Researchers at The Ohio State University Wexner Medical Center are connecting the dots between the past and the future of gene therapy for spinal muscular atrophy (SMA), looking for ways to improve quality of life for patients. 

“We are leveraging past successes in gene therapy for spinal muscular atrophy to apply to other neuromuscular and neurodegenerative diseases, including loss of muscle function during aging,” says W. David Arnold, MD, a physiatrist and neuromuscular specialist at Ohio State. 

A timeline of gene therapy research at Ohio State:

  • 1995: The Survival Motor Neuron (SMN) gene was discovered as the cause of SMA.
  • 2000: Report of the first animal model of SMA was published by an Ohio State team led by Arthur Burghes, PhD. 
  • 2005: The most commonly used animal model of SMA was published by an Ohio State team led by Dr. Burghes.  
  • 2001: Researchers from Ohio State and Nationwide Children’s Hospital first showed the ability of gene therapy to rescue the phenotype in SMA mice. The SMA mice usually lived for two weeks; after treatment, they lived up to 500+ days. This was the first dramatically effective therapy in spinal muscular atrophy in a preclinical study. 
  • 2010: The first antisense oligonucleotide therapy studies were published. 
  • 2013-2015: The Ohio State team developed a pig model of SMA and showed that gene therapy could prevent SMA symptoms in a large animal model. 
  • 2016: The Food and Drug Administration (FDA) approved SPINRAZA, an antisense oligonucleotide therapy. 
  • 2017: Results of the first-in-human clinical trial of gene therapy for SMA were published by a team of researchers at Nationwide Children’s and Ohio State.
  • May 2019: The FDA approved gene therapy Zolgensma (onasemnogene abeparvovec-xioi), which uses adeno-associated virus subtype 9 to deliver the SMN gene to SMA patients. 

Treatment options for spinal muscular atrophy 

There are two SMN genes that produce the protein that is low in spinal muscular atrophy patients: SMN1, which is efficient at making the protein, and SMN2, which is only about 10% as efficient. Current treatment options for spinal muscular atrophy include:

  • Gene therapy (FDA-approved): A one-time treatment in which a virus is delivered systemically to replace the SMN gene. The goal of gene therapy is to replace SMN1. Currently, gene therapy is approved only for children under age 2. This method requires a significant amount of the virus, which is why it’s not yet feasible to treat adults.
  • Antisense oligonucleotide (FDA-approved): An injection delivered into the spinal fluid several times a year. The goal of this treatment is to make SMN2 more efficient, like SMN1. Antisense oligonucleotide doesn’t distribute well throughout the body, which is why it must be injected into the spinal fluid. Many SMA patients must receive the injection in the neck because of previous spinal fusions or scoliosis. 
  • Small-molecule oral medication (under FDA review): An oral medication that must be taken daily for life. Like antisense oligonucleotide, this medicine helps the SMN2 gene produce protein more efficiently like SMN1. 

“Fortunately, there are multiple strategies available for SMA treatment,” Dr. Arnold says. “Gene therapy and small-molecule medication have some potential advantages over the antisense oligonucleotide approach. Gene therapy is a one-time treatment by intravenous injection and the small molecule treatment is an oral medication that is taken daily. I predict the antisense oligonucleotide will be less frequently used once the small-molecule drug is approved, as this therapy requires an intrathecal injection.” 

Gene therapy research in the future 

Ohio State is conducting a number of ongoing studies looking at gene therapy for other neuromuscular diseases, including another type of SMA (SMARD1) and Charcot-Marie-Tooth disorder, a degenerative nerve disease. Additionally, Dr. Arnold, who is an associate professor – clinical at the College of Medicine, is investigating genetic-based therapies to improve age-related loss of physical function.

“Gene therapy is being used for many different applications,” he says. “The technology for hitting the right cells and having the right dose is still in progress so that it can be applied to more diseases. There are different strategies for different diseases, and other Ohio State researchers are studying how best to deliver gene therapies to address different disorders.”

Reflecting on decades of research

“I was part of several of the pivotal preclinical studies, as well as the first-in-human clinical study, and was fortunate to be able to see the whole progression,” Dr. Arnold says. “There were days when I worked on all three studies (mouse, pig and human) on the same day. It was like I was stepping through different phases of the future.”

He was able to see firsthand what a difference gene therapy made in the lives of young patients.

“I got to see the first 15 babies who were treated with gene therapy every three months as part of the initial phase 1 study,” Dr. Arnold says. “They had this disease with a life expectancy of eight to 10 months, and we were seeing some of these children walking, talking and eating. Looking back, I don’t think I knew how amazing and historic it really was.”

 

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