Onasemnogene abeparvovec

Spinal muscular atrophy is a genetic disorder caused by mutations in the SMN gene, which encodes the SMN protein. SMN protein is found ubiquitously but it is highly expressed in the spinal cord where it is responsible for the survival and maintenance of specialized nerve cells called motor neurons. SMN1 and SMN2 genes encode the SMN protein but many mutations in the SMN1 gene have been found to cause spinal muscular atrophy, as SMN1 is the primary gene responsible for functional production of SMN protein. A common mutation that causes spinal muscular atrophy involves a bi-allelic deletion of exon 7 in the SMN1 gene. The number of copies of the SMN2 gene varies among individuals: while higher number of SMN2 gene copies may protect against SMN protein deficiency caused by SMN1 gene mutations, it is generally proposed that the bi-allelic mutation in the SMN1 gene cannot be compensated by the SMN2 gene. The mutation results in insufficient SMN protein expression and inefficient assembly of the machinery needed to process pre-mRNA for motor neuron development and survival. Spinal muscular atrophy involves a progressive degeneration and loss of lower motor neurons, leading to muscle weakness and atrophy.

Onasemnogene abeparvovec is gene therapy that consists of a recombinant self-complementary adeno-associated virus serotype 9 (AAV9) as a gene delivery vector, which contains a transgene encoding the human survival motor neuron (SMN) protein. AAV9 is commonly used in gene therapy applications because it is capable of crossing the blood-brain barrier and transducing neurons in the CNS. After administration, this viral vector is shed and a copy of the gene encoding the human SMN protein is delivered, leading to cell transduction and expression of the SMN protein.