A recent demonstration by Van Alstyne and colleagues (1) of long-term toxicity following short-term successful treatment of an animal model of spinal muscular atrophy (SMA) by gene transfer-mediated overexpression of survival motor neuron (SMN) protein raises immediate questions for SMA patients, their families, and advising clinicians. This finding, however, also highlights the limits of safety data associated with any new therapy validated in small clinical trials of a rare disease as well as the potential inadequacy of current procedures for assuring long-term safety in gene-therapy programs under development. Optimal assessment of the safety of rare disease therapies may require improvements at multiple levels of the drug development, regulatory review, and postapproval monitoring processes.
Short versus long-term toxicity
A dramatic success for gene therapy of neurological disease occurred in 2019 when onasemnogene abeparvovec (OA) was found to be both safe and highly effective in treating infants with spinal muscular atrophy (SMA) (2), a recessively inherited motor neuron disease caused by loss-of-function mutations of the survival motor neuron 1 (SMN1) gene. OA consists of a constitutively active cytomegalovirus enhancer/chicken p actin promoter driving a human SMN cDNA transgene packaged within a small nonpathogenic adeno-associated virus 9 (AAV9) vector. AAV9 has particular tropism for motor neurons following a single intravenous administration (3), and the transgene remains episomal, theoretically expressing indefinitely in postmitotic cells. Treated SMA infants, who otherwise would have been destined to relentless progressive weakness and early mortality, instead steadily improve. A principle focus in the development of OA and other gene-therapy programs has been on minimizing short-latency adverse events, including inflammatory and individual idiosyncratic reactions that likely relate to host immune responses to capsid proteins, transgene product, or both (4).
Although the possibility of viral host DNA integration and oncogenesis is a recognized long-term safety concern of gene therapy, Van Alstyne (1) raises a new potential "on-target" mechanism for the long-term toxicity of SMN gene therapy. They demonstrate that while SMA model mice injected with AAV9-SMN via i.c.v. delivery showed the expected amelioration of the motor neuron degeneration disease phenotype during the first weeks and months of disease, they also observed unexpected and novel deterioration in motor behavior between 6 and 10 months in a dose-dependent manner. This was associated with loss of proprioceptive dorsal root ganglion (DRG) neurons and less severe loss of motor neurons. While overexpression of SMN protein has generally been considered to be benign (5), particularly as its stability is associated with incorporation into the multiprotein SMN complex (6), the Van Alsytyne report shows that the gene transfer-mediated high-expression levels of SMN protein in DRG and motor neurons cause SMN aggregation in the cytoplasm with sequestering of components of small nuclear ribonucleoproteins and altered splicing and gene-expression patterns. Together, these findings indicate that sufficiently high unregulated, longterm overexpression of SMN can itself cause neuronal degeneration.
This demonstration in an animal model of long-term toxicity following short-term successful therapy and the proposed mechanism raises plausible concern for similar long-term complications in OA-treated SMA patients. There are multiple reasons...