NATIONAL HARBOR, Maryland — Gene editing is one of the more recent novel approaches in the world of rare disease therapies. At the 2021 World Orphan Drug Congress, LogicBio Therapeutics presented its innovative nuclease-free approach to gene editing called GeneRideTM, which involves a synthesized viral vector to deliver the corrective transgene to a precise and predetermined location on the patient’s chromosome.
According to CEO Frederic Chereau, GeneRide is a direct response to the question, “Can we do better than naturally occurring capsids?” He explained that “naturally occurring capsids may not be sufficient for patients.” Therefore, it is important to design and manufacture the capsids demonstrating the best efficacy for targeting tissue and penetrating cell membranes.
GeneRide is a manufactured viral capsid enclosing the corrective transgene for the rare disease being treated. The transgene itself is composed of strands of DNA anywhere from 500 to 1500 nucleotides long. This transgene is delivered to the patient in a single therapeutic infusion.
The efficacy and safety of GeneRide in the treatment of pediatric methylmalonic acidemia (MMA) is currently being tested. LogicBio researchers are also examining its possible use in treating Pompe and Fabry diseases, hemophilia B, and alpha-1-antitrypsin deficiency (AATD).
The treatment operates within 2 main platforms — the gene editing platform and the adeno-associated virus capsid platform. The capsid allows targeted cell entry and transportation to the nucleus where the fused mRNA genetic material within can be transcribed and translated.
The gene editing portion allows for site-specific recognition and homologous recombination-driven integration into the patient’s genome. The corrective transgene enclosed within the capsid is flanked by the patient’s own specific genome sequence, allowing easier and more natural integration into the patient’s genome.
Once the transgene integration has occurred, the protein of interest is expressed and released into the patient’s circulation as a biomarker of successful genomic integration. These particular proteins — such as albumin, the most commonly produced protein in the liver — are tagged to expedite identification via blood testing.
Ordinarily, corrective genes used in traditional gene therapy do not integrate with the patient’s genome, rather they remain free-floating within the nucleus. Conversely, GeneRide fully integrates into the genome, becoming an inherent part of it and allowing for continued replication of the corrective genetic material. The corrective genome accumulates over time and increases the therapeutic benefit, expressing more and more of the necessary proteins found absent or in deficient quantities due to gene mutations causing rare diseases.
Another feature that makes GeneRide unique, Chereau said, is that it “does not carry a nuclease,” unlike the engineered CRISPR/Cas9 nucleases typically used for gene therapy. Since these nucleases are derived from bacteria, the treatment is at risk of failing due to a strong immune response. GeneRide, being nuclease-free, does not carry that same risk of rejection.
GeneRideTM: an innovative nuclease-free gene editing approach to durably treat pediatric patients suffering from severe early onset disease. Presented at: World Orphan Drug Congress USA 2021: August 25, 2021; National Harbor, MD.
GeneRide. LogicBio Therapeutics. Accessed August 25, 2021.