Efforts to Cure SMA Follow Multiple Pathways

NeurologyLiveApril 2019
Volume 2
Issue 2

The approval of nusinersen in 2016 to treat spinal muscular atrophy marked an important milestone in efforts to treat the disease, but even more breakthroughs could be coming soon.

For people with spinal muscular atrophy (SMA), now is an exciting time. New understandings of the mechanisms behind the debilitating neuromuscular disorder have aligned with a new era of disease-modifying therapeutics, ushering in renewed hope for physicians and patients alike. Instead of wondering when a therapy will be available, people with SMA and their loved ones can now ponder the question of when better and more accessible therapies will be available.

The battle against SMA is far from over. The first therapy designed to treat SMA was approved 3 years ago, but researchers continue to investigate different methods and strategies with which to reverse or overcome the genetic mutations underpinning the disease. Although we now have a method by which to counteract the disease, the hope of a permanent cure remains distant.

Rosangel Cruz, MA, director of research and clinical affairs at the advocacy group Cure SMA, said efforts to advance treatment of SMA are continuing down broad scientific pathways. Cure SMA has funded more than $75 million worth of research since its founding in 1984.

“We’re actively working both on additional treatments that target the underlying genetics of SMA and on therapies that target other systems, pathways, and processes affected by SMA,” Cruz told NeurologyLive®.

Spinal Muscular Atrophy Overview

SMA is a debilitating, genetic disease that was untreatable, until recently. It is caused by mutations in the SMN1 gene, or a lack of the gene, on chromosome 5. The mutation means little or no spinal motor neuron (SMN) protein is produced, thus causing the deficiency in motor function. Another gene, SMN2, can also produce SMA; however, it does so inefficiently as much of the SMN protein produced is not full length and therefore nonfunctional. The more copies of SMN2 a patient has, the better his or her function. Patients with SMA experience disruption in the motor neurons, which leads to weakness and atrophy in the muscles controlled by those neurons. The most common type of SMA is chromosome 5 SMA. The National Institutes of Health estimates that 1 in every 8000 to 10,000 people in the world are affected by SMA.1

Chromosome 5 SMA is split into 4 subtypes. Those with the lowest motor function are categorized as type 1. These patients might only have 2 SMN2 genes, whereas patients with type 3 or 4 could have between 4 and 8 copies of SMN2. Type 1 SMA typically has an earlier age of onset, including infants who are born showing symptoms of SMA. These children often have difficulty with basic functions like swallowing. These children usually die by age 2.2 According to the Muscular Dystrophy Association, more than half of new SMA cases are type 1.3

If symptoms are not apparent until they are several months old, patients are classified as type 2, which is considered intermediate disease. Those who get the diagnosis as a toddler generally have type 3 SMA. Type 4, the least severe, is known as adult-onset SMA because it is not diagnosed until the patient is a teenager or adult. The Muscular Dystrophy Association reports that patients in the least severe categories generally live normal life spans, albeit with sometimes severe limitations and risks. People with type 3 SMA, for instance, usually lose the ability to walk.

Other Forms

There are other forms of the disease besides chromosome 5 SMA that are caused by mutations in other genes. One form, based on a mutation in the IGHMBP2 gene, causes severe respiratory distress. And several genetic mutations have been linked to distal SMA, which primarily affects the hands and feet. Finally, a mutation in the X-chromosome gene UBA1 can lead to X-linked SMA, which is characterized by the onset of severe symptoms in infancy that include joint and muscle weakness.

First Therapy Is Approved

The landmark treatment breakthrough for chromosome 5 SMA came in late 2016 when the FDA approved nusinersen (Spinraza, Biogen).4 Nusinersen is administered directly into the cerebro- spinal fluid using an intrathecal injection and works by causing the SMN2 gene to produce additional full-length SMN protein. Because it had the potential to become the first FDA-approved therapy for SMA, the drug was granted orphan drug designation, fast-track designation, and priority review.

