The CMT Research Foundation, in partnership with the 1J Foundation, has funded a new study at the University of Miami led by Dr. Stephan Züchner to evaluate a newly-identified genetic variant linked to Charcot-Marie-Tooth disease type 1J and to test whether a targeted genetic medicine can address it.
CMT1 is the type of CMT that damages the protective coating around nerve fibers, disrupting the electrical signals nerves use to control movement and sensation. Researchers identified a recurring variant of ITPR3 gene in 31 individuals across eight different families, all of whom presented with the slowed nerve conduction velocities characteristic of CMT1. The same variant, T1424M, appears independently across multiple families, making it a specific and compelling target for development of a genetic medicine.
Previous work in Dr. Züchner’s group focused on three pre-clinical models of this gene to understand the function of ITPR3 and what can go wrong when it is altered. These studies ruled out one initially promising approach called “exon skipping” whereby the region of the gene containing the mutation is removed in the process of making the ITPR3 protein.
In mice designed to model this exon skipping strategy, the function of the ITPR3 protein was compromised, proving to researchers that this exon is critical.
Moving forward, the team will use antisense oligonucleotides, or ASOs, short synthetic molecules already in clinical use for other neurological diseases, which can be designed to selectively dial down the faulty T1424M version of the gene. The team will optimize these ASOs in preclinical cell models and then move into early in vivo studies, building the foundation needed to attract a commercial development partner.
“ITPR3 represents a significant cause of CMT1 and the recurring T1424M allele is a specific target for ASO technology that is already in clinical use.”
Dr. Stephan Zühhner, University of Miami
Because ASO technology is already an established clinical tool, a well-supported preclinical case for this target has a realistic path toward partnership and, ultimately, patients.
