Researchers at the Scheie Eye Institute, University of Pennsylvania, has reported that a mutation-independent strategy for treating autosomal dominant retinitis pigmentosa (adRP) prevents photoreceptor cell death in the retina.  The research team developed a gene therapy approach using a single adeno-associated viral (AAV) system delivering the experimental treatment to a large animal model of RP.  Sub-retinal injections provided a nearly complete suppression of endogenous rhodopsin, then replacing rhodopsin cDNA resulting in up to 30% of normal rhodopsin protein levels.  The study is now posed to pave the way for gene therapy trials within an estimated 5 years.

The technology takes advantage of developing a mutation-independent gene therapy previously identified by researchers in Trinity College, University of Dublin.  In the earlier research, every 3 bases of DNA specify an amino acid and a string of amino acids making up a working protein, such as rhodopsin.  However, the third base of each group of 3 can be changed without altering the structure of the protein, always termed as the “degeneracy of the genetic code”.  The strategy takes advantage of this feature of the human genome by using gene editing to knock out all copies of a given gene and replacing them with a functional gene copy changed at several third base sites. The new replacement functions normally and cannot be knocked down by genetic editing using either antisense, ribozymes, RNAi or CRISPR technology.  The retina represents an ideal target for gene medicine.  It is a readily accessible tissue within a confined chamber composed of mostly non-replicating cells existing in an immune privileged environment.  These characteristics represent significant advantages over other gene medicine targets.

Additionally, there are over 150 different mutations in the rhodopsin gene that may cause retinitis pigmentosa.  Consequently, a gene medicine approach for such a disease could require 150 different therapies.  The suppression and replacement approach overcomes this difficulty through allowing a single treatment to treat all 150 different mutations (or patients). A significant advantage of this mechanism is that it is entirely independent of an individual’s mutation.  Rather than focusing on each specific mutation, this approach uses a set of molecular “scissors” (antisense/RNAi/CRISPR) to remove all copies of a particular RNA transcript associated with disease. At the same time as the mutated and normal RNA transcripts are removed a new functioning gene is provided, altered at one or more bases, such that its transcript escapes excision by the molecular scissors.  This approach circumvents the necessity to address individual mutations and represents the core competitive advantage, i.e., suppression and replacement.  This innovative technology now permits the potential treatment of a wide range of dominant disorders which previously were both clinically and economically unviable.