Targeted Treatments for Inherited Neuromuscular Diseases of Childhood

Alex J. Fay, MD, PhD; Renatta Knox, MD, PhD; Erin E. Neil, DO; Jonathan Strober, MD


Semin Neurol. 2020;40(3):335-341. 

In This Article

Spinal Muscular Atrophy

New SMA treatments mark the most dramatic successes of genetically targeted therapeutics, turning a fatal disease (SMA type I) into a treatable condition over the last 3 to 4 years. SMA is a recessive disease of the anterior horn cells caused by loss of both copies of the SMN1 gene (usually deletion of exon 7) on the long arm of chromosome 5. An unusual feature of SMA genetics is the presence of a highly homologous gene, SMN2, also on chromosome 5q. SMN2, however, has a mutation in the exon 7 splice site, which leads to an unstable protein product by exclusion of exon 7. Individuals with SMA typically have one to four copies of SMN2, and the number of copies influences the severity of disease.[1] Thus, one copy of SMN2 is generally associated with a severe, neonatal onset form of SMA (SMA type 0), whereas the most common form, SMA type 1, is often associated with two copies of SMN2, with symptoms appearing before the age of 6 months. Later onset forms, SMA type 2 (onset at 6–18 months), SMA type 3 (onset at 18 months to 21 years), and SMA type 4 (onset after age 21 years), are usually associated with more copies of SMN2, though there are other disease-modifying factors. Infants with type 0 disease often die in the first months of life from respiratory failure, whereas type 1 disease is fatal before the age of 2 years prior to the treatments discussed in the following, with infants never achieving independent sitting. In SMA type 2, independent standing is not achieved without treatment, whereas most individuals with SMA type 3 are ambulatory but may lose this ability anytime from childhood to late adulthood. The treatments discussed below are radically shifting the trajectory of SMA, especially when therapy can be initiated in the presymptomatic or mildly symptomatic stages of disease.

Targeted Therapies for Spinal Muscular Atrophy: SMN2 Splicing Modification

Nusinersen is an ASO medication, and, in 2016, it became the first U.S. Food and Drug Administration (FDA) approved treatment for SMA in the United States. ASOs are synthetic, modified oligonucleotides that bind to specific sequences of ribonucleic acid (RNA) and alter expression of the encoded gene product.[2] ASOs can be used to silence a disease-causing gene or to modify splicing to restore the function of a protein. Nusinersen acts to increase the inclusion of exon 7 into the SMN2 messenger RNA (mRNA) transcript and therefore increase SMN protein production.[2,3] Nusinersen is delivered intrathecally, and after four loading doses, it is administered every 4 months indefinitely.[2,4] Side effects seen with ASOs include thrombocytopenia, renal tubular toxicity, and hepatotoxicity.[2]

FDA approval was based on results of a phase 3, randomized, double-blind, sham-controlled study of nusinersen in 121 patients with SMA type 1 under 7 months of age with early symptom onset.[5] More patients who received nusinersen compared with the control group had a motor milestone response on the HINE-2 (Hammersmith Infant Neurological Exam – Part 2) and had longer event-free survival, defined as time to death or permanent assisted ventilation. More benefit of nusinersen was seen in patients with shorter disease duration.[5] Results have been even more promising in the open-label NURTURE study of presymptomatic infants with SMA type 1, with some children showing essentially normal motor development.[6,7] A phase 3, double-blind, sham-controlled study of 126 children aged 2 to 12 years with SMA types 2 and 3 who developed symptoms after 6 months of age was also completed. The primary end point was change in the HFMSE (Hammersmith Functional Motor Scale—Expanded) score, and more patients who received study drug had increased scores compared with control patients.[8]

Risdiplam is an oral, small molecule that is an SMN2 pre-mRNA splicing modifier.[9] Because it is administered orally, it distributes into both the central nervous system (CNS) and peripheral tissues.[10] The first-in-patient study was a phase 1, randomized, double-blind, 12-week, placebo-controlled, multiple doses, of 13 SMA type 2/3 patients. Single oral doses of risdiplam led to increased amounts of full-length SMN2 mRNA, decreased SMN2 Δ7 mRNA, and increased inclusion of SMN2 exon 7, therefore demonstrating the effectiveness of risdiplam.[10] Two unpublished studies, FIREFISH and SUNFISH, are evaluating SMA type 1 and SMA type 2/3 patients, respectively, with FIREFISH demonstrating improved survival and attainment of motor milestones, whereas SUNFISH is still in progress.[10] Side effects reported throughout the studies included headache, abdominal pain, diarrhea, nasopharyngitis, influenza, dry mouth, erythema, and pyrexia.[10,11]

Gene Therapy and Application to SMA

The potential for gene therapy to correct human diseases at their genetic origin was first postulated by Friedmann and Roblin in 1972.[12] This vision was realized in December 2017, when the FDA approved the first gene therapy for a genetic disease, Voretigene neparvovec, for patients with Leber congenital blindness secondary to biallelic RPE65 mutation,[13] which makes use of an adeno-associated virus (AAV) vector. The AAVs have emerged as attractive viral delivery systems for neuromuscular disorders due to stable expression of transgenes as episomes with minimal genome integration, and tropism for particular tissues.[14,15] For example, AAV1, AAV6, and AAV9 are tropic for heart and skeletal muscle, whereas AAV1, AAV5, AAV8, and AAV9 have tropism for the CNS. Gene therapy is an attractive approach for monogenic neuromuscular disorders and is currently being investigated in several clinical trials.

In 2017, a phase 1 clinical trial of a single dose of AVXS-101, which expresses SMN1 from a modified AAV9 vector, was published and showed that motor milestones were improved with longer survival compared with historical controls.[16] Treatment was associated with an asymptomatic transaminitis, which improved with steroid pretreatment. Children with antibodies to AAV were excluded from the trial. Based on these results and interim analysis of a phase 3 trial of children with SMA type 1, the FDA approved zolgensma as a gene replacement therapy for children under 2 years of age with any type of SMA.[17] Trials are in progress for older patients with SMA types 2 and 3, with intrathecal delivery of the AAV vector carrying the SMN1 gene. Although the cost may be prohibitive in most cases, it is plausible that nusinersen and zolgensma might have a synergistic effect in treating individuals with SMA, given their distinct mechanisms of action.

Other Neuropathies

Beyond SMA, gene therapy treatments for several other neuropathies have shown promise in preclinical animal models, and a trial is underway for giant axonal neuropathy. This trial is using an AAV9 vector carrying the gigaxonin (GAN) gene and is infused intrathecally in a single dose. Preclinical data in cultured cells and in GAN knockout mice showed that AAV9-GAN can reverse aggregation of intermediate filaments and improve pathological markers of disease and motor function, even when treating adult mice.[18] Knockout mouse models of X-linked Charcot–Marie–Tooth (CMT),[19] due to hemizygous loss of Cx32, and CMT4C, due to biallelic loss of SH3TC2 function, have both been treated with lentiviral gene therapy vectors carrying the wild-type gene and have demonstrated marked improvements in pathological, electrophysiological, and functional measures. CMT1A, the most common form of CMT and caused by duplication of the PMP22 gene, is a more challenging target, as either increased or reduced dosage of PMP22 can cause peripheral nerve disease. An indirect approach to treating CMT1A through gene therapy delivery of neurotrophin-3, a growth factor that facilitates peripheral nerve regeneration and remyelination, has shown promise in a mouse model of CMT1A[20] and is the basis for an open clinical trial (NCT03520751).