AAV hamartin gene therapy in a stochastic, cerebral mouse model of tuberous sclerosis type 1.

Tuberous sclerosis complex (TSC) is a dominantly inherited disease in which most individuals are born with one defective allele encoding for either hamartin (TSC1) or tuberin (TSC2), with a somatic loss of the other allele leading to abnormal neurodevelopment and upregulation of cell growth in susceptible tissues. Ninety percent of affected individuals have brain involvement, including epilepsy, cognitive impairment, autism, and/or sleep disorders. In the stochastic, cerebral mouse model of Tsc1, loss of function of hamartin is induced in the CNS by injection of an adeno-associated virus (AAV) vector encoding Cre recombinase into the cerebral ventricles of homozygous Tsc1flox/flox mice at birth. In the brain, Tsc1 loss leads to increased proliferation of subventricular zone cells, disrupted neuronal migration and cortical cytoarchitecture, dysmyelination, and microglia-mediated inflammation, ultimately resulting in early mortality. Systemic administration of an AAV9 vector encoding human hamartin at postnatal day 21 significantly ameliorated these abnormalities at 3 and 6 weeks post-injection and markedly extended survival in this TSC1 mouse model. This work reveals the ability of hamartin replacement therapy to reverse some of the brain abnormalities caused by its loss in different cell types and provides support for the potential use of gene replacement therapy in the treatment of TSC1 patients.