In the ENDEAR clinical trial (NCT02193074), 121 patients who had SMA diagnosed before 6 months of age were enrolled and randomly assigned to receive either nusinersen injection or sham treatment.5 An interim analysis of 82 patients showed that 40% of the treatment group demonstrated improvements in motor milestones, such as head control, sitting, rolling, standing, and walking, while no participants in the sham group showed improvements. The trial was ultimately terminated early to allow patients to enroll in an open-label extension. In a press release announcing the approval, Billy Dunn, MD, director of the Neurology Products Division at the FDA’s Center for Drug Evaluation and Research, said the agency worked hard to evaluate the results as quickly as possible due to the high level of need.

“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants and a disease that can affect people at any stage of life,” he said.

Results of the subsequent CHERISH trial (NCT02292537) published in 2018 show that children with late-onset SMA also benefit from the drug.6 The study included 126 children 2 to 12 years who had SMA diagnosed after 6 months and were nonambulatory. At 15 months, children who received the study drug demon- strated a least-squares mean improvement of 4.0 points on the Hammersmith Functional Motor Scale Expanded (HFMSE), a scale developed specifically to assess motor function in children with SMA. Comparatively, children in the control group declined by a least-squares mean of 1.9 points. Compared with 26% of the control group, 57% of patients in the treatment group had an improvement of at least 3 points on the HFMSE scale.

The researchers, led by Eugenio Mercuri, MD, PhD, of the Catholic University of the Sacred Heart in Milan, Italy, wrote that although some patients in the control group had initial improvements (likely due to the placebo effect or the clinicians’ inexperience at using the HFMSE scale), many later suffered significant setbacks.

“Some children in the control group had a decrease in the HFMSE score of up to 10 points...but those treated with nusinersen had a more stable course,” Mercuri and colleagues wrote.

However, Cruz noted that the existing literature shows the most dramatic impact comes when patients begin nusinersen therapy soon after symptoms appear.

“This makes increased awareness of the early clinical presentation and diagnosis of SMA a medical emergency and essential to the effec- tive treatment of SMA type I,” she said. “Both clinical and preclinical studies [results] indicate that early treatment exposure is critical to modifying the rapid and irreversible loss of motor neurons, ultimately leading to muscle atrophy and weakness.”

Because of this, Cure SMA has joined with industry partners to launch an awareness campaign called SMArt Moves to help parents and clinicians more quickly identify potential cases of SMA.7

Nusinersen Update

Since its approval, nusinersen’s rollout has been swift. As of March, Biogen said more than 6600 patients with SMA have been treated with the drug worldwide, including 2600 in the United States. Those patients range in age from 3 days to 79 years. Thirty-five percent of patients on the drug are over the age of 18, and the majority of patients who started the drug (95%) remained on it as of the date of the update. Like many new disease-modifying drugs, nusinersen comes with a heavy price tag. Published reports list the price at $750,000 for the first year and $375,000 for subsequent years. However, a draft report from the Institute for Clinical and Economic Review found that all of the insurers evaluated covered nusinersen for most types of SMA, with prior approval.8

Gene Replacement Approach

The next major breakthrough might not be far off. Novartis expects regulatory action in May 2019 on its biologics license application for AVXS-101 (Zolgensma, Novartis), a proprietary gene therapy that takes a different approach from that of nusinersen. Instead of boosting SMN protein production in the SMN2 gene, AVXS-101 aims to replace the primary faulty SMN1 gene. And unlike nusinersen, AVXS-101 would not require repeat dosing.

“As a 1-time infusion that addresses the genetic root cause of SMA without the need for repeat dosing, Zolgensma represents a potentially significant therapeutic advance for these patients and their families,” said David Lennon, PhD, president of AveXis, the Illinois-based developer of Zolgensma, in a press release. AveXis was acquired by Novartis in 2018. Like nusinersen, AVXS-101 has been granted priority review by the FDA, as well as breakthrough and orphan drug statuses.

Other Avenues

Even with nusinersen on the market and AVXS-101 potentially headed for approval, research continues. While both of those drugs take the approach of trying to stimulate additional SMN protein production, other strategies under investigation involve curtailing the effects of SMA without requiring the production of additional SMN protein. One hypothesis in this line of research pertains to the protein senataxin.

