Mini-PCDH15 for treatment of deafness
T2019-313 A gene therapy solution for Usher Syndrome Type 1F.
Mutations in PCDH15 cause Usher 1F, a recessive syndrome characterized by profound congenital deafness and absence of vestibular function, and progressive blindness beginning in the second decade. Because patients who lack hearing and balance rely on vision for communication and mobility, the late-onset blindness is particularly devastating. Currently, treatment for Usher 1F is limited to cochlear implants, and there is no treatment for the related blindness. Gene addition therapy could be an attractive treatment for those with homozygous recessive mutations. However, the PCDH15 coding sequence of ~5.8 kb is too large to fit into a single AAV capsid, which is limited to ~4.7 kb of transgene. Moreover, although conventional AAV vectors are safe and are currently used in clinical trials, none has led to efficient expression in most types of cells in the inner ear and the cells in the eye. Thus, new therapeutic approaches for the treatment of congential deafness are needed.
Dr. Marcos Sotomayor of the Ohio State University has designed a mini-PCDH15 gene based on the protocadherin-15 protein structural biochemical determinants. The strategically designed mini-PCDH15 gene is small enough to fit into a single AAV genome for delivery into cells of the inner ear across multiple species for the treatment of hereditary hearing loss, for example, as in Usher Syndrome Type 1F. The mini-PCDH15 construct demonstrated functional competency in multiple aspects when evaluated in vitro. The constructs were then evaluated in a floxed mouse having hair cell-specific knockout of PCDH15. AAV was injected into the inner ear of mice. Treated and untreated mice were evaluated using functional and behavioral readouts of auditory function. Treated mice showed significant improvements compared to controls. Thus, this invention may be a viable therapeutic for the treatment of Usher Syndrome Type 1F.
- Gene therapy solution to incurable disease
- Strong intellectual property position
Stage of Development
- pre-clinical, target validation
- in vitro and in vivo studies
- International Patent Application filed (currently unpublished)