Gene therapy in the dog model of Sanfilippo B syndrome – GETSAND

Sanfilippo B syndrome (SFB) is a rare recessive genetic disease (approx 1/100 000 life births) due to the deficiency of a lysosomal enzyme that leads to a neuro-developmental alteration appearing early in life, before two years. Subsequent clinical expression of the neurodegenerative process leads to progressive loss of intellectual and motor skills, with brain atrophy. Premature death occurs in the second decade. No therapy is currently available to stop or slowdown the course of the disease. In 2012, we conducted a phase I intracerebral gene therapy trial that has shown promising results in four patients with SFB. Neurocognitive benefit was higher when treatment was given at an early stage but was in all cases only partial, presumably because enzyme was not delivered to the periphery of the brain. We now consider launching a complementary phase I trial combining intracerebral and peripheral delivery of a new AAV serotype, PHPe.B coding for the deficient enzyme. Due to a new vector and a new procedure, we performed a preclinical study on SFB mouse model as well as a biodistribution study on non-human primates. The very promising results push us to confirm these results on a large animal model, the canine SFB model. This model is being imported into our team soon. With our partner at the ICM, and our service provider collaborators, we have all the expertise and equipment to carry out this project, which is divided into 5 axes including dog surgeries, tolerance monitoring, vector biodistribution, anatomopathological study of the brain and peripheral organs to ensure the effectiveness of the treatment and to detect possible insertions of the vector, the quantification of biomarkers of the pathology and finally a proteomic study to identify new surrogate markers for monitoring therapy usable later in children. This project should allow us to confirm our preclinical results in order to be able to propose a therapeutic option for this pathology in the short term.