Medical illustration of a scientist replacing part of a DNA molecule with tweezers, representing genome editing.

Once a concept saved for science fiction and superheroes, progress in the gene therapy field has brought human DNA modification into the realm of reality. Researchers have made tremendous breakthroughs in treating inherited diseases by replacing, repairing, or reconstructing defective genetic material in cells. For spinal muscular atrophy (SMA), a progressive motor neuron disease, developing a gene therapy that edits the DNA may be the key to correcting an evolutionary genetic mistake. 

In patients with SMA, mutations in the SMN1 gene lead to loss of SMN protein expression, causing life-long muscle wasting and weakness, and respiratory insufficiency in infancy. As a result, SMA is the most frequent genetic cause of infant mortality.1,2 To improve motor function and prognosis for patients, current treatments for SMA increase SMN protein levels by targeting SMN1 or the related SMN2 gene. Such therapeutics often require repeated drug administration, and only partially recover normal SMN protein levels.1,2 “Those treatments have really benefited thousands of SMA patients…and I think they will continue to be used,” explained David Liu, a professor at Harvard University who specializes in developing gene editing approaches aimed at therapeutic discovery. “I think even with these three existing therapies, there may be a need for a one-time permanent treatment.”

See "Targeting a Genetic Accident to Treat Disease"

In a study published in Science, Liu’s research group took a thorough approach to developing such a treatment.3 His team investigated 79 editing strategies to more permanently restore SMN levels in cells and translated the most effective method into an SMA mouse model. “The two students who co-led the work, Mandana Arbab and Zaneta Matuszek…were incredibly hardworking and insightful in leading this project,” said Liu “I really admire the fact that they took this kitchen sink approach of let's not leave any stone unturned.” 

I think even with these three existing therapies, there may be a need for a one-time permanent treatment. 
–David Liu, Harvard University

The most effective strategy that the researchers found relies on a CRISPR-based technology called base editing, which they used to target and change a coding point mutation in a defective copy of SMN1 called SMN2. Every human has at least one copy of the SMN2 gene, and although protein made from this gene is typically rapidly degraded and does not completely compensate for SMA mutations, SMN2 expression does produce some full-length SMN protein. The number of SMN2 gene copies, which varies from person to person, affects disease severity—more SMN2 copies leads to more SMN protein and milder forms of SMA in the presence of SMN1 mutations.1,2 Building on this idea, the researchers found a base editing strategy that effectively converted SMN2 to SMN1 and fully restored normal SMN protein levels in cultured cells.

Using an adeno-associated virus (AAV) delivery system, the researchers administered a single dose of the base editor components to the SMA mice. This treatment improved motor function and extended lifespan in the mice, but the improvement was more lackluster than the researchers expected based on the SMN protein levels their strategy produced. “We realized that this SMA mouse model develops very quickly, and the therapeutic window for rescuing the motor neurons before their fate is sealed is about six days,” said Liu. “But we know from our past work that base editing delivered by an AAV in a mouse takes more like one to three weeks.” 

To expand the mouse model’s brief therapeutic window, Liu’s team paired their strategy with a breakthrough SMA therapeutic, nusinersen—an antisense oligonucleotide that targets SMN2 splicing and improves survival and motor function in SMA patients. This combination gave the base editor time to act, which enhanced survival to an average of 111 days versus 17 days for untreated mice and 28 days for nusinersen-only controls.

See "A CRISPR Alternative for Correcting Mutations That Sensitize Cells to DNA Damage"

Nusinersen treatment is typically delivered by continued spinal injections throughout a patient’s life—a repetitive process that gene editing has the potential to eventually bypass. “It's fantastic work and I think SMA has been such an amazing disease in which to really further all of these different novel therapeutics platforms," explained Charlotte Sumner, professor of neurology and neuroscience at Johns Hopkins University, who was not involved in the study. "It's allowed proof of concept for all these different kinds of [therapeutic] ways of altering either RNA or DNA, and this is the latest example. It's exciting to see."


  1. I.E.C. Verhaart et al., “Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review,” Orphanet J Rare Dis, 12(1):124, 2017. doi: 10.1186/s13023-017-0671-8
  2. D.M. Ramos et al., “Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment,” J Clin Invest, 129(11):4817-31, 2019. doi: 10.1172/JCI124120
  3. M. Arbab et al., “Base editing rescue of spinal muscular atrophy in cells and in mice,” Science, online ahead of print, eadg6518, 2023. doi: 10.1126/science.adg6518
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