Clinical and Research Progress in Spinal Muscular Atrophy
Spinal muscular atrophy (SMA), a recessively inherited motor neuron disease characterized by progressive muscle weakness and atrophy, is one of the most devastating neurological diseases of childhood. Until recently, there was no treatment.
“It is a very exciting time for SMA because until recently there were no disease-modifying therapies and really no symptomatic therapies,” says Jacqueline Montes, PT, EdD, NCS, a clinical researcher at the Spinal Muscular Atrophy Clinical Research Center and the Pediatric Neuromuscular Clinical Research Network at NewYork-Presbyterian/Columbia University Irving Medical Center.
“It is a very exciting time for SMA because until recently there were no disease-modifying therapies and really no symptomatic therapies.”
— Dr. Jacqueline Montes
Access to Novel Trials
The SMA Clinical Research Center was the first site in the world to administer nusinersen in a clinical trial, before the drug’s 2016 FDA approval. The discovery and approval of nusinersen for the treatment of patients of all ages and stages of SMA has dramatically changed the treatment landscape. The U.S. Department of Health and Human Services has even added SMA as the 35th disease to the Recommended Uniform Screening Panel for newborns. New York is one of a handful of states that has included it in their newborn screening protocol. Because it is important to treat newly diagnosed patients quickly, newborns who screen positive for SMA are referred to academic medical centers or children’s hospitals such as NewYork-Presbyterian to be immediately treated with nusinersen.
“We treated three infants presymptomatically who were likely to develop type 1 spinal muscular atrophy. The patients are now three and four years of age, achieving motor milestones, walking and with no obvious symptoms. It is really quite amazing,” says Dr. Montes, who joined NewYork-Presbyterian in 2007.
Because insurance companies require motor function testing for the reimbursement of costly drugs, Dr. Montes frequently conducts function testing and assists families in negotiating with payors. “We are perfectly equipped to provide motor function testing and can potentially collaborate with regional centers as they treat their patients,” she says.
Currently, researchers at the center are working on a multitude of studies that run the gamut from translational research to pivotal multisite clinical trials that are changing the course of spinal muscular atrophy diagnosis and treatment. Columbia neurologists at the SMA Clinical Research Center were part of the pivotal STR1VE trial that led to the first-ever gene therapy to treat a neuromuscular disease. In 2019, onasemnogene abeparvovec-xioi received FDA approval for children with SMA up to two years of age.
SMN Deficiency and Oxidative Stress
Through her research, Dr. Montes is seeking a better understanding of the disease mechanisms underlying weakness, fatigue, and motor impairments to inform the development of more targeted therapy. Specifically, she has played a key role in a randomized, controlled, clinical trial of exercise in patients with SMA.
“While motor neurons are selectively vulnerable as a result of survival motor neuron [SMN] protein insufficiency, there is reason to believe there are other vulnerable organs,” says Dr. Montes. “Our hope is to better understand the vulnerability of other tissues, specifically the relationship between muscle and muscle mitochondria to SMN deficiency. We think this deficit might be related to exercise intolerance and fatigue that we see in SMA patients.”
For instance, in the newly approved SMA treatment nusinersen, patients do not receive systemic exposure because the drug is administered via intrathecal injection during a lumbar puncture. “If it is, in fact, due to lack of SMN protein, it will be interesting in theory to understand if systemic treatment has an impact on this observed muscle deficit,” says Dr. Montes, pointing to risdiplam, another gene-splicing modifier drug that is in clinical trials but is an oral compound that is systemically distributed.
To that end, Dr. Montes’ current research in the Programs in Physical Therapy and the Department of Rehabilitation and Regenerative Medicine at Columbia University focuses on the oxidative capacity of muscles during exercise. The path that led her to her current NIH-funded study is two-fold.
In 2014, Dr. Montes was a co-investigator of a study funded by the Department of Defense that examined the effects of exercise on measures of function, strength, and exercise capacity in patients with ambulatory SMA. “Although nearly all patients reached target exercise volume, there was a blunted physiological response in that the magnitude of peak aerobic capacity seemed out of place,” says Dr. Montes. At the time, research being conducted in Italy caught her eye as it showed mitochondrial depletion and a potential problem with mitochondrial biogenesis in the muscle tissue of patients with SMA (Ripolone M et al. Impaired muscle mitochondrial biogenesis and myogenesis in spinal muscular atrophy. JAMA Neurology. 2015;72(6):666-675). Typically, an increase in aerobic exercise translates to an increase in mitochondria to boost aerobic capacity.
