Genetic Engineering of Red Blood Cells for Therapeutic Function

Robert J. Deans Ph.D, Chief Scientific Officer at Rubius Therapeutics, a Cambridge Massachusetts based biotechnology company, started the Emerging Research: Delivery Strategies and Genome Engineering Technologies session by introducing Rubius Therapeutics’ work developing red blood cells (RBC) as a therapeutic agent. Rubius Therapeutics is a Flagship VentureLabs sponsored company that arose from research originating out of Harvey Lodish’s and Hidde Ploegh’s laboratories at MIT. Rubius Therapeutics’ goal is to develop RBCs as a therapeutic delivery vehicle for the treatment of chronic and acute diseases. According to Robert J. Deans, RBCs show great potential as a delivery vehicle as they have have a long persistence time, show a predictable bio-distribution, have a natural immune evasion capability, and confer no risk of oncogenicity. He also spoke at length on the company’s overall process of growing cells derived from Human Stem Cells in vitro and then engineering them to express desired genes so that the product, produced and retained in the RBC, is then delivered by the RBC to the target cells. He finished his talk by presenting research results from a study that used the RBC delivery system to treat phenylketonuria, a disease of the metabolism.

Novel Approaches to Gene Editing and Gene Delivery

The second presentation in the session was delivered by Andrew M. Scharenberg M.D., a Professor of Pediatrics at the University of Washington and Co-Director of the Program in Cell and Gene Therapy at the Seattle Children’s Research Institute. He started his presentation by explaining that main goal of gene therapies is to deliver DNA to the nucleus of the primary cell. However, the current, traditional methods used for delivery are often victims of the response by the innate immune system, and that repeated aggressive immune response my not be well tolerated by the patient. Hence, there is a requirement for a delivery system that can block or evade the immune response. He spoke in detail on his research teams discovery that the the Hepatitis B virus (HBV) had a life-cycle that is amenable to acting as a vector for transgene delivery.  The method he devised does not actually use the virus itself as the delivery agent, but rather components of the HBV along with DNA transposon flanked RNA payloads directed to the genome by co-delivery with transposase mRNA.

Development of Stem Cell Derived Extracellular Vesicles into a Non-Living Regenerative Therapeutic Drug Candidate

The third and final talk in the session was given by Kiel Peck, the Associate Director of Process Development at Capricor Therapeutics Inc. Capricor Therapeutics, a biotechnology company that focuses on the discovery, development, and commercialization of first-in-class therapeutics. Capricor Therapeutics specializes in products that target the prevention and treatment of heart failure and myocardial infarction. They currently have three products under investigation. During his presentation, Kiel spoke in depth about Cardiosphere Derived Cells (CDC), produced from primary cardiac tissue from donor hearts. He went on to explain that what Capricor Therapeutics did was to remove the exosomes, small lipid-bilipid vesicles, from the CDCs. The CDC-derived exosomes are called CDC-EV. The CDC-EV can be used as a non-living cell free technology. He went on to show that treatment with CDC-EV led to cardio-protection in acute models as measured by decreased myocyte death, and was pro-regenerative in a chronic model, indicating angiogenesis occurred. Furthermore, CDC-EV appeared to have anti-apoptotic, anti-fibrotic, immunomodulatory, and wound-healing functions. He went on to explain how Capricor Therapeutics took what was essentially a bench-top production model and scaled this up. He also addressed the testing of a number of parameters including buffer composition, storage stability, particle size, and concentration that the company undertook. Kiel concluded that their manufacturing process showed consistent yield and concentration, and that they were able to produce a final formulation that is sterile, IV approved, and stable.

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