AAV-CRISPR engineering brown-like adipocytes targeting obesity and metabolic disorders

Abstract Obesity and metabolic disorders prevalence has increased dramatically over the last decades. Obesity is a major risk factor for type II diabetes mellitus, hypertension, cardiovascular disease, osteoarthritis, and certain forms of cancer. Despite years of intense studies, there is still substantial need for safe, more effective and more convenient therapeutics for treating obesity. Developing a novel bioengineered brown adipocyte transplant may offer a new paradigm for treating obesity and associated metabolic disorders, which can complement the current standards of care. The present STTR collaborative consortium is based on our previous successfully developed proprietary technologies to generate highly potent brown adipocyte-like cells, so-called HUMBLE cells, from abundantly available white preadipocytes, by using the innovative CRISPR/dCas9-SAM technology. The HUMBLE cells have demonstrated potentially superior efficacy and persistency in vivo than other brown-like cells. The present Phase I study aims to further develop a safer and efficient episomal AAV vector to replace our previous lentiviral system and investigate the applicability of the AAV system to donor-derived, non-immortalized white preadipocytes to mimic real clinical use. The present study will generate new CRISPR-engineered, safer HUMBLE cells suitable for clinical development. Success of the technology will lead to new therapeutics addressing the obese patient needs that existing pharmaceuticals cannot adequately address.