Science Spotlight: Delivering full-length dystrophin, intracellular bioPROTACs, and more

With the controversial approval of micro-dystrophin gene therapy Elevidys from Sarepta Therapeutics Inc. (NASDAQ:SRPT), inducing safety concerns, and the recent Phase III miss of a mini-dystrophin gene therapy from Pfizer Inc. (NYSE:PFE), strategies that enable expression of full-length dystrophin are needed. The hypothesis is that it may require restoration of the full protein to achieve full protein functionality in patients with Duchenne muscular dystrophy. 

A University of Washington team described in Nature a method to produce large dystrophin proteins that involved splitting the gene’s coding sequence into two or three parts that are separately delivered via AAVs, then reconstituted into a single protein in vivo. The reconstitution was accomplished via polypeptide elements known as “split inteins.” Each half of a split intein was appended to the ends of dystrophin fragments that needed to be joined. When split inteins come together, they become active, joining the dystrophin fragments and excising themselves from the resulting larger protein (see Figure)...