Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders

Abstract

Genetic disorders of the central nervous system (CNS) comprise a significant portion of disability in both children and adults. Several preclinical animal models have shown effective adeno-associated virus (AAV) mediated gene transfer for either treatment or prevention of autosomal recessive genetic disorders. Owing to the intricacy of the human CNS and the blood–brain barrier, it is difficult to deliver genes, particularly since the expression of any given gene may be required in a particular CNS structure or cell type at a specific time during development. In this review, we analyzed delivery methods for AAV-mediated gene therapy in past and current clinical trials. The delivery routes analyzed were direct intraparenchymal (IP), intracerebroventricular (ICV), intra-cisterna magna (CM), lumbar intrathecal (IT), and intravenous (IV). The results demonstrated that the dose used in these routes varies dramatically. The average total doses used were calculated and were 1.03 × 1013 for IP, 5.00 × 1013 for ICV, 1.26 × 1014 for CM, and 3.14 × 1014 for IT delivery. The dose for IV delivery varies by patient weight and is 1.13 × 1015 IV for a 10 kg infant. Ultimately, the choice of intervention must weigh the risk of an invasive surgical procedure to the toxicity and immune response associated with a high dose vector.

A Novel CRISPR-Cas9 Strategy to Target DYSTROPHIN Mutations Downstream of Exon 44 in Patient-Specific DMD iPSCs

“…Although the primary goal of these early clinical trials has been to evaluate the safety and efficacy of AAV micro-DYSTROPHIN, it is difficult to compare outcomes as they differ with respect to AAV serotype, promoter, micro-DYSTROPHIN construct, AAV manufacture, patient age, and targeted mutation [ 17 , 22 ]. While the recent FDA approval of Sarepta’s AAV-based micro-DYSTROPHIN Elevidys is a historic step, AAV gene therapy still encounters several limitations, such as AAV-associated lung, heart, and liver toxicity, which has been fatal for some patients, including DMD [ 23 , 24 , 25 , 26 , 27 ]. Additionally, immune responses pose a current obstacle to the successful treatment of a substantial portion of patients [ 25 , 27 ] due to the considerable number of patients with pre-existing antibodies to AAV [ 28 ] and the inability to redose.…”

“…While the recent FDA approval of Sarepta’s AAV-based micro-DYSTROPHIN Elevidys is a historic step, AAV gene therapy still encounters several limitations, such as AAV-associated lung, heart, and liver toxicity, which has been fatal for some patients, including DMD [ 23 , 24 , 25 , 26 , 27 ]. Additionally, immune responses pose a current obstacle to the successful treatment of a substantial portion of patients [ 25 , 27 ] due to the considerable number of patients with pre-existing antibodies to AAV [ 28 ] and the inability to redose. Thus, while early-stage studies show encouraging results, the field is still actively tackling these hurdles.…”