Emergence of Gene-Specific Therapies for SMA Brings Promise, Questions

As the promise of gene-specific therapies continues to unfold for neurological disorders, such as spinal muscular atrophy (SMA), a group of researchers reviewed the latest developments in this field.

Approaches to such therapy typically span 3 classes—RNA interference by antisense oligonucleotides (ASOs) or small interfering RNAs, splice modification by small molecules, and gene (transfer) therapy.

There are several treatments that have made their mark in the SMA space, including the ASO nusinersen, and small molecule risdiplam, which both entered the market and specifically mediate the inclusion of exon 7 into the mature SMN2 mRNA.

While nusinersen is administered intrathecally every 4 months following a 1-year dosing phase, risdiplam is given orally and, according to researchers, could in principle reach all tissues of the body. Fornusinersen, approval for all forms of SMA is expected soon.

Meanwhile, the investigational small molecule branaplam is currently being studied in a phase 1/2 trial.

Although these therapies continue to revolutionize the treatment landscape for SMA, they are not without shortcomings or challenges, researchers yielded. “Although optimism regarding gene-specific therapies is justified, we may not forget that they are still in their infancy and must be considerably improved in many aspects,” they wrote.

For example, most ASOs currently need to be administered intrathecally, which the researchers note presents stress for the patient and creates an infrastructural and financial burden. As a result, the researchers say the success of these therapies relies on the development of suitable vector platforms and conjugate substances capable of penetrating brain or muscle tissue following systemic administration.

Among the most notable approvals for SMA is onasemnogene abeparvovec-xioi (Zolgensma), the first gene therapy approved by the FDA for this population. While the treatment is approved for use in patients with SMA type 1 who are under age 2 without end-stage weakness, a study assessing intrathecal administration of a single dose of the gene therapy was halted by the FDA based on a preclinical study showing dorsal root ganglia mononuclear cell inflammation in non-human primates.

The advent of gene therapies also brings questions regarding genetic testing along with the dilemma of who should be screened.

“While it is unquestionable that newborns should be screened for treatable infantile onset genetic diseases (such as SMA), many questions related to genetic testing of adult-onset genetic diseases for which gene-specific therapies exist remain unresolved,” researchers wrote. “Who shall be tested – only members of families with a known genetic disease or also sporadic patients without a family history? Who shall be treated?”

Reference: Brenner D, Ludolph AC, and Weishaupt JH. Gene specific therapies – the next therapeutic milestone in neurology. Neurol Res Pract. 2020;2:25. doi:10.1186/s42466-020-00075-z