Laxman Gangwani, PhD, a neuroscientist at the Texas Tech University Health Sciences Center in Lubbock, is currently investigating whether the protein can play a protective role of limiting SMA severity. He wants to know whether increasing senataxin will decrease the symptoms of SMA. Gangwani’s process involves genetically modifying a mouse model so that the animal produces extra senataxin, then crossing that animal with a mouse model of SMA. If all goes well, Gangwani, who has been researching SMA for more than 20 years, said the therapy could potentially heal SMA, rather than simply stop its progression.

“Senataxin works downstream of SMN,” he said. “So even if SMN is not there, it can prevent the degeneration,” he told NeurologyLive®.

If the theory is borne out in mouse models, Gangwani says the next step would be to try and find a small molecule drug that could increase production of senataxin. His past work revealed that the protein ZPR1 played an important role in SMA. An interaction between ZPR1 and SMN protein is necessary in order for the latter to accumulate in cells, and ZPR1 is downregulated in patients with SMA. He therefore theorizes that protecting ZPR1 might result in better outcomes for patients with SMA. He’s currently continuing that line of research as he works on senataxin.

Meanwhile, in 2015, Gangwani discovered that the neuron-specific isoform JNK3 must be present in order for SMN protein deficiency to cause neuron degeneration. A deficiency in JNK3 therefore leads to a reduction in SMN-deficiency—related neuron degeneration. When Gangwani tested the hypothesis by genetically inhibiting JNK3, the resulting deficiency stopped the loss of spinal cord motor neurons and led to improvements in motor function, overall growth, and lifespan in mice with the SMA model.9 As with senataxin, Gangwani said this potential target could be tackled by a small molecule drug.

Focusing on Motor Neuron Receptors

Another inquiry aimed at addressing SMA by a means other than producing more SMN protein was explored by researchers at Brown University and the University of Cologne in Germany. Investigators discovered that the deficiency in SMN protein is linked to a hindrance of the protein gemin3. That lack of gemin3 inhibits related microRNA, which in turn causes an overexpression of the motor neuron receptor m2R. The function of m2R is to monitor the release of the neurotransmitter acetylcholine, which signals the movement of muscle cells.

Anne Hart, PhD, a professor of neuroscience at Brown and the lead author of the study, hypothesized that the overabundance of m2R receptors in patients with SMA causes motor neurons to be oversensitive to their acetylcholine output, leading to prema- ture cessation of the release of acetylcholine, thereby inhibiting the signals that lead to proper muscle function.10 That lengthy chain of causes and effects created a number of opportunities to reverse the end result of lessened muscle function. In their tests, the team experimented with the drug methoctramine, which blocks m2R, which resulted in the restoration of certain motor neuron function in mice. Hart is not actively working on the m2R project, but she still believes m2R could be a viable target for new SMA therapies.

Remaining Questions

In addition to the various therapeutic tactics currently under investigation, Cruz said a number of questions remain to be explored surrounding the pathophysiology of SMA. “This includes focus on the tissue or timing requirements for SMN protein, the cellular autonomy of the disease in motor neurons and other cells, peripheral versus central manifestations of SMA, and others,” she said.

Key questions being examined include where and when SMN protein is needed to prevent the disease, when and how to deliver therapies, why motor neurons die, and what other cells are impacted by low SMN protein levels. Cruz said she hopes all of the new research helps to create a more compre- hensive and personalized menu of treatments for people with all types of SMA.

“Our goal is a combination of therapeutic approaches that can be tailored to each individual’s age, stage, and type of SMA,” she said.

Cruz also noted that research has shown disease manage- ment can have important impacts on patients’ health.11 “In addition to the early treatment of SMA, a multidisciplinary approach to the care of SMA is essential in the optimal management of all [patients with SMA], including nutritional, respiratory, physical therapy, and orthopedic care, among others,” she said.

