This is what the Chief Research Officer for the Foundation Fighting Blindness had to say about ddRNAi treating RP and Cone-Rod Dystrophy.
"To shut down the GCAP1, Dr. Baehr developed a gene therapy which produces messages known as short-hairpin RNA (shRNA). The shRNA block GCAP1’s naturally occurring RNA messaging system, rendering the gene inactive.
“What is most impressive about this gene therapy approach is its simplicity,” says Stephen Rose, Ph.D., chief research officer of the Foundation Fighting Blindness. “The strategy of shutting down the gene altogether will not work for a vast majority of other retinal degenerations, but for GCAP1, it is the most straightforward therapeutic path, so it makes sense to take it.”
While only at the pre-clinical stage, this research is just more evidence of the potential for ddRNAi to be a major technology in the treatment of eye diseases.
The research was carried out by the University of Utah and can be found at:
The experimental goal was to test whether allele-specific or nonallele-specific knockdown of a dominant GCAP1 mutant is able to ameliorate photoreceptor dystrophy. We demonstrated the feasibility of shRNA knockdown first with an allele-specific approach in a retinitis pigmentosa mouse model expressing GCAP1(Y99C). A scAAV robustly expressed shRNAs in photoreceptors at 1 week post-injection and gene silencing activity persisted as long as 1 year without any apparent off-target interference. Delayed disease onset, significantly improved rod photoreceptor survival and increased visual function support that the methodology can be useful for human gene therapy.
For nonallele-specific knockdown, we generated a sophisticated set of transgenic mouse models expressing GCAP1-EGFP fusion proteins with and without L151F mutation. The L151F mutation, discovered in our lab, was shown to cause dystrophy in two unrelated families. Nonallele-specific shRNA knockdown of both wild-type and mutant GCAP1s may serve as a therapeutic strategy to rescue the dominant degeneration caused by any of the eleven known EF-hand GCAP1 mutations. An advantage of dominant GCAP1 mutations is that a nonalle-specific approach promises to be successful, while mutations in other CORD genes require gene replacement to rescue the disease. Successful knockdown by RNAi suppression of both wild-type and mutant GCAP1s may be a potent therapeutic strategy, applicable to all affected family members with CORD based on GCAP1 mutations in EF3 and EF4, as long as the shRNA guide strand is located external to the disease-causing mutations.
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