Recombinant Adeno-Associated Virus Serotype 9 Gene Therapy in Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11,000 live births and before the era of treatment SMA was a leading genetic cause of mortality in infants. Recently, disease modifying therapies have been introduced in clinical practice. They include intrathecal and oral antisense oligonucleotides binding to pre-mRNA of SMN2 gene and increasing the translation of fully functional SMN protein as well as SMN1 gene replacement therapy. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trials showed that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA. Currently, phase 3 trials in SMA1 and SMA2 patients, as well as presymptomatic infants diagnosed with SMA, are ongoing. The drug was approved for medical use in the US in 2019, and in Japan and the European Union in 2020. Thus, first real-world data on efficacy and safety of onasemnogene abeparvovec in SMA patients are available.

Adenovirus type 34 and HVR1-deleted Adenovirus type 5 do not bind to PF4: clearing the path towards vectors without thrombosis risk

“…Future developments on polymer modification of non-Ad5 types will be required to assess its full potential, notably in the context of repeated Ad delivery as often required by vaccination or therapy regimens. Thrombotic disorders have been associated not only with adenoviral vaccines, but also adenoassociated gene therapy vectors (AAVs) (27). Even though the AAV-associated thrombotic microangiopathy differs from the Ad-related VITT in its clinical presentation, it is striking that the AAV9 type associated with all identified cases binds to PF4 (28).…”

Gene Therapies for Spinal Muscular Atrophy and Duchenne Muscular Dystrophy: A Pathbreaking Moment in Therapeutics

“…This therapy uses viral vectors to convert the mutated or unstable gene into a stable gene [24]. Viral vectors are researched extensively and are one of the safest and most effective carriers [24][25][26].…”

“…Based on the serotypes of AAV which are from 1 to 13, AAV9 has the highest capability for reaching the CNS [24]. Recombinant AAV9 serotype vector based onasemnogene abeparvovec (zolgensma) was approved by FDA in May 2019 in the treatment of SMA [26].…”

“…The efficacy of this drug was also documented with a single-dose, the systemic administration i.e., intravenously or intrathecally. Further, the systemic route targets the motor neurons directly and widespread CNS biodistribution [22,25,26]. When given intravenously, it targets all regions of the central nervous system's neurons including the alpha motor neurons.…”

“…The most reported adverse reactions are elevated liver transaminases, acute liver injury, thrombotic microangiopathy, high troponin levels and thrombocytopenia. Regular monitoring of cardiac function, complete blood count and liver function are needed for 3 months of drug administration [26]. Prednisolone was used in the START trial, after the first patient reported an elevation of liver enzymes 16 times more than normal [35] (Table 1).…”