The elucidation of the mechanisms underlying maturation/splicing of pre-messenger RNA has opened the prospect of new RNA-targeting allele specific therapies. Effectively, by Watson and Crick pair association, the use of antisense oligonucleotides (ASO) masking splicing determinant sequences allows highly selective rehabilitation of mutated mRNAs.
For example, it is now possible to selectively destroy or correct the reading frame of a target mRNA by the skipping/exclusion of a deleterious exon (e.g., the dystrophin-coding DMD gene in the case of Duchenne Muscular Dystrophy) or the re-inclusion of an exon discarded by the remote effect of a mutation (e.g., the SMN2 gene in the case of spinal amyotrophy - SMA). Specifically, the exonic organization of the dystrophin gene (79 exons) and the fact that the dystrophin protein contains many non-essential areas at its center make DMD a textbook case for the development of therapeutic ASO.
One of the company's flagship activities is the development of a new generation of tricyclo-DNA class (tcDNA), antisense oligonucleotides (ASO), which are third generation non-natural nucleotidic analogs hybridizing with their target RNA with higher affinity in comparison to the existing offer. ASO-tcDNA is compatible with intravenous administration and efficiently reaches the entire skeletal musculature and the heart, the primary targets in Duchenne Muscular Dystrophy.
The company has perpetuated this technology by increasing its capacity for large-scale synthesis of tcDNA phosphoramidites required for the production of ASO-tcDNA; it has also designed several ASO candidates, among which the first one targeting exon 51 of the DMD gene in the case of Duchenne Muscular Dystrophy, which is in development for a Phase 1/2a clinical trial in the future. Finally, this knowledge is transposable to other diseases for which new ASO-tcDNA are being developed.
They are capable of transducing numerous post-mitotic cell types; the vector genome persists as an episome, thus reducing the risk of insertional mutation; large-scale production in bioreactors is now possible. However, since vectors are generated by living technology (e.g., produced by cells), the batch quality is inevitably variable. In addition, there is the limitation that, given the current state of the art, AAV vectors can only be administered to naive subjects (i.e., seronegative subjects who have never been exposed to a vector related virus and who do not have antibodies neutralizing the therapeutic gene vector).
The challenge of our second line of research lies in the design of a new type of vector combining the advantages of AAV vectors and synthetic vectors from organic chemistry. The objective is to create a production technology that is as free as possible from living technology to produce batches of vectors of consistent quality, ideally non-immunogenic in order to authorize recurrent treatments if necessary, or to escalate doses, a therapeutic approach that is impossible with the current AAV vectors.