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Gene therapy is a promising approach for treating a large spectrum of human diseases and particularly monogenic diseases that can be corrected through gene replacement therapy based on introducing a functional copy of the defective gene.

 

Gene therapy for neurodegenerative disorders

Lysogene’s development strategy focusses on diseases with neurological involvement. Our first programs are for neuropathic Lysosomal Storage Disorders (LSD), which are particularly good candidates for gene therapy as the genetic correction of a small subset of neural cells should be sufficient to target large regions of the central nervous system (CNS) as secreted lysosomal enzymes can diffuse and be captured by adjacent and distal cells. Moreover, tight regulation of produced enzyme levels is not required because low levels (about 10%) of enzyme activity is anticipated as sufficient for a therapeutic effect. Furthermore supraphysiological levels of many acidic hydrolases have no deleterious effect.

 

AAV vectors

Lysogene is developing adeno-associated viral (AAV) vectors that have demonstrated their effectiveness in safely delivering genetic material to the CNS. These vectors have been developed from non-pathogenic and replication deficient viruses. They have been used in clinical trials since the mid-1990s treating hundreds of subjects with currently no known related serious adverse events. AAV gene therapy vectors are emerging as the gene transfer vehicle with high potential for use in the CNS as they transduce post mitotic cells that mediate the sustained, long term gene expression required in chronic progressive diseases.

 

CNS administration

Lysogene’s gene therapy route of administration is direct delivery of the vector to the CNS. This may be one of the most efficient methods to treat neurological pathologies of LSDs. The structure of the CNS provides advantages for direct delivery in that vectors can be transported along neuronal connections to distal sites and secreted enzymes can be transported anterograde and retrograde to cross correct cells distal from the injection site. This delivery approach has shown to be safe in several clinical trials in LSDs (Batten’s disease, Canavan disease, MPS IIIA and MPS IIIB), in Parkinson and Alzheimer diseases. Furthermore, direct injection in this small and immunologically privileged site can potentially overcome limitations linked to systemic injection which would require a very high dose to target the CNS and can be neutralized by anti AAV antibodies or may trigger the activation of CD8+ T cell response.

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