Stem Cell Therapies are Closer to Not Needing Anti-Rejection Drugs

Universal stem cells that would not need anti-rejection drugs would be transformative for regenerative medicine. New research by AgeX and Juvenescence brings us much closer to Universal stem cells. They are getting success modifying the immune signaling molecule that protects the fetus from rejection during pregnancy.

Nextbigfuture interviewed Greg Bailey and Nafees Malik.

Gregory Bailey, M.D., is CEO of Juvenescence Ltd., a biotechnology and investment company focused on longevity therapeutics, and Chairman of AgeX Therapeutics (AGE), a biotech startup focused on extending human healthspan.
Dr. Bailey has been starting and financing life science companies since 1995, with a total combined market capitalization of over $18 billion. In 1995 he co-founded Ascent Healthcare Solutions, which was sold to Stryker in 2009 for $525 million. In 2004, he was the initial financier and a board member of Medivation, Inc., which had a successful IPO before being acquired by Pfizer in 2016 for $14.3 billion. In 2014, Dr. Bailey and his partners capitalized Biohaven Pharma through their investment vehicle, Portage Biotech, with $3.5 million, subsequently adding an additional $3.5 million over the next two years. Biohaven went public on the NYSE in May 2017, and Portage remained its largest shareholder until Biohaven executed a dividend of $210 million’ worth of Biohaven shares to Portage. Dr. Bailey remains a Director as well as a major shareholder of Biohaven, which currently has a market cap of approximately $2.3 billion. A former emergency room physician for ten years, Dr. Bailey received his MD from the University of Western Ontario.

Nafees Malik, MD is Chief Operating Officer at AgeX Therapeutics and Head of Cell & Gene Therapy at Juvenescence, Ltd. Nafees’ 15 year career has involved roles spanning clinical medicine, investment banking, biopharmaceutical companies, research and academic institutions, and strategy consulting. For many years now, he has focused on the strategic and commercial analysis of cell and gene therapies and regenerative medicines. Nafees has an M.D. from the Univerisity of Liverpool and a Master’s degree in Bioscience Enterprise from the University of Cambridge.

Nafees and Greg explained the paper they published in the Regenerative Medicine journal and explained the potential and importance of the work. They have made huge progress toward universal stem cells which would not need the patient to have anti-rejection drugs.

The promise of stem cells is that they could provide healthy cells to treat or mitigate many diseases.

It would be one of the biggest advances toward the wide-spread translation of cell therapies from bench to bedside since the generation of human pluripotent stem cells (hPSCs) of embryonic origin in 1998 and through cellular reprogramming in 2007. Importantly, human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) provide a cell source with unlimited proliferation capacity and a potential to generate any human cell type. A paper outlines the scientific principles underlying the generation of universal allogeneic cells, considers the main comparative strategies that have been explored to date, and discusses recently published experimental data.

Cell therapy can be autologous, where it is derived from a patient’s own cells, or allogeneic, where it is produced from nonself donor cells and where large numbers of doses are generated from one donor to treat multiple patients.

The allogeneic approach is superior almost every way. They are:
high-quality source cells;
industrially scalable and lower-cost manufacturing;
potential to treat genetic disorders with cells free of disease-causing mutations;
commercialization using a simpler ‘off-the-shelf’ rather than a much more complicated ‘service-based’ business model;
availability in acute medical situations;
traditional pharma supply chain logistics;
greater potential for reimbursement prices that are acceptable to payers;
and ease of clinical adoption.

The biggest challenge with allogeneic therapy is the powerful immunological response mounted by the host’s immune system to nonself donor cells, leading to rejection.

Making a universal hPSC (human pluripotent stem cell) line will need one or more of three key engineering strategies: deletion of HLA class Ia/II molecules,
expression of HLA class Ib molecules, and
manipulation of immune checkpoints.

There has been some success reducing or eliminating some of the immune system response. However, there are many immune system cells and previous experiments worked on two or fewer types of immune system cells. The new work could virtually eliminate the immune response and cell rejection in 8 types of immune system cell types.

Immune System Control Molecules

HLA-G is a nonclassical HLA class Ib molecule, which is minimally polymorphic. Its main job is to protect the fetus from destruction by the mother’s immune system during pregnancy. It is the only genuine physiological state of tolerance toward a semi-allograft. HLA-G is strongly expressed on fetal-derived placental cells at the maternal–fetal interface. It is widely considered to be the major driver of tolerance in pregnancy. HLA-G is unique among immunomodulatory molecules in that it has a potent immunosuppressive action on virtually all arms of the innate and adaptive immune systems.

In 2018, the AgeX and Juvenescence group bought patents to a proprietary, novel, modified form of the HLA-G1 gene in order to engineer hypoimmunogenic cells. They call this immunotolerance technology platform UniverCyte™. Previously, in vitro, this modified HLA-G1 gene had been shown to reduce the immunogenicity of hPSCs and their epidermal derivatives, as well as of human dermal fibroblasts, when inserted directly into this nonpluripotent cell type. In both cases, no manipulation of HLA class Ia or class II was performed. Moreover, this modified HLA-G1 gene was strongly resistant to the intense silencing pressure exerted on native HLA-G expression in virtually all human cell types after birth. Hence, the modification allowed for persistent, stable and high expression of HLA-G1, with up to 99% of engineered cells displaying cell surface positivity.

Under normal conditions, HLA-G is not expressed after birth, except in very few immune-privileged tissues, such as the cornea. However, cancer and pathogens utilize it as an immune escape mechanism. Growing evidence supports the role of HLA-G in allograft acceptance in solid organ transplantation.

When an organ like a kidney is transplanted sometimes the donated kidney will produce HLA-G to lower the chance of rejection by the new host.

No approach has been shown to be conclusive in engineering universal cells and many issues remain unresolved.

The most important remaining questions include:
* given their role in eliminating cancerous and pathogen-infected cells, will deletion of HLA class Ia proteins in humans be safe?
* This is particularly important given transplanted cells may remain engrafted for years or decades to come. Which immunomodulatory molecules will prove to be safe and effective?
* Will the expression of one highly potent immunotolerant agent, like HLA-G, acting on multiple arms of the immune system be the optimal strategy?
* Or will a better approach be to knock in several immunomodulatory molecules, with each one providing protection against a specific type of immune cell?
* Given the immune system is highly complex, cross regulated and cascade dependant, are multiple modifications more likely to produce unpredictable and unwanted downstream immunological effects?
* Moreover, will large numbers of gene insertions result in an unacceptable oncogenic risk?

If Universal Stem cells are created then we will be able to make any human cell type, in any quantity, at a reasonable cost, for anyone needing it, without immune system matching or dangerously suppressing the immune system of the patient.

SOURCES – AgeX, Interviews of Greg Bailey and Nafees Malik, Regenerative Medicine paper
Written By Brian Wang, Nextbigfuture.com

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