Rallying a backup gene could boost strength in spinal muscular atrophy


Ed note: As of November 2016, Vivienne remains stable. On December 23, 2016, her test drug, to be marketed as SPINRAZA (TM), was approved by the Food and Drug Administration for all forms of SMA.

Spinal muscular atrophy (SMA), a condition affecting one in every 6,000 to 10,000 children, is caused by a defect in a gene called SMN1 — which stands for “survival of motor neuron.” The defect leaves children with too little functioning SMN protein to maintain their motor neurons, which begin wasting away. Muscle strength declines and children eventually develop difficulties eating and breathing.

For Vivienne, whose name means “to live,” that meant being slow to reach motor milestones like crawling, cruising and walking as a toddler. For her parents, it meant hearing that her life expectancy would not be normal.

But a new back-door approach seems to be helping Vivienne, now in first grade, at least thus far.

As it happens, most of us carry a backup gene for SMN1 — namely SMN2. SMN2 is almost identical to SMN1, but the small letter change (a “T” rather than a “C” in the coding region known as exon 7) usually causes the entire exon 7 to be spliced out. As a result, the SMN protein that’s made is shorter and less functional.

But some people have extra copies of SMN2 and can produce more full-length SMN; the more copies, the less severe their disease. Children with type 1 SMA, the most severe form, have only one or two copies and usually die before the age of 2. Vivienne, with type 2 SMA, has three copies of SMN2. People with four or more copies can have mild disease with few symptoms, and are usually able to walk independently.

A number of pharmaceutical companies see an opportunity here. “Everybody is trying to develop drugs that will induce more full-length SMN protein production from the SMN2 gene,” Basil Darras, MD, director of the Spinal Muscular Atrophy Program at Boston Children’s, told Nature Medicine in 2012.

Darras is site principal investigator for a clinical trial sponsored by ISIS Pharmaceuticals that is testing an experimental antisense drug called SMNRx or nusinersen. The drug is an 18-letter string of DNA that binds to SMN2’s pre-messenger RNA, thereby preventing exon 7 from being spliced out and allowing full-length SMN protein to be produced.

spinal_diagram-Wikimedia commons
Click to enlarge (Wikimedia Commons)

In mice whose SMN1 gene was knocked out, this approach increased production of full-length SMN protein from SMN2 in motor neurons, improved muscle strength and extended lifespan. Darras hopes it will do the same in children with SMA and allow them to enjoy better motor function. (At right, the red dots in this spinal cord show the motor neurons affected by SMA.)

A few months after Vivienne was diagnosed with SMA, her pulmonologist at Boston Children’s mentioned the clinical trial. “We were very interested and followed every step of pre-clinical trials,” Vivienne’s mother, Helena, told Boston Children’s Hospital’s consumer blog, Thriving. “We decided we would go through any door that opens for Vivienne.”

Vivienne entered Isis’s first phase 1 trial, and in 2012 she received her first 6-mg SMNRx injection, delivered intrathecally — into the fluid-filled space at the base of her spinal cord. Because the trial was open-label, her doctors and family knew she was receiving active drug rather than placebo. (All patients, including Vivienne, are now receiving a higher 12-mg dose.)

Vivienne’s parents noticed a change in their daughter within days. Her energy level increased, she talked more and she stopped napping. Instead of losing weight, she gained five pounds in six months and even took 10 independent steps.

Since then, Vivienne has crawled and managed to sit straight without a body brace. But toward the end of every 6 month-period between doses, she loses some of the abilities she’s gained and has to re-learn motor skills with the next dose, whereas before she needed assistance.

Results overall have thus far been encouraging. In October 2014, at the World Muscle Society Congress, Darras and others reported interim results of the ISIS open-label Phase 2 studies, indicating time- and dose-dependent increases in muscle function scores in infants and children treated with multiple doses of SMNRx. In infants, the drug appeared to prolong life and forestall the need for permanent artificial ventilation. So far the drug has been safe and well tolerated.

“Given the number of ongoing and planned clinical trials and the pharmaceutical industry’s interest in SMA, we may be on the verge of an effective therapy for this disease.”

Two phase 3 randomized, controlled trials of SMNRx are currently enrolling at Boston Children’s: A trial called Endear is enrolling children 7 months or younger who have just two copies of SMN2, and a trial called Cherish is enrolling children 2 to 12 years old with later-onset SMA. Controls in these trials will receive sham injections, but some children will then be able to enroll in an open-label study and receive active drug. (For more information and entry criteria, email heather.szelag@childrens.harvard.edu.)

SMNRx isn’t the only SMN-focused approach being tried. Another approach has been the use of histone deacetylase inhibitors, epigenetic modulators that boost the expression of broad groups of genes, including SMN2. These have been shown to increase SMN protein levels in mice and human cells, but the drugs have disappointed in clinical trials. Novartis, Roche and other pharmaceutical companies are pursuing oral small-molecule drug trials aimed at including exon 7 in SMN2’s splicing. Yet another approach would increase levels of SMN messenger RNA by inhibiting a process that destroys it. Researchers are also exploring gene therapy techniques to replace the missing or defective SMN1 gene.

“SMA continues to be a leading genetic cause of infant mortality and a debilitating disease in children with milder forms,” says Darras. “ we may be on the verge of an effective therapy for this disease.”