Teams from Genethon and The Institute of Myology have demonstrated the efficacy of injecting a gene therapy product into the cerebrospinal fluid (CSF) of a spinal muscular atrophy (SMA) mouse model.
Spinal muscular atrophy is related to abnormalities in the SMN1 gene, encoding the motor neuron survival protein, SMN. In SMA, a therapeutic approach involves gene transfer of the SMN1 gene using an adeno-associated virus (AAV), such as AAV9, to produce the missing SMN protein. AAV9 has the advantage of being able to cross the barrier between blood circulation and the central nervous system (the blood-brain barrier). AAV9-SMN thus allows the production of SMN protein not only in the muscle but also in the central nervous system.
Intravenous administration of gene therapy products has been shown to be effective in animal models, however, high doses are required for the SMN protein to be produced in the central nervous system as well.
Administration of a gene therapy product in the CSF is sufficient to improve the clinical signs of SMA mice
Teams of French researchers from Genethon, led by Dr A. Buj Bello, and Institute of Myology, led by M. Barkats, studied the effects of an injection of a gene therapy product, scAAV9.PGKcoSMN1, directly into the cerebrospinal fluid of SMA mice in order to produce a greater quantity of SMN protein in the central nervous system.
The results were published in September 2016 and showed an improvement in the clinical signs of the treated mice as well as an increase in their lifespan (346 days on average). The SMN protein is not only found in the spinal cord but also in the peripheral organs of mice (muscles, heart, liver …).
Intravenous administration of the gene therapy product associated with administration in the cerebrospinal fluid did not increase the effects of gene therapy: the production of SMN protein was not increased in either muscle or heart mouse; However, their life span is shorter (188 days).
A gene therapy trial underway in the United States
A Phase I gene therapy trial is underway in 15 children less than 9 months of age, with type 1 SMA. This open-label trial is designed to test the safety and the efficacy of increasing doses of a gene therapy product, scAAV9.SMN, after a single intravenous administration. Encouraging preliminary results have shown that the gene therapy product has been well tolerated and that the motor function of the participants has been improved.
> On Clinicaltrials.gov : NCT02122952
