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Antisense Therapy Potential Tool to Reduce Activity in MS Via Protein Expression Inhibition

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Antisense Therapy Potential Tool to Reduce Activity in MS Via Protein Expression Inhibition EDITORIAL Antisense therapy Potential tool to reduce activity in MS via protein expression inhibition Robert T. Naismith, MD Molecularly engineered therapeutics can provide the In the study by Limmroth et al., 77 patients with Anne H. Cross, MD advantage of promoting specific biologic effects. More- relapsing-remitting MS were enrolled in a trial of over, disease treatments with few or no “off-target” 200 mg of ATL1102 given subcutaneously twice effects have great potential to improve safety and side weekly for 7 weeks, following an initial induction week Correspondence to effect profiles. Monoclonal antibodies represent one of 3 injections. Patients were randomized 1:1 to either Dr. Cross: [email protected] category of engineered therapeutics that is increasingly ATL1102 or to placebo for the 8 weeks. Brain MRIs utilized in many different disorders, often offering were obtained at baseline and weeks 4, 8, 12, and Neurology® 2014;83:1776–1777 enhanced efficacy compared to therapies with more 16. Based upon MRIs performed at 4, 8, and 12 generalized and nonspecific mechanisms of action. weeks, ATL1102 was associated with a 54% reduction Despite the success of many monoclonal antibody ther- in cumulative new active lesions compared to placebo apies, concerns remain with regard to safety, dosing, and a 68% reduction in gadolinium-enhancing lesions. neutralizing antibody formation, and CNS penetration. The number of relapses in the 2 groups was not Another way to alter a biologic effect is by blocking significantly different, but the study was not powered translation of proteins at the level of the body’sown to detect a difference. The ATL1102 trial is remarkable protein production. Proteins are produced by transla- for its beneficial imaging effects after 8 weeks of treat- tion of single-stranded messenger RNA (mRNA), tran- ment, and that this study is one of the first reports of an scribed from its gene. For translation to occur, the antisense oligonucleotide used to successfully treat a mRNA must be single-stranded. Antisense RNA neurologic condition. tightly binds to its mirror image mRNA, resulting in As of this writing, the Food and Drug Adminis- highly specific inhibition of production of the protein tration has approved 2 drugs based on antisense it encodes. For these reasons, development of antisense technology: fomivirsen (used for treatment of cyto- oligonucleotides to treat human disease has been pur- megalovirus retinitis but now withdrawn from the sued vigorously over the past several decades. market for commercial reasons) and mipomersen In this issue of Neurology®, Limmroth et al.1 (targets the mRNA for apolipoprotein B-100; used describe a multicenter phase II trial in patients with to treat homozygous familial hypercholesterole- relapsing-remitting multiple sclerosis (MS) using a mia).6,7 A survey of ClinicalTrials.gov revealed that novel second-generation antisense drug (ATL1102) dozens more drugs based on antisense technology are that targets the mRNA that encodes for human at various stages in human clinical trials. The potential CD49d. CD49d forms the a subunit of the very late uses for antisense agents could include anti-infectious antigen 4 (VLA-4) integrin heterodimer expressed by treatments, therapy of genetic or degenerative disorders activated T and B lymphocytes, and that is critical for in which abnormal proteins are produced,8 as well as these cells to adhere to CNS venules and then migrate to block production of normal proteins that represent into the CNS to form MS lesions. The CD49d sub- critical steps in pathophysiology of diseases, as in the unit of VLA-4 is the target of the monoclonal present study. antibody natalizumab.2 Natalizumab is highly effica- MRI in MS is established as a sensitive and powerful cious for relapsing MS, although it has also been biomarker of a clinical response to anti-inflammatory associated with risk of developing progressive multi- treatments.9 The present proof-of-concept trial is encour- focal leukoencephalopathy.3–5 As an antisense agent, aging in that positive MRI results were obtained within ATL1102 targets the same CD49d molecule but only 2 months in 77 patients. However, validation that through inhibition of protein expression. The present ATL1102 works through its intended effects will be study was insufficiently powered to assess long-term important. This is because some antisense therapies risks of progressive multifocal leukoencephalopathy can provoke a generalized and nonspecific “antiviral” or and other infectious complications. anti-inflammatory response. Further human studies to See page 1780 From the Department of Neurology (R.T.N., A.H.C.) and Hope Center for Neurological Disorders (A.H.C.), Washington University School of Medicine, St. Louis, MO. