Top 10 SMA stories of 2023

Throughout 2023, SMA News Today brought you the most up-to-date news on scientific breakthroughs and treatment advances related to spinal muscular atrophy (SMA).

These are the top 10 most-read articles we published throughout that year, with a brief reminder of what made them relevant to the SMA community. We look forward to offering you continued coverage of the latest in SMA research in 2024.

No. 10 – Benefits continue over 3 years of apitegromab’s use in TOPAZ trial

A late June update from the Phase 2 TOPAZ clinical trial (NCT03921528) reported that three years of monthly into-the-vein (intravenous) infusions of apitegromab, as an add-on to other SMA treatments, continued to be associated with sustained gains or stabilization in motor function among patients with SMA type 2 and type 3. Patients and caregivers also reported an easing in fatigue and improved functional abilities.

Apitegromab is an investigational antibody from Scholar Rock designed to increase muscle mass and preserve muscle function by inhibiting myostatin, a protein that normally limits muscle growth.

No. 9 – New gene therapy shows promise in SMA mouse model

In May, CANbridge Pharmaceuticals announced that its investigational second-generation gene therapy, called CAN203, led to greater motor function improvements and longer survival in a mouse model of SMA compared to a benchmark treatment reported to be similar to Novartis’ approved gene therapy Zolgensma (onasemnogene abeparvovec-xioi).

While Zolgensma is given as an intravenous infusion, the gene therapy candidate was injected directly into the brain. Both treatments intend to provide patients with a working version of the SMN1 gene — whose mutations are the cause of SMA — but the investigative gene therapy is designed to minimize certain side effects.

No. 8 – Spinraza and Zolgensma could restore nerve-muscle connections in SMA

In SMA, motor nerve cells (motor neurons) — the cells that communicate with muscles to coordinate voluntary movements — are progressively lost, leading to muscle weakness and wasting. Researchers in Japan reported that two young children with SMA type 1 showed increases in the electrical activity of their motor neurons after initial treatment with Spinraza (nusinersen) followed by one-time gene therapy Zolgensma. Both were diagnosed with SMA in infancy and quickly started on treatment, with motor gains noted. Tests of motor neuron activity were given before treatment, and again when the children were ages 1 and 2.

These findings suggest a restoration of nerve-muscle connections previously lost to the disease, the scientists wrote, noting a need for more detailed studies into how SMA treatments might impact motor neuron and muscle activity.

No. 7 – CANbridge planning to bring gene therapy into clinical trials in 2024

With preclinical work supporting the potential of its second-generation gene therapy in treating SMA (see No. 9 on this list), CANbridge announced plans to seek U.S. Food and Drug Administration clearance to launch clinical trials of the gene therapy in SMA patients before the end of 2024.

Results of CANbridge-sponsored preclinical studies at the Horae Gene Therapy Center at the University of Massachusetts Chan Medical School, where the investigational treatment was initially developed, indicated that its use as a single into-the-vein (intravenous) infusion may be safer and less toxic than Zolgensma.

No. 6 – Mechanism linking SMN protein loss to SMA possibly identified

In SMA, a lack of the SMN protein causes motor neurons to progressively die. While SMN’s importance for motor neuron health is established, the mechanisms by which it influences neuromuscular function are not known. In this study, scientists used SMA mouse models to identify a group of proteins that appear to be implicated in this process, and could be targets for new SMA treatments.

Called the SNARE complex, this protein group normally works to regulate how nerve cells receive chemical signals from each other, but its workings are disrupted in motor neurons lacking SMN. The scientists found evidence indicating that a lack of SMN affected neuromuscular function by preventing the formation of the SNARE complex. A particular SNARE-stabilizing protein called HSPA8 was identified as a possible SMA therapeutic target.

No. 5 – Work suggests Evrysdi may be better than Spinraza for SMA type 1

Both Spinraza and Evrysdi (risdiplam), approved SMA therapies, work through a similar mechanism to increase SMN protein production. Researchers, indirectly comparing data from clinical trials that separately tested the two treatments in children with SMA type 1, found that Evrysdi may be associated with longer survival and greater motor function gains.

Sponsored by Roche, the company that markets Evrysdi, the analyses also indicated that serious adverse events were less frequent with Evrysdi. However, the scientists emphasized that these indirect analyses could be biased by unknown factors, and Evrysdi’s superiority cannot be established from this work alone.

No. 4 – Muscle health seen on ultrasounds match with SMA motor function

Researchers in Brazil evaluated the usefulness of muscle ultrasound imaging in monitoring SMA progression. Muscle abnormalities were evident in people with SMA types 1 to 4  relative to healthy people, with some differences observed between SMA types. Observed differences included evidence of muscle atrophy and hyperechogenicity, or fat and connective tissue where muscle should be.

Among those with SMA type 1, motor function scores significantly correlated with muscle ultrasound findings, including bicep muscle size and hyperechogenicity in several muscles. Long-term studies are warranted to better establish these relationships, the researchers noted.

No. 3 – Zolgensma treats twins born with severe SMA type 0

SMA type 0 is the most severe form of the disease, typically leading to death in the first months of life. In a case report presented at a conference, scientists detailed clinical findings of twin girls diagnosed with SMA type 0 shortly after their birth and treated about three weeks later with Zolgensma, who are continuing to thrive as 2-year-olds.

The girls were born at 30 weeks gestational age by cesarean section, and genetic testing showed they had no SMN1 gene copies, the gene that provides instructions for producing the SMN protein, and only one copy of the SMN2 gene that serves as a backup to SMN1. Both were able to walk independently by 15 months of age, and could run, feed themselves, and speak in short sentences at age 19 months.

No. 2 – Gene-editing therapy boosts motor function in mice

The SMN2 gene can produce SMN protein, but in a form that is shorter and more quickly degraded, unable to completely compensate for the deficiency caused by SMN1 mutations. In the study, researchers developed a gene-editing tool that could alter SMN2‘s genetic code to convert it into a working copy of SMN1.

In a mouse model of SMA, the gene-editing therapy led to similar — and sometimes greater — motor improvements relative to the three approved SMA therapies: Spinraza, Evrysdi, and Zolgensma. Mice given the treatment along with Spinraza also were similar to healthy mice in terms of muscle strength, coordination, and activity levels, and lived 6.5 times longer than untreated animals.

No. 1 – Muscle strengthener pyridostigmine eases SMA fatigue in small trial

Pyridostigmine eased patient-reported fatigue compared with a placebo, and was well tolerated in a Phase 2 clinical trial (NCT02941328) involving 37 adults and adolescents with SMA types 2-4. But pyridostigmine, a muscle strengthening medication used to treat a neuromuscular disease called myasthenia gravis, failed to significantly improve patients’ motor function or ease their motor fatigue, which were the trial’s main goals.

Because the trial began before SMA disease-modifying therapies were available, its researchers suggested that further studies are needed to establish pyridostigmine’s potential benefits as an add-on to such therapies.

At SMA News Today, we hope these stories and the rest of our reporting throughout 2023 helped to inform and improve the lives of those in the SMA community. As we look forward to bringing you the most accurate and up-to-date news in 2024, we wish our readers a very happy new year!