demyelinating encephalomyelitis or MS) and with regards to the co-occurrence of anti-AQP4 and antiMOG antibodies.9 Better characterisation of anti-AQP4negative NMO spectrum disorders might be useful for choosing appropriate therapeutic strategies. Together, these studies show the increasing attention being given to the search for markers of disease phenotypes in MS and related disorders, and the steps being taken towards the ultimate goal of more personalised treatments.
*Maria Trojano, Carla Tortorella Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari 70124, Italy [email protected]
MT has served on scientiﬁc Advisory Boards for Biogen Idec, Novartis, and Merck-Serono; has received speaker honoraria from Biogen-Idec, Sanoﬁ Aventis, Merck-Serono, Teva, and Novartis; and has received research grants from Biogen-Idec, Merck-Serono, and Novartis. CT has served on scientiﬁc Advisory Boards for Novartis and Farmades Shering; and has received speaker honoraria from Biogen-Idec, Sanoﬁ Aventis, Merck-Serono, Teva, Novartis, and Genzyme.
Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007; 61: 14–24. Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66: 460–71. Lublin FD, Reingold SC, Cohen JA, et al. Deﬁning the clinical course of multiple sclerosis: the 2013 revision. Neurology 2014; 83: 278–86. Villar LM, Casanova B, Ouamara N, et al. Immunoglobulin M oligoclonal bands: biomarker of targetable inﬂammation in primary progressive multiple sclerosis. Ann Neurol 2014; 76: 231–40. Tur C, Ramagopalan S, Altmann DR, et al. HLA-DRB1*15 inﬂuences the development of brain tissue damage in early PPMS. Neurology 2014; 83: 1712–18. Du S, Itoha N, Askarinam S, Hill H, Arnold AP, Voskuhl RR. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2014; 18: 2806–11. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012; 79: 1273–77. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014; 82: 474–81. Kezuka T, Usui Y, Yamakawa N, et al. Relationship between NMO-antibody and anti-MOG antibody in optic neuritis. J Neuroophthalmol 2012; 32: 107–10.
Neuromuscular diseases: progress in gene discovery drives diagnostics and therapeutics Most neuromuscular diseases are caused by mutations in single genes. During 2014 the widespread use of next-generation sequencing technology has continued to unravel the genetic basis of many neuromuscular diseases. This technology is transforming clinical and prenatal genetic diagnostics and changing clinical practice. It seems inevitable that the responsible genes and mutations for all single-gene neuromuscular diseases will all be discovered in the foreseeable future. Even for sporadic disorders such as amyotrophic lateral sclerosis and inclusion body myositis, discovery of the causative genes in rare familial forms is advancing our understanding of molecular mechanisms. Gene discovery is one important anchor-point on which disease mechanisms can be understood. This mechanistic knowledge can lead to experimental therapeutics. Advances are most eﬀectively realised when there is strategic coordination and partnership between academia, industry, and patients. Health-care and research systems that allow integration of clinical, biomarker, genetic, and tissue-based omics data are especially powerful. www.thelancet.com/neurology Vol 14 January 2015
Novel RNA-directed molecular strategies have shown encouraging progress as potential therapies. Antisense oligonucleotides can intervene in at least two ways: by knocking-down toxic gain-of-function RNA transcripts and by modifying RNA splicing. In Duchenne muscular dystrophy, intravenous antisense oligonucleotides have been used to modify gene splicing to skip the diseasecausing mutations. Although a phase 3 trial in 2013 reported no signiﬁcant beneﬁts, a phase 2 trial carried out in a more homogeneous and younger cohort showed improvement in the 6-min walk test.1 The use of an oral small-molecule approach to stop-codon suppression (ataluren [PTC124]) showed eﬃcacy in patients with Duchenne muscular dystrophy. These positive trial data have enabled ataluren to achieve conditional ﬁrst approval in USA.2 These ﬁndings potentially pave the way for stop-codon suppression therapy in other neuromuscular diseases. In amyotrophic lateral sclerosis, antisense oligonucleotides will need to be delivered intrathecally. Investigators are applying this approach to C9orf72 hexanucleotide expansions, which account for 6–10% 13
