Spinal muscular atrophy type 1, once uniformly fatal by age two, is now treatable with a single intravenous infusion of a gene therapy called onasemnogene abeparvovec (Zolgensma) that delivers a functional copy of the missing SMN1 gene. The pivotal single-dose trial by Mendell and colleagues, published in the New England Journal of Medicine in 2017, showed that all 15 treated infants were alive and free of permanent ventilatory support at 20 months of age, an outcome unheard of in the disease’s natural history. The transformation is one of many that place rare diseases, most of them driven by single-gene defects, at the frontier of genetic medicine.
Rare diseases are individually uncommon but collectively common
The Rare Diseases Act of 2002 codified the US definition first laid out in the 1983 Orphan Drug Act: a disease that affects fewer than 200,000 people in the United States. The European Union uses a prevalence threshold of fewer than 1 in 2,000. The individual disease may be extraordinarily rare, sometimes fewer than a hundred known cases worldwide, but the sum is not. The FDA now counts more than 10,000 identified rare diseases, together affecting an estimated 30 million Americans and about 300 million people worldwide. About half of those affected are children. Many rare diseases are chronic, progressive, and life-threatening, and about 95% currently have no FDA-approved treatment specifically for them.
Most rare diseases are genetic, and most of the genetics is simple
Roughly 80% of rare diseases are genetic in origin, and a large fraction of those follow classic single-gene (Mendelian) inheritance: one defective gene produces one specific missing or malfunctioning protein, which produces the disease phenotype. That structure is different from most common diseases, in which small effects from many genes combine with environmental exposures. Single-gene diseases are cleaner scientific targets. If the causal gene can be repaired, silenced, or supplied in a working copy, the disease can potentially be reversed or prevented, an approach that runs into much greater complexity when hundreds of genes contribute individually small effects.
The Orphan Drug Act reshaped the incentive structure
Before 1983, the pharmaceutical industry had almost no financial reason to develop drugs for patient populations of a few thousand people. The US Orphan Drug Act changed the calculus by offering three specific benefits to sponsors of orphan-designated drugs: a 25% tax credit for qualified clinical trial costs (originally 50%, reduced in 2017), waiver of the FDA user fee for the orphan indication, and seven years of market exclusivity independent of patent status. The result is measurable. From 1973 to 1983, the FDA approved only 10 drugs specifically for rare conditions; since 1983, it has approved more than 800 orphan-designated drugs and biologics for over 250 rare diseases.
Spinal muscular atrophy is the clearest recent example
Spinal muscular atrophy (SMA) is a genetic motor neuron disease caused by biallelic mutations in the SMN1 gene, which encodes the survival motor neuron protein required for motor neuron function. Type 1, the most severe form with onset in the first six months of life, was uniformly fatal by age two before disease-modifying therapy became available. Three drugs, using three different genetic approaches, are now FDA-approved. Nusinersen (Spinraza), an antisense oligonucleotide given by lumbar puncture, was approved in 2016 and modifies splicing of the backup SMN2 gene to produce more functional SMN protein. Onasemnogene abeparvovec (Zolgensma), a one-time intravenous gene therapy delivering a working SMN1 gene through an adeno-associated virus, was approved in 2019. Risdiplam (Evrysdi), an oral small molecule that also modulates SMN2 splicing, was approved in 2020. In the pivotal STR1VE trial of Zolgensma, 91% of treated infants were alive without permanent ventilation at 14 months of age, compared with about 8% in historical natural-history cohorts. Jerry Mendell, the principal investigator on the phase 1 trial, told Neurology Today that “the findings put gene therapy in a special place in the history of medical interventions. We have changed the name of the game for children with SMA and possibly for similar types of genetic neuromuscular diseases.”
The technology suite is broader than any single approach
The modern rare-disease pipeline draws on tools that were not clinically available a decade ago. Antisense oligonucleotides are short synthetic DNA sequences that bind to specific messenger RNA molecules and change how they are read or degraded. RNA interference drugs silence gene expression using the cell’s own regulatory machinery. Adeno-associated virus (AAV) gene therapy delivers a working copy of a gene into cells. CRISPR-based editing rewrites the underlying DNA. Enzyme replacement therapy supplies missing metabolic enzymes directly. Each has its indications, delivery routes, and durability profiles, and choosing among them for a given disease is now part of the design work of drug development.
Diagnostic delay remains a major problem
The average person with a rare disease waits four to seven years for a correct diagnosis, according to patient surveys, and often sees six or more physicians in the process. Genomic sequencing is closing this gap. Whole-exome and whole-genome sequencing, once research-only tools, are increasingly used clinically to identify causal mutations in undiagnosed patients. The NIH Undiagnosed Diseases Network has demonstrated that systematic sequencing plus deep phenotyping can produce a diagnosis in about a third of previously unsolved cases.
What the evidence cannot yet answer
Rare-disease therapies now include some of the most expensive drugs ever priced: Zolgensma’s list price is about $2.1 million per dose. Whether health systems will sustainably pay for these therapies as the pipeline expands is unresolved. Long-term durability of gene therapies is not yet known beyond the follow-up periods of the pivotal trials. And the successes so far have concentrated in diseases with clear single-gene mechanisms and available delivery routes; extending them to conditions that are rare but genetically complex, or where the target organ is harder to reach, remains an unsolved problem.
References
- Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine, 2017; 377: 1713-1722. DOI: 10.1056/NEJMoa1706198
- US Food and Drug Administration. Rare Diseases at FDA. Available at: fda.gov
- US Food and Drug Administration. Designating an Orphan Product: Drugs and Biological Products. Available at: fda.gov
- National Organization for Rare Disorders. Rare disease facts and definitions. Available at: rarediseases.org