PracticeUpdate Neurology Best of 2018

TOP STORIES 2018 5

Gene Therapy is Here By Mark Hallett MD

The promise of gene therapy is finally coming to fruition. Three articles that were stories of the week in 2018 feature two different types of gene therapy.

N usinersen, which had been demonstrated for early-onset spinal muscular atrophy (SMA), was shown in an article in The New England Journal of Medicine also to be of value in patients with later-onset disease. 1 SMA is caused by a loss of function of the SMN1 gene. There is an SMN2 gene that can produce the protein, but, ordinarily, it does not due to a splice-site variant that leads to the production of a dysfunctional protein. Nusinersen is an antisense oligonucleotide. It binds to a specific sequence in the SMN2 pre-messenger RNA, modifying its splicing, and promoting the expression of a full-length SMN protein. The CHERISH study was a double-blind, sham-con- trolled study with an endpoint at 15 months. Nusinersen was given intrathecally at days 1, 29, 85, and 274 in a 2:1 ratio, real to sham. The study was terminated at a prespecified interim analysis due to a large statistically significant difference between groups: real group with an average increase of 4.0 points on a functional scale and the sham group declining on average by 1.9 points. Two articles published together, also in The New England Journal of Medicine , showed that gene ther- apy could be useful for the treatment of hereditary transthyretin amyloidosis . This disorder is due to an autosomal dominant toxic gain-of-function mutation, wherein mutant transthyretin (TTR) gets deposited as amyloid in peripheral nerve, heart, kidney, and gastro- intestinal tract. The first paper used the technique of RNAi, RNA interference, which cleaves the messen- ger RNA that would lead to the production of TTR. 2 The APOLLO trial used the agent patisiran. The study was randomized and placebo-controlled in an adult population with polyneuropathy in a 2:1 ratio, real to

sham. Patients received the drug (or placebo) intra- venously once every 3 weeks until the endpoint at 18 months. The treated group improved on a neuropa- thy impairment scale by 6 points, while those on sham deteriorated by 28 points. There were also statistically significant improvements in secondary measures. The second article used an antisense oligonucleotide to inhibit the production of TTR. 3 The agent, inotersen, was used in a randomized, double-blind, placebo-con- trolled trial of patients with polyneuropathy over 15 months. Patients were assigned 2:1, real to placebo, to receive weekly subcutaneous injections of drug or placebo, with primary endpoints of a neuropathy impairment scale and quality-of-life scale. There was statistically significant benefit on both scales. However, it was of note that inotersen was associated with some patients developing glomerulonephritis or thrombocy- topenia, including 1 death from the latter complication. These articles are the leading edge of RNA-directed therapies, and already there are variations in the meth- ods. There is little doubt that we will be seeing much more work in this area. It is clear that such therapies will have to be monitored carefully for toxicity. Another issue will be their high cost, which will raise a variety of other problems. References 1. 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. 2. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018;379(1):11-21. 3. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):22-31. www.practiceupdate.com/c/74280

" These articles are the leading edge of RNA-directed therapies, and already there are variations in the methods. There is little doubt that we will be seeing much more work in this area. "

VOL. 3 • NO. 4 • 2018