This week, researchers halted a Phase 3 clinical trial for a treatment of the devastating childhood disease spinal muscular atrophy (SMA). Early success, rather than failure, motivated this November 7 announcement by trial co-sponsors Biogen of Cambridge, Massachusetts, and Ionis Pharmaceuticals of Carlsbad, California. The companies reported that an interim analysis conducted 15 months after starting the trial revealed that the drug nusinersen boosted motor function in children with Type 2 SMA. The drug is a form of antisense oligonucleotide (ASO) therapy, which targets RNA sequences to alter gene expression. Prompted by these positive interim results, the sponsors moved participants into an open-label study, ensuring that all of them will now receive the drug. The move comes just three months after the companies did the same thing following positive interim results of another Phase 3 study with nusinersen on infants with Type 1 SMA, the most severe form of the disease. The move to open-label studies is crucial in these youngest of patients, who rapidly succumb to SMA without treatment, Biogen spokeswoman Ligia Del Bianco told Alzforum.

Besides raising hope in the SMA community, the news gave a welcome shot in the arm to researchers applying ASO therapy to other neurodegenerative diseases. “The news is highly uplifting,” commented Don Cleveland of the University of California, San Diego. “It supports the general approach of using designer DNA drugs for changing synthesis of genes in a spectrum of neurodegenerative diseases.” Cleveland, who was not involved in this study, was an early pioneer of ASO strategies and actively supports efforts to treat amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) with similar strategies.

SMA is an autosomal-recessive neurodegenerative disease of motor neurons. The disorder is caused by mutations in survival motor neuron (SMN) protein 1 that abolish its expression or destroy its function. While all patients with SMA share this loss of functional SMN1, the severity of their disease varies greatly depending on the expression level of SMN1’s sibling, SMN2. The two proteins are nearly identical, except for a single nucleotide difference that triggers removal of exon 7 from SMN2 via alternative splicing, resulting in a stunted transcript that yields an unstable protein (see Lorson et al., 1999). Even so, a fraction of full-length SMN2 protein still gets made, and some people have multiple copies of the gene. Therefore, the severity of a given person’s disease depends on how much full-length SMN2 they muster in the face of their total loss of SMN1. Symptoms of the most severe form of the disease, Type 1 SMA, appear in babies younger than six months of age. They never sit independently, ultimately cannot move or breathe, and die before their second birthday. Children with Type 2 SMA sit and stand at the peak of their function, but they never walk independently. Symptoms start cropping up after six months of age, and progression is slower. Type 3 and 4 versions of the disease are less severe still.

In early work led by Adrian Krainer of Cold Spring Harbor Laboratory in New York, researchers devised a strategy to elevate expression of the full-length SMN2 gene (see Hua et al., 2007). They designed an ASO sequence to adhere to a sequence in SMN2 that normally engages a splicing repressor, thus blocking this interaction and coaxing the spliceosome to incorporate exon 7. This dramatically boosted expression of full-length SMN2 and improved motor function in animal models of SMA (see Mar 2011 news). Phase 1 and 2 clinical trials deemed the treatment safe.

The current interim results come from the Phase 3 trial known as CHERISH, which treated 84 children aged two to 12 who had Type 2 SMA with the oligonucleotides, and another 42 with placebo. Over the 15 months the trial ran, participants received three monthly intrathecal infusions of treatment or placebo, followed by two more infusions spread six months apart. The ASOs improved motor function by an average of 4 points on the Hammersmith Functional Motor Scale Expanded, while kids on placebo declined by 1.9 points on the HFMSE.

What does this difference of 5.9 points mean in terms of motor function? This is a difficult question to answer, said Del Bianco. Although none of the children were able to walk when they started the trial, their ages spanned a decade and they had drastically different baseline function. The HFMSE is designed specifically to assess motor function in children with SMA. It includes 13 tasks such as rolling, crawling, kneeling, standing, and walking, each of which are scored on a 3-point scale (see O’Hagen et al., 2007). A 3-point difference is considered clinically meaningful.

The patients in the CHERISH Phase 3 trial will now be moved to an open-label study called SHINE, which will follow the same dosing regimen as CHERISH. “This is great news, especially for patients in the placebo arm of the trial,” Krainer told Alzforum. “The sooner they start getting the drug, the better.”

Del Bianco told Alzforum that Biogen could not yet comment on how long patients will continue receiving infusions of the drug, although the chronic nature of the disease suggests they might need to do so indefinitely.

Following similar positive results in a Phase 3 trial called ENDEAR, which tested nusinersen in infants with Type 1 SMA, those patients were also moved into the SHINE open-label study. Biogen has filed applications in the United States and Europe for approval of the drug, and both the Food and Drug Administration and the European Medicines Agency have agreed to accelerate review. Biogen has initiated a global expanded-access program for Type 1 SMA patients. Del Bianco said the company is still considering whether to do the same for Type 2 patients, as well.

Early trials using gene therapy to elevate expression of SMN1 are also underway. Late last year at the 26th International Symposium on ALS/MND, Brian Kaspar of Nationwide Children’s Hospital in Columbus, Ohio, presented promising results from a Phase 1 clinical trial of an adeno-associated virus that expresses SMN1. A video of a treated baby with Type 1 SMA sitting independently struck a chord with the audience (see Dec 2015 conference news). 

ASO therapies are in preclinical development and Phase 1 and 2 clinical trials for ALS and HD. However, unlike the splicing alteration that nusinersen accomplishes, other ASOs aim to wipe out expression of their target genes. Cleveland and other researchers are collaborating with Ionis to target ASOs to mutant SOD1 and hexanucleotide repeat expansions in the C9ORF72 genes that cause ALS, as well as the mutant htt gene that triggers HD (see Nov 2015 conference news; Apr 2016 news; and Jun 2012 news). While these knockdown strategies differ from the splicing approach, Cleveland said the SMA study demonstrates that ASOs can be effectively delivered broadly across the central nervous system, where they engage their target genes. This bodes well for ongoing studies in other neurodegenerative disease, Cleveland said, adding. “Cautious optimism is the order of the day.”

Jeffrey Rothstein of Johns Hopkins Medical Institute in Baltimore, who collaborates with Ionis to develop ASOs for C9ORF72, was more direct in his reaction to the SMA news. “It is exceptionally exciting,” Rothstein wrote to Alzforum.—Jessica Shugart


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News Citations

  1. Research Brief: Researchers Solicit SMN Understudy to Treat SMA
  2. Gene and Stem Cell Therapies Make Strong Showing at ALS/MND Meeting
  3. Listen Up, Gene Silencing Strikes a Chord at RNA Meeting
  4. Paper Alert: Could Antisense Therapy One Day Squelch Toxic Repeats in ALS or FTD?
  5. “Huntingtin Holiday” Helps Mice Back to Health

Paper Citations

  1. . A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6307-11. PubMed.
  2. . Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol. 2007 Apr;5(4):e73. PubMed.
  3. . An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord. 2007 Oct;17(9-10):693-7. Epub 2007 Jul 19 PubMed.

Further Reading

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