. Together with our licensees, drug development partners, investors, and individuals who would like to participate in banking hiPSCs for research and therapy, we anticipate even faster pace in our business development in this area.”


Allele Biotechnology & Pharmaceuticals, Inc.
Jiwu Wang, 858-587-6645

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Press Release: Ocata Therapeutics Licenses Induced Pluripotent Stem Cell Technology from Allele Biotechnology and Extends Leadership Position in Cell Therapy Capabilities

Ocata Announces Proof-of-Concept Results in Restoring Vision and Prevention of Blindness

MARLBOROUGH, Mass., Mar 24, 2015 (BUSINESS WIRE) — Ocata Therapeutics, Inc. (“Ocata” or “the Company”; NASDAQ: OCAT), a leader in the field of Regenerative Ophthalmology™, today announced that it has entered into a definitive agreement with Allele Biotechnology & Pharmaceuticals, Inc. of San Diego, CA (“Allele”) to access Allele’s proprietary technology for generating human induced pluripotent stem cells (“iPSCs”).

“This agreement with Allele is part of our strategy to broaden our technology platform and increase our leadership in regenerative ophthalmology,” said Paul Wotton Ph.D., President and CEO of Ocata. “Ocata can now take advantage of induced and embryonic pluripotent stem cells to produce commercially viable human tissue for transplantation. We recently confirmed proof of concept in creating photoreceptors capable of preventing blindness and restoring vision in established animal models. Data from these studies will be published later this year.”

Since Dr. Yamanaka discovered how to generate iPSCs in 2007 there has been tremendous enthusiasm about the potential to use these pluripotent cells to develop commercially viable therapies. Despite many efforts to develop iPSC derived therapies in the same scalable and reliable way as embryonic stem cells, many of those efforts have been unsuccessful due to issues relating to the growth capacity, differentiation potentials and epigenetic properties of iPSCs. The “footprint-free” reprogramming technology developed by Allele potentially offers a reliable and scalable process for producing iPSCs with superior properties and is a major step for translation of iPSC technology to practical clinical use. These iPSCs can potentially be used to manufacture millions of treatment doses as off-the-shelf therapies for any patient.

“We have had a strong leadership role in this area,” said Robert Lanza, M.D., Chief Scientific Officer of Ocata. “Ocata has extensive experience and patent rights in generating both ocular and non-ocular cell types from human iPSCs. We have painstakingly and patiently evaluated many different iPSC technologies and selected the Allele technology only after we were satisfied and confident that this represented the best of all approaches and could permit us to generate transplantable tissues that would be potentially safe in human patients. In our hands, the iPSCs we are generating are comparable to our embryonic stem cells in those features required for use in potential human therapies.”

“It is particularly rewarding to us that Ocata, a company whose understanding of the science and regulatory requirements in this space is unparalleled, has selected the iPSC technology developed at Allele for application in its own pipeline,” said Jiwu Wang Ph.D., President and CEO of Allele. “It only serves to confirm our belief that our iPSC platform is a solution to what otherwise have been unresolved issues associated with the maturation of iPSCs to a fully functional state. The ability to predictably derive stable iPSC lines without using any viral element or foreign DNA enables both fundamental scientific research and clinical applications, which has been the mission of Allele Biotechnology from its inception.”

For Contact at Allele:
P 858-587-6645, 800-991-RNAi(7624)
F 858-587-6692

For full release with Ocata contact, see MarketWatch

Allele’s SBIR Grant to Develop All-RNA CRISPR

Precise engineering of the genomes of mammalian cells enabled biological and medical applications researchers had dreamed of for decades. Recent developments in the stem cell field have created even more excitement for genetically modifying genomes because it enables delivering more beneficial stem cell-derived therapeutic cells to patients [1]. For instance, by correcting a gene mutation known to be critical to Parkinson’s disease, LRRK2 G2019S, in patient-specific iPSCs (induced pluripotent stem cells), it appeared possible to rescue neurodegenerative phenotypes [2].