“Those two stories put together led us to our current NIH- funded study using near-infrared spectroscopy to estimate muscle oxygen uptake during exercise, which implicates the oxidative capacity of muscles,” says Dr. Montes, who is the Principal Investigator.
The observational study sample includes 42 patients (14 ambulatory SMA patients, 14 ambulatory mitochondrial myopathy patients, and 14 healthy controls). Patients undergo a standard cardiopulmonary exercise tolerance test at baseline and six months, while researchers use near-infrared spectroscopy to measure oxygen uptake in muscle in vivo. Other measures include the six-minute walk test and a DEXA (dual-energy X-ray absorptiometry) scan. Study inclusion criteria include patients with ambulatory SMA, aged 8 to 55 years, with the ability to ride a recumbent stationary bicycle and perform a cardiopulmonary tolerance test.
As Dr. Montes’ team recruits and enrolls their final patients, preliminary results are encouraging. Early findings show reduced muscle oxygen uptake during exercise in patients with SMA that cannot be explained by body composition alone. In other words, patients with SMA do not have reduced muscle oxygen uptake just because they have less muscle.
“If our results suggest that muscle mitochondria may be vulnerable, the next proof of concept would be examining whether treatment with SMN splicing modifiers would benefit or change muscle oxygen uptake,” says Dr. Montes. Study results may also help link findings from other research showing mitochondrial depletion in SMA, informing targeted therapy as well as future interventions to improve oxidative capacity and fitness in SMA patients. Ultimately, her team hopes to improve the quality of life for patients with spinal muscular atrophy.
Novel Research Tool
With two recently approved SMA drugs and more on the horizon, the need to develop new research tools to evaluate treatment effects and benefits is paramount. To that end, Dr. Montes, in collaboration with Damiano Zanotto, PhD, a mechatronics engineer and former Columbia University research scientist who is now at the Stevens Institute of Technology in Hoboken, New Jersey, have been awarded a grant by the Muscular Dystrophy Association to investigate the use of instrumented insoles in patients with SMA and Duchenne muscular dystrophy (DMD). The study is the first to investigate the use of machine learning models to improve the accuracy of a wearable system for gait analysis.
“It is a terrific collaboration,” says Dr. Montes, whose clinical expertise in the SMA patient population complements Dr. Zanotto’s mechatronics engineering expertise. “It is also an exciting time for DMD because while not as far along as SMA in disease-modifying therapies, they are in development and available for patients with DMD.”
“It is also an exciting time for Duchenne muscular dystrophy because while not as far along as SMA in disease-modifying therapies, they are in development and available for patients with DMD.”
— Dr. Jacqueline Montes
The research team will use the instrumented insoles to collect precise quantitative kinematic data on gait in patients with SMA and DMD. “The beauty of the instrument is that although there are other similar commercial-grade devices, ours has machine learning and the algorithm is calibrated to the individual. Patients with spinal muscular atrophy have a very different gait, and we can’t just apply a healthy algorithm to be able to capture their gait accurately,” explains Dr. Montes, who frequently trains physical therapists around the world on obtaining outcome measures in neuromuscular disease.
Dr. Montes and Dr. Zanotto hope that the wearable technology can be used as a research tool in the clinical setting. “We know that capacity measures in clinical trials do not necessarily reflect what happens in real life. If proven useful, this would be a real, quantitative way to assess an intervention in this patient population in a real-world setting,” says Dr. Montes.
One goal of the research study is to validate the instrumented insoles against the gold standard, ZenoTM Walkway, ProtoKinetics, during assessments at the Programs in Physical Therapy in the Department of Rehabilitation and Regenerative Medicine at Columbia. The investigators will also be evaluating the insoles in a subset of SMA and DMD patients as well as healthy controls to collect one week of real-world, precise quantitative data. From home, participants will upload data to an app to be processed. Results from the study will help fine-tune the device to potentially be utilized as a research tool in not only clinical trials for SMA and DMD, but also other neuromuscular diseases where ambulatory function is compromised.
Dr. Montes and colleagues at the SMA Clinical Research Center are certainly moving the science forward in both the lab and the clinic. “Our team members are experts in rehabilitation for spinal muscular atrophy,” says Dr. Montes. “This sort of expertise is not found regionally. I hope to give patients feedback or guidance on physical therapy, function, and exercise, as well as provide collaboration on motor function assessments.”
Montes J, Garber CE, Kramer SS, Montgomery MJ, Dunaway S, Kamil-Rosenberg S, Carr B, Cruz R, Strauss NE, Sproule D, De Vivo DC. Single-blind, randomized, controlled clinical trial of exercise in ambulatory spinal muscular atrophy: Why are the results negative? Journal of Neuromuscular Diseases. 2015;2(4):463-70.