Our approach is to use miCas9 to develop therapies for Usher Syndrome patients
Usher syndromes are autosomal recessive disorders characterized by progressive loss of hearing, vision, and balance, due to genetic mutations in specific proteins (table below). There are three types of Usher Syndrome, Type 1, Type 2, and Type 3 which differ in the phenotypic progression of disease. Each subtype varies in the causative protein. For example, Usher Type 2A results from mutations in the Usherin gene, while Usher Type 2D results from mutations in the Whirlin gene. Currently, GeneToBe is focusing on therapies for Usher Syndrome Types 2A and 3A.
We recently developed rabbit models carrying the CLRN1 frameshift (Clrn1−/−) or the Clrn1N48K/N48K point mutation. Preliminary characterization of these rabbits has shown that this CLRN1 mutation leads to severe progressive retinal degeneration and hearing loss. To our knowledge, these are the first USH3A animal models that manifest convincing retina degeneration phenotype. We have also developed rabbit models of Usher Syndrome Type 2A with both a hearing and vision deficiency. We intend to use these models to determine the safety and efficacy of our gene-editing platform in treating these diseases.
Reduced field of vision as usher syndrome progresses
Most Usher Syndrome Type 2A’s have a variety of mutations localized to exon 13 in the Usherin gene. A global gene-editing approach for most of these patients may be addressed by a complete replacement of exon 13. Two point mutations in the Clarin1 gene are the major cause of Usher Syndrome Type 3A. The N48K Clarin1 mutation (Ashkenazi form) produces the full-length protein with an altered glycosylation site. This causes the Clarin1 protein to undergo intracellular degradation. The Y176X Clarin1 mutation (Finnish form) introduces a stop-codon and produces a non-functional truncated Clarin1. Usher syndrome patients will usually require cochlea implants by teen years and thereafter have progressive loss of vision by mid-to-late adulthood and will be classified as legally blind. The management of the chronic, progressive, severe vision loss (retinitis pigmentosa) in USH3A remains a challenge.
Hearing impaired patient with cochlear implant