Significant amount of fund and energy had been invested in technologies such as ZFN and TALEN, however, judging from the explosion of publications and business activities in just about 2 years since the illustration of its mechanism (just today, Jan 8th, 2015, Novartis announced CRISPR collaborations with Intellia, Caribou, applying it in CAR T cell and HSCs), the CRISPR/cas system is the rising star. This system uses a guide RNA to direct the traffic of a single nuclease towards different targets on a chromosome to alter DNA sequence through cutting. The nuclease, cas9, can be mutated from a double-stranded DNA endonuclease to a single-strand cutter or a non-cutting block, or further fused to various functional domains such as a transcription activation domain. This system can also be used to edit RNA molecules.

A weak spot on the sharp blade of CRISPR is, like any methods for creating loss-of-function effects (RNAi if you remember), the potential of off-target effects. While they can never be completely avoided, with the ever growing popularity of deep sequencing, at least we can know all unintended changes on the edited genome. Almost a perfect storm! As an interesting side story, when we at Allele Biotech first saw the paper in Science describing the CIRPSR/cas system [3], we immediately wrote an SBIR grant application for applying the bacterial system to mammalian cells. The first round of review in December 2012 concluded that it would not work due to eukaryotes’ compact chromatin structures. Of course, the flurry of publication in early 2013, while our application was being resubmitted, proved otherwise. The good news is, Allele Biotech still received an SBIR grant from NIGMS in 2014. Unlike most of the genome editing platforms known in the literature, our goal was to build an all-RNA CRISPR/cas system, thereby with higher potency, less off-target effects, and, as a footprint-free platform, more suitable for therapeutic applications. This system will be combined with our strengths in iPSC and stem cell differentiation, fluorescent protein markers, and deep sequencing based bioinformatics to improve cell therapy and cell based assays.

1 Urnov, F.D., et al., Genome editing with engineered zinc finger nucleases. Nat Rev Genet, 2010. 11(9): p. 636-46.
2 Reinhardt, P., et al., Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression. Cell Stem Cell, 2013. 12(3): p. 354-67.
3 Jinek, M., et al., A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science, 2012.

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Combining mRNA-Mediated Phenotype Rescue and CRISPR-Created Isogenic Genome

There has been a good volume of publications on using patient-specific iPSCs for disease modeling. Among them, a recent study by Wang et al. published in Nature Medicine is unique because it not only created cardiomyocytes from both Barth Cardiomyopathy patient and wildtype samples for functional analysis, but also combined some of the most exciting new technologies to strengthen the correlation between gene change and disease.

First, functional rescue by mRNA transgene. After mRNA that encodes wild-type cardiolipin aclation enzyme encoding gene tafazzin (TAZ) was transfected into Barth iPSC-CM cells, their defects in mitochondrial functions were corrected. Second, loss of function by genome editing. When CRISPR was used to make genome changes in wildtype cells that mimicked the disease-specific mutation, we recreated the patient’s iPSC-CM phenotype in otherwise wildtype cells. Third, next generation sequencing to confirm genomic changes. And forth, the cardiomyocyte contractibility was assayed on bioengineered chips.

This paper should set an example of how patient iPSCs should be used to create disease models to the fullest extent of usefulness and reliability. We are true believers of the idea that technology development empowers the advancement of science.

“Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies.” Wang, G., McCain, M.L., Yang, L., He, A., Pasqualini, F.S., Agarwal, A., Yuan, H., Jiang, D., Zhang, D., Zangi, L., Geva, J., Roberts, A.E., Ma, Q., Ding, J., Chen, J., Wang, D.Z., Li, K., Wang, J., Wanders, R.J., Kulik, W., Vaz, F.M., Laflamme, M.A., Murry, C.E., Chien, K.R., Kelley, R.I., Church, G.M., Parker, K.K., Pu, W.T. (2014) Nature Medicine, Jun;20(6):616-23. doi: 10.1038/nm.3545. Epub 2014 May 11.