Therapeutic advancement in spinal muscular atrophy

Recent advances in therapeutic approaches for spinal muscular atrophy (SMA) were highlighted by Prof. Sabrina Sacconi (Nice University Hospital, France). The focus was on genetic underpinnings, current therapies, and future perspectives for this debilitating neuromuscular disorder.

SMA pathology is predominantly due to a deletion in exon 7 of the SMN1 gene, seen in 95% of cases. The SMN protein plays a critical role in several cellular processes, including ribonucleoprotein assembly, RNA transport, protein translation, endocytosis, autophagy, and mitochondrial homeostasis.

Three main current therapeutic strategies were discussed by Prof. Sacconi [1]. Nusinersen is an antisense oligonucleotide therapy that enhances the inclusion of exon 7 in the nearly identical paralogue SMN2 mRNA , leading to increased production of functional SMN isoform. Clinical trials, including the ENDEAR and NURTURE studies, have shown significant motor function improvements and increased survival rates in infants treated early [2,3]. Risdiplam, an oral SMN2 splicing modifier, has demonstrated efficacy in increasing SMN protein levels systemically, including within the central nervous system. Clinical trials such as FIREFISH and SUNFISH indicate sustained improvements in motor milestones and functional outcomes in both pre-symptomatic and symptomatic patients [4,5]. Gene therapy with onasemnogene abeparvovec uses an adeno-associated virus (AAV) to deliver a functional copy of the SMN gene, dramatically altering the disease trajectory. Onasemnogene abeparvovec has been shown to improve survival and motor function in SMA1 patients; 15 out of 15 trial participants were event-free at 13.6 months [6].

Prof. Sacconi underscored the need for early intervention, highlighting the benefits of newborn screening programs globally. Future directions include improving drug delivery systems, optimising dosing, and developing combination therapies to address multiple aspects of SMA pathology. Ongoing trials like DEVOTE (NCT04089566) and MANATEE (NCT05115110) are exploring higher doses and combination regimens to enhance therapeutic outcomes.

“We are entering a new age of molecularly targeted therapies for inherited diseases of nerve and muscle,” said Prof. Sacconi. Continued research and development are essential to further refine these therapies and expand their accessibility. Comprehensive newborn screening and personalised medicine approaches remain critical components for early and effective intervention in SMA.

1. Sacconi S. From gene to RNA therapies: New treatment horizons for genetic neuromuscular disorders. 10th EAN Congress, 29 June–2 July 2024, Helsinki, Finland.
2. Finkel RS, et al. N Engl J Med 2017 Nov 2;377(18):1723-1732.
3. De Vivo DC, et al. Neuromuscul Disord. 2019 Nov;29(11):842-856.
4. Darras BT, et al. N Engl J Med 2021 Jul 29;385(5):427-435.
5. Mercuri E, et al. Lancet Neurol. 2022 Jan;21(1):42-52.
6. Strauss KA, et al. Nat Med. 2022 Jul;28(7):1390-1397.

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Posted on 25 July 202426 July 2024