SUMMARY:
Nuclear respiratory factor (NRF) -array promoter has been shown to drive transdifferentiation of alpha cells into beta cells. Production of beta cells could allow for treatment in type 1 diabetes. Additionally, in type 2 diabetes rejuvenation of beta cells could improve patient outcomes through conversion of alpha cells into insulin-producing and insulin secreting cells.Advantage
The NRF shortened promoter significantly decreases the number of base pairs required in a sequence allowing for the development of double stranded AAV viruses including NRF promoters, Pdx1 and MafA transcription factors to convert human alpha cells to insulin producing and secreting cells facilitating the treatment of diabetes.
In vivo testing has been carried out. Human studies are required for further optimization of treatment plan and approach.
Various AAVs have been synthesized with gene inserts containing shorter (4x) or longer (10x) NRF promoter, Pdx1 and MafA sequences, containing <5000 base pairs (bps).
Infection of human alpha cells with AAVs containing these specific gene inserts have been shown to lead to the secretion of insulin within 2 days, demonstrating the potential for double-stranded AAV vectors for use in gene therapy for diabetes.
George Gittes, MD, Department of Surgery and Pediatrics, University of Pittsburgh
Robert David Nicholls, DPhil, Department of Pediatrics, University of Pittsburgh
Ting Zhang, PhD, Department of Surgery, University of Pittsburgh