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1776 © 2014 American Academy of Neurology fully clarify the mechanism of action of ATL1102 should and Stroke, National MS Society, Missouri Spinal Cord Injuries Research be done. Program, Barnes-Jewish Hospital Foundation, and Consortium of MS Centers. Go to Neurology.org for full disclosures. Antisense RNA-based therapies have potential to provide precise effects in MS and other neurologic REFERENCES and neurodegenerative disorders. In comparison to 1. Limmroth V, Barkhof F, Desem N, Diamond MP, monoclonal antibodies, these therapies might provide Tachas G, for the ATL1102 Study Group. CD49d anti- improved means of delivery and safety. Antisense oli- sense drug ATL1102 reduces disease activity in patients gonucleotides have for decades been a valuable tool in with relapsing-remitting MS. Neurology 2014;83:1780–1788. laboratory research to understand biological systems. 2. Miller DH, Khan OA, Sheremata WA, et al. A controlled Now, with advances in the understanding of the trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. molecular pathophysiology of neurologic disorders, 3. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multi- the goal of using highly specific therapies such as anti- focal leukoencephalopathy complicating treatment with sense therapies to meet the imminent needs of our natalizumab and interferon beta-1a for multiple sclerosis. patients is becoming within reach. N Engl J Med 2005;353:369–374. 4. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, STUDY FUNDING Pelletier D. Progressive multifocal leukoencephalopathy in No targeted funding reported. a patient treated with natalizumab. N Engl J Med 2005; 353:375–381. DISCLOSURE 5. Van Assche G, Van Ranst M, Sciot R, et al. Progressive R. Naismith serves on a Scientific Advisory Board for Acorda Therapeu- multifocal leukoencephalopathy after natalizumab therapy tics; has received funding for travel or speaker honoraria from Acorda for Crohn’s disease. N Engl J Med 2005;353:362–368. Therapeutics, Bayer Healthcare, Biogen Idec, Genzyme Corporation, 6. Fattal E, Bochot A. Ocular delivery of nucleic acids: anti- National MS Society, Consortium MS Centers, EMD Serono, Questcor sense oligonucleotides, aptamers and siRNA. Adv Drug Therapeutics, Genentech, and Novartis; serves as an Associate Editor for – Journal Watch; serves on speakers’ bureaus for Acorda Therapeutics, Deliv Rev 2006;58:1203 1223. Bayer Healthcare, Biogen Idec, and Genzyme Corporation; and receives 7.RaalFJ,SantosRD,BlomDJ,etal.Mipomersen,an research support from Acorda Therapeutics and the National MS Society. apolipoprotein B synthesis inhibitor, for lowering of LDL cho- A. Cross serves/has served on scientific advisory boards for Hoffman–la lesterol concentrations in patients with homozygous familial Roche, Genzyme, GlaxoSmithKline, Novartis, and the National MS hypercholesterolaemia: a randomised, double-blind, placebo- Society; has received funding for travel or speaker honoraria from Projects controlled trial. Lancet 2010;375:998–1006. in Knowledge, Inc., Sanofi-Aventis (Genzyme), WebMD 2014, CME- 8. Miller TM, Pestronk A, David W, et al. An antisense ducation, and Med-IQ; serves on editorial boards for Brain Pathology and oligonucleotide against SOD1 delivered intrathecally for Journal of Neuroimmunology and Associate Editor of Annals Clinical patients with SOD1 familial amyotrophic lateral sclerosis: Translational Neurology; serves/has served as a consultant for Biogen- a phase 1, randomised, first-in-man study. Lancet Neurol Idec, Sanofi- Aventis, Novartis, Teva Neuroscience, Gerson Lehrman – Group, Guidepoint Global, LLC, and Frankel Group; has served on 2013;12:435 442. speakers’ bureaus for Genzyme and Novartis; and receives/has received 9. Sormani MP, Bruzzi P. MRI lesions as a surrogate for research support from Sanofi-Aventis, Hoffman–La Roche, Teva Neuro- relapses in multiple sclerosis: a meta-analysis of randomised science, EMD-Serono, NIH/National Institute of Neurological Disorders trials. Lancet Neurol 2013;12:669–676. Neurology 83 November 11, 2014 1777.
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