of cases of amyotrophic lateral sclerosis in Europe. Importantly, molecular data show a toxic mechanism for C9orf72 through dipeptide repeats derived from the unconventional translation of the hexanucleotide repeat.3 Although other mechanisms, including RNA toxicity, might also have a role, these ﬁndings support progress to planned trials for antisense oligonucleotides in C9orf72 amyotrophic lateral sclerosis. Small-molecule approaches have also been used to correct splicing events in spinal muscular atrophy, a progressive motor neuron disorder in infants. Spinal muscular atrophy is most commonly caused by mutations in the survival motor neuron SMN1 gene that results in decreased levels of the SMN protein. Another closely related gene, SMN2, normally produces only small amounts of full transcript of a virtually identical gene due to a single nucleotide polymorphism that alters its splicing pattern. Restoration of SMN1-like splicing in SMN2 could be beneﬁcial in patients with spinal muscular atrophy. A 2014 study used patient-derived cells to screen more than 200 000 small molecules to identify compounds that restore splicing of SMN2.4 Cell lines and two mouse models showed the preclinical eﬃcacy of this approach and conﬁrmed speciﬁcity of the molecular eﬀect.4 There were also important preclinical and clinical developments in stem-cell therapies in 2014. An interesting proof-of-principle study in mice showed how optogenetically modiﬁed embryonic-stem-cell-derived motor neurons can be transplanted into a peripheral nerve that had previously undergone constriction to denervate the muscles it supplied. The transplanted cells survived and extended axons to reinnervate the denervated muscle.5 Optical stimulation of these grafted neurons resulted in physiological activation of motor units leading to muscle contraction. This technique could lead to developing beneﬁcial applications such as
diaphragmatic pacing in amyotrophic lateral sclerosis. A phase 1/2A cell therapy trial was done in patients with the late-onset autosomal-dominant genetic muscle disease oculopharyngeal muscular dystrophy. The investigators injected patient-derived autologous muscle cells from an unaﬀected quadriceps muscle into the aﬀected pharyngeal muscles. Tolerability and safety of the procedure were established, along with encouraging eﬀects on swallowing that will need to be conﬁrmed in larger trials.6 However, the role that intraspinal injections of neural stem cells might have in the treatment for amyotrophic lateral sclerosis needs further study. Multistakeholder coordination and data integration through experimental therapy centres that drive trial networks will accelerate progress towards treatments. The increasing numbers of experimental therapy interventions indicate that a genuine transition from gene discovery to experimental therapeutics is starting to occur for patients with neuromuscular diseases. Pietro Fratta, *Michael G Hanna MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK [email protected]
We have no competing interests. 1
Voit T, Topaloglu H, Straub V, et al. Safety and eﬃcacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol 2014; 13: 987–96. Bushby K, Finkel R, Wong B, et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerv. 2014; 5: 47–87. Rohrer J, Isaacs A, Mizlienska S, Mead S, Lashley T, Wray S. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol (in press). Naryshkin NA, Weetall M, Dakka A, et al. Motor neuron disease. SMN2 splicing modiﬁers improve motor function and longevity in mice with spinal muscular atrophy. Science 2014; 345: 688–93. Bryson JB, Machado CB, Crossley M, et al. Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice. Science 2014; 344: 94–97. Périé S, Trollet C, Mouly V, et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol Ther J Am Soc Gene Ther 2014; 22: 219–25.
Concussion research: new horizons With a growing number of youth and adolescents participating in sports worldwide, understanding the acute assessment and treatment of sport-related concussion and the possible long-term consequences is imperative. Our knowledge of concussion has advanced substantially over the past two decades, but many questions remain unanswered. 14
During the early 2000s, most research was focused on the validation of concussion assessment tools, and the eﬀectiveness of a multimodal assessment battery (symptom checklists, cognitive tests, and balance tests) was subsequently established. Attention is now turning towards education, acute diagnostic biomarkers, and treatment. In 2014, innovative investigations that www.thelancet.com/neurology Vol 14 January 2015