Novartis is shoring up its portfolio on gene therapies for inherited neuromuscular diseases by acquiring Kate Therapeutics in a deal worth up to $1.1 billion in up-front and milestone payments. The biotech company is developing preclinical therapeutic candidates for Duchenne muscular dystrophy (DMD), facioscapulohumeral dystrophy and myotonic dystrophy type 1. It has also developed a platform for generating adeno-associated virus (AAV) capsids, or outer viral protein shells, combined with machine learning to evolve capsids that target skeletal and cardiac muscle while avoiding the liver. Several AVV-based gene therapies, including Sarepta Therapeutics’ Elevidys (delandistrogene moxeparvovec) for DMD, use naturally occurring AAVs that mostly end up in the liver, requiring high and potentially toxic doses to ensure that enough reaches the muscles. Kate’s co-founder Sharif Tabebordbar, from the Broad Institute of MIT and Harvard, and collaborators showed that when AVV’s capsid is modified to contain cell-adhesive peptides known as RGD motifs, it shuns the liver. The researchers successfully delivered genes to mouse models of genetic muscle disease at around 100-fold lower doses than with regular AVVs. Kate’s platform approach for engineering RGD-modified AAVs — known as DELIVER: directed evolution of AAV capsids leveraging in vivo expression of transgene RNA — can be used for any tissue type.

Also, Regenxbio and Genethon each announced plans for moving into larger trials in DMD. Regenxbio’s RGX-202 uses a conventional AAV8 vector but includes the dystrophin gene’s C terminus to prevent contraction-induced muscle loss. Muscle expression was better than that seen in an Elevidys trial, and in five patients treated RGX-202, the gene therapy led to stable or improved motor ability as compared with natural history controls at nine months. Genethon’s AAV8-based gene therapy GNT0004 allows functional dystrophin protein expression while applying lower AAV doses than those used in other DMD gene therapy trials. In three treated patients, GNT0004 stabilized motor activity at 12 months as compared with natural history controls.