Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Jul 23. doi: 10.1038/gt.2017.52. [Epub ahead of print]
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene provides, for the first time, a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.
From the article
THE FUTURE OF SMA THERAPY
The children treated in the recent nusinersen trial showed acceptable tolerance to the intrathecal procedure and the vast majority of serious adverse events reported were disease related. However, it is important to note that these children showed progress but did not achieve completely normal motor function in the timescale reported in the trial, and face an uncertain future as they grow and develop from a baseline of established neuromuscular weakness. Therefore, despite the promise provided by nusinersen, it should be seen as the ﬁrst step in a transformative environment for SMA therapy. There is still much progress to be made and a number of other approaches are under investigation, including modiﬁed ASOs to increase cell penetration, oral small molecule approaches aimed at increasing SMN levels, and virally delivered gene replacement therapy (a list of ongoing clinical trials in SMA is available at https://www.clinicaltrials.gov/). It will be difﬁcult to recruit any drug naïve patients in which these agents can be tried, making it challenging to identify the clinical effectiveness of newer agents, except perhaps as adjunctive therapy. Clinical trial methodology in SMA will have to accommodate this complexity, as it will not be ethically acceptable to prevent subjects in new trials taking an established therapy, if available. Trials and protocols of combinatorial therapies aiming for synergies and complementation are envisaged. It remains possible that SMN restoration might not be a sufﬁcient therapy for all patients with SMA, either because it functions in a time-dependent window in early development and will never prevent the slow progressive decline seen in older children and adults, or because the typical insidious clinical presentation of milder forms of SMA does not allow early treatment in the absence of post-natal screening. For these reasons, a whole range of other, non-SMN, pathways are under investigation, including those based on modiﬁers of the pathobiology and phenotype. The future of SMA therapy covering the whole period from infancy to late life may well require a range of therapies in combination. Even if SMA can be treated pre-clinically, it is well established that in the most severely affected children, the pathological process begins in utero.15Even with the best approaches to SMN replacement, there may be late effects in neuromuscular weakness due to a reduced functional reserve.