One question hovering over SMA is how nusinersen’s approval will affect the pace and scope of SMA research. On one hand, the drug offers proof that SMA can be successfully treated. On the other hand, it moves SMA out of the most urgent category of “untreatable” rare diseases. Hart said the approval of nusinersen likely won’t affect the pace of new research, in part because for all its promise, nusin- ersen has significant drawbacks, including its cost and the method of administration. “My personal opinion is that this will not slow down the impetus to find better targets and therapies for SMA,” she told NeurologyLive®. “After all, we are still working on better therapies for migraines, heart disease, and other conditions, despite having partially effective therapeutic approaches available.”

Genentech, Roche, and PTC Therapeutics are working together on the development of risdiplam, an investigational medication that, like nusinersen, would help the SMN2 gene produce complete SMN protein. However, unlike nusinersen, risdiplam would be administered orally. As of early 2019, risplidam was the subject of 3 multicenter trials, with a fourth slated to begin soon.

Cure SMA says 7 promising therapeutics are currently in the pipelines of biopharmaceutical firms. “Today, there’s great reason for hope that is founded not only in the availability of a treat- ment approved for all types of SMA, but also in a robust therapeutic pipeline,” Cruz said.

On the other hand, Gangwani worries that all of this progress could have an unintended consequence of making it harder for SMA researchers to find funding. Gangwani, who received a grant from CureSMA for his senataxin research, said the approval of nusinersen could make SMA seem like a lower priority.

“I think the momentum is declining because of the limited research funding,” he said. “SMA researchers are finding it very difficult because when their grant proposals are going into the hands of non-SMA researchers, they [the non-SMA researchers] feel that there is already a treatment, so why do they need more money to do research.”

Gangwani would like to see the National Institutes of Health step in to create a fund for research into diseases like SMA. He said although the science is moving swiftly and enthusiasm is high, investigators like him will also need a continued supply of research funds.

“That’s the limitation,” he said. “Funding is the limitation."


1. Spinal muscular atrophy. NIH website. ghr.nlm.nih.gov/condition/spinal-muscular-atrophy#statistics. Published March 19, 2019. Accessed March 19, 2019.

2. Park HB, Lee SM, Lee JS, et al. Survival analysis of spinal muscular atrophy type I. Korean J Pediatr. 2010;53(11):965-970. doi: 10.3345/kjp.2010.53.11.965.

3. Spinal muscular atrophy. Muscular Dystrophy Association website. mda.org/disease/spinal-muscu- lar-atrophy. Accessed March 19, 2019.

4. FDA approves first drug for spinal muscular atrophy [news release]. Silver Spring, MD: FDA; December 23, 2016. www.fda.gov/newsevents/newsroom/pressannouncements/ucm534611.htm. Accessed March 19, 2019.

5. Spinraza [prescribing information]. Cambridge, MA: Biogen; 2016. www.accessdata.fda.gov/drugsatfda_ docs/label/2016/209531lbl.pdf. Accessed March 19, 2019.

6. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625-635. doi: 10.1056/NEJMoa1710504.

7. SMArt Moves. Cure SMA website. events.curesma.org/site/PageNavigator/SmartMoves/SMArtMoves. html. Accessed March 19, 2019.

8. Ellis AG, Mickle K, Herron-Smith S, et al. Spinraza and Zolgensma for Spinal Muscular Atrophy: Effectiveness and Value. Boston, MA: Institute for Clinical and Economic Review; 2018. icer-review.org/wp-content/uploads/2018/07/ICER_SMA_Draft_Evidence_Report_122018-1.pdf. Accessed March 19, 2019.

9. Genabai NK, Ahmad S, Zhang Z, Jiang X, Gabaldon CA, Gangwani L. Genetic inhibition of JNK3 amelio- rates spinal muscular atrophy. Hum Mol Genet. 2015;24(24):6986-7004. doi: 10.1093/hmg/ddv401.

10. O’Hern PJ, Gonçalves ICG, Brecht J, et al. Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in spinal muscular atrophy models. eLife. 2017;6. doi: 10.7554/eLife.20752.

11. Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

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