A Gene,A Breakthrough,A Challenge: Lessons From the History of Spinal Muscular Atrophy

In the late nineteenth and early twentieth centuries, genetics was an esoteric pursuit, which began in a monk's gardens with Gregor Mendel's peas. For decades, it languished in obscurity, overshadowed by the insidious ideology of eugenics and far removed from the hustle and bustle of clinical medicine. Genetic illnesses were curiosities to be studied and admired—and ultimately dismissed as untreatable. With the unraveling of the genetic code and the Human Genome Project, the tide turned. Along with disease-modifying treatments came the insight that a genetic diagnosis improves holistic care—providing prognostic information, guiding screening for systemic associations, clarifying the risk of recurrence in the family, and often bringing closure to a long diagnostic odyssey. The story of spinal muscular atrophy (SMA) exemplifies how human genetics, pursued ethically and clinically, can rewrite destiny.

SMA was described as several entities: the severe infantile form (Beevor, Sylvestre), the intermediate form (Werdnig and Hoffmann), and the milder chronic form (Kugelberg and Welander). By a quirk of history, the severe form became known as Werdnig-Hoffmann disease, the intermediate form as Dubowitz disease, and the mild form as Kugelberg-Welander disease. ¹ Over the years, it was recognized that these were different forms of the same illness, which were named as SMA 1, 2, and 3, in decreasing order of severity.

The discovery of the SMN1 gene on chromosome 5q in 1995, followed by the recognition of SMN2 as a modifier gene, marked the turning point in the history of SMA. ² This discovery provoked a spurt of scientific activity, actively seeking the holy grail of human genetics: disease-modifying therapy. Testing for SMN1 deletion gave precise epidemiologic data, revealing that SMA occurs in 1 of 10 000 to 20 000 live births.

Nusinersen, an intrathecal SMN2 antisense oligonucleotide, was approved for treatment of SMA in the United States in 2016 as the first disease-modifying agent.^3,4 Subsequently, 2 other drugs were approved: onasemnogene abeparvovec (an intravenous SMN1 gene therapy) and risdiplam (an oral SMN2 splicing modifier).^5,6,7 There is abundant literature on the efficacy of all 3 drugs.^8–12 Clinical trials on children with presymptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) resulted in them achieving independent sitting and/or walking. ¹³ The success of these trials has paved the way for newborn screening programs for SMA. Newborn screening and presymptomatic treatment are expected to revolutionize the care of SMA.

History teaches us that with great achievements come new challenges. The high cost of these disease-modifying agents has prevented their uniform adoption, especially in low income and lower-middle income countries (World Bank, 2024). Newborn screening programs and early diagnosis are meaningful only when treatment is available and affordable in that setting. Although crowdfunding and compassionate access programs have transformed individual lives, a long-term global plan is essential to ensure equitable and sustained access to these drugs.

Achieving sustained and equitable access requires moving beyond ad hoc compassionate use programs toward established mechanisms. Key frameworks include differential or tiered pricing models, which adjust the cost of medications based on a nation's purchasing power, and the exploration of voluntary licensing and technology transfer to facilitate the production of biosimilars or other affordable versions of therapy in lower- and lower-middle income countries. A crucial step is establishing global consensus on the fair value of these life-saving therapies. Transnational standards can be set through initiatives like the World Health Organization's (WHO) Fair Pricing Forum and by implementing greater price transparency. Although geopolitical realities may limit the engagement of some high-income countries with the WHO, the organization's role as a standard-setter and convener remains relevant. Experience suggests that diversified funding and governance are essential to preserve financial and scientific independence in global health initiatives. The intersection between transnational biopharma companies and national regulatory authorities (NRAs) is a bottleneck for timely access. Although newer medications are often developed by multinational companies, each country's NRA needs to approve the same. Often, this is a lengthy process and many NRAs may lack the capacity for rapid approval of complex genetic therapies. A data-sharing model may help in the rapid approval of such therapies by using the data analyzed by stringent authorities like the US Food and Drug Administration and the European Medicines Agency.

There are studies ongoing to clarify various aspects of SMA treatment, including polytherapy with disease-modifying agents and the long-term and adverse effects of these treatments. Data are being collected from children who were switched from one agent to another. These include the JEWELFISH study (Nusinersen to onasemnogene/risdiplam), the RESTORE registry (Nusinersen as add-on to onasemnogene) and the SRK-015 anti-myostatin study (apitegromab as add-on to Nusinersen).^14–16 Novel drug delivery systems are another focus of study, with intrathecal onasemnogene showing promising results. ¹⁷

We have come far, and there is much further to go. If the past century of SMA shows us how despair can be transformed into hope, the present demands that we transform hope into equitable access. Only then will the story of SMA stand not as a tale of exclusion, but as a testament to how history, science, and ethics together can reshape the destiny of children worldwide.