| Coordinating Panel on Rare Neurological Diseases  

Is treatment of SMA with onasemnogene abeparvovec associated with an immune response against the AAV vector?

The world has changed for patients and parents of children suffering from spinal muscular atrophy (SMA) type 1. Without treatment these children usually die around age 7 months, but the availability of Nusinersen which increases the SMN protein production has significantly changed the prognosis of these children.

However, this drug has to be administered intrathecally and every 4 months. Onasemnogene abeparvovec (Zolgensma®) is an adeno-associated viral (AAV9) vector-based gene therapy, which introduces a functional copy of the SMN1 gene into motor neurons by means of a single intravenous injection, thus offering the advantage of a one-off intervention. Clinical trias have been performed on SMA type 1 patients up to the age of 8 months, yet the FDA approved the treatment for all SMA types up to the age of 2 years. EMA even extended the label to all patients either showing a phenotype of SMA type1 or having up to three SMN2 copies, raising the concern about off-target effects due to the dose of the drug being proportional to the body weight leading to higher viral vectors. This study reported preliminary safety findings from a series of eight consecutive patients older than eight months (10-37 months). All patients who had been treated with Nusinursen received the standard dose of onasemnogene abeparvovec and prednisolone treatment which was started on the day before administration of gene therapy. Despite prophylactic steroid treatment all patients showed a (sometimes markedly) increase of transaminase levels, which was associated with impaired liver function in one patient. Asymptomatic throm-bocytopenia was observed in 6 out of 8 patients. According to the authors these findings most likely reflect an acute immune response to the treatment with onasemnogene abeparvovec. The rate of clinical and laboratory findings in this case series is much higher than reported in the pivotal clinical trial conducted by Mendell et al. (1) and may be ascribed to the difference in age and body weight between the two cohorts.

This study states that it shows evidence that treatment of SMA with onasemnogene abeparvovec is often associated with an immune response against the AAV vector which mainly effects the liver and the hematopoietic system, and can be severe in some cases. Another study (2) reporting prospectively collected data on 325 SMA type 1 children (clinical trials or compassionate use) undergoing gene therapy below the age of 8 months showed that 90% had elevated transsaminases after gene therapy of whom 61% already had these elevations prior to dosing. The authors make the case that SMA children may have an impaired fatty acid metabolism and pre-existing liver enzyme elevations may represent underlying liver disease. This could represent a predisposition to acute liver injury challenged by gene therapy. Animal studies showed onasemnogene abeparvovec–related liver damage which are likely associated with hepatocellular uptake of AAV.



  1. Mendell JR, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med 2017;377(18):1713-22.
  2. Chand D, et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol 2021;74 (3): 560-6.