Funding for spinal muscular atrophy research must continue

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder and is the leading genetic cause of infant mortality [1,2]. SMA is a monogenic disease caused by complete loss of the SMN1 gene and the full-length (FL) functional SMN protein it produces [3]. A recent duplication in the human genome, however, has resulted in a second almost identical copy of SMN1, called SMN2, which, due to a silent point mutation, mostly produces a truncated nonfunctional protein [4]. The SMN2 gene nevertheless retains the ability to generate a small amount of FL protein, thus allowing the survival of individuals born with homozygous deletions/mutations within SMN1 [4]. A total absence of SMN protein is indeed not compatible with life [5]. Furthermore, the number of SMN2 copies varies from person to person and there is a clear and accepted negative correlation between the number of SMN2 copies (i.e., FL SMN protein produced) and severity of disease manifestation [6]. The identification of SMN as the gene that causes SMA dates back to 1995 [3]. Since that seminal discovery, a series of fundamental, pre-clinical and clinical research endeavours have been aimed at identifying and developing pharmacological strategies that could increase SMN abundance, either by exogenously re-introducing the SMN1 gene or by promoting the production of FL SMN protein from the SMN2 gene [7]. This arduous and approximately 25-year journey, which was supported by the entire SMA community (fundamental researchers, clinicians, families, patients and funders), reached its intended goal in December 2016, when the first gene therapy for SMA was approved by the US FDA for all SMA patients. It was subsequently approved by the European Medicines Agency (EMA) in June 2017. The drug, an antisense oligonucleotide that promotes FL SMN expression from SMN2, is sold under the commercial name of SpinrazaTM by Ionis and Biogen [8]. Saying that the approval of SpinrazaTM has changed SMA research would be quite an understatement. It has in fact completely transformed both the SMA therapeutic landscape and the SMA patient population [7,8]. Indeed, in a blink of an eye, we went from having no available therapies to having one with the potential to completely alter the fate of SMA children. Newly diagnosed patients that typically could not expect to live beyond their second birthday, now not only live beyond that timeframe, but do so by reaching motor function milestones that surpass what was ever thought possible [9,10]. Our research and clinical priorities had to therefore naturally adapt and shift overnight [11]. Shift yes, but not stop. Spinraza is an incredible life-changing treatment but, unfortunately, not a cure [8]. Indeed, treated SMA patients can still display neuromuscular symptoms and decline, and for reasons still unknown, patients respond differently to the treatment, roughly dividing into groups of responders that improve, responders that plateau and non-responders [8,12–15]. While recent data support an increased benefit in patients treated pre-symptomatically, the ‘earlier the better’ dogma does not always hold true [8,16]. Furthermore, it remains unclear how Spinraza will be beneficial in older patients, in which significant neuromuscular decline has already occurred, and can most likely not be recovered [8,17]. Thus, more research into factors that influence the efficacy of Spinraza and its impact on different patient populations is of essence [8]. While the issues discussed above relate to Spinraza, similar inquiries and investigations will most likely arise following the approval of other SMN gene therapies (e.g. the Avexis/Novartis AAV9-SMN1 viral therapy and orally available small molecules by Roche and Novartis) that are anticipated to be approved by regulatory bodies