Antisense therapy: Potential tool to reduce activity in MS via protein expression inhibition Robert T. Naismith and Anne H. Cross Neurology published online September 19, 2014 DOI 10.1212/WNL.0000000000000927 This information is current as of September 19, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/early/2014/09/19/WNL.0000000000000927.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Published Ahead of Print on September 19, 2014 as 10.1212/WNL.0000000000000927
EDITORIAL
Antisense therapy Potential tool to reduce activity in MS via protein expression inhibition
Robert T. Naismith, MD Anne H. Cross, MD
Correspondence to Dr. Cross:
[email protected] Neurology® 2014;83:1–2
Molecularly engineered therapeutics can provide the advantage of promoting specific biologic effects. Moreover, disease treatments with few or no “off-target” effects have great potential to improve safety and side effect profiles. Monoclonal antibodies represent one category of engineered therapeutics that is increasingly utilized in many different disorders, often offering enhanced efficacy compared to therapies with more generalized and nonspecific mechanisms of action. Despite the success of many monoclonal antibody therapies, concerns remain with regard to safety, dosing, neutralizing antibody formation, and CNS penetration. Another way to alter a biologic effect is by blocking translation of proteins at the level of the body’s own protein production. Proteins are produced by translation of single-stranded messenger RNA (mRNA), transcribed from its gene. For translation to occur, the mRNA must be single-stranded. Antisense RNA tightly binds to its mirror image mRNA, resulting in highly specific inhibition of production of the protein it encodes. For these reasons, development of antisense oligonucleotides to treat human disease has been pursued vigorously over the past several decades. In this issue of Neurology®, Limmroth et al.1 describe a multicenter phase II trial in patients with relapsing-remitting multiple sclerosis (MS) using a novel second-generation antisense drug (ATL1102) that targets the mRNA that encodes for human CD49d. CD49d forms the a subunit of the very late antigen 4 (VLA-4) integrin heterodimer expressed by activated T and B lymphocytes, and that is critical for these cells to adhere to CNS venules and then migrate into the CNS to form MS lesions. The CD49d subunit of VLA-4 is the target of the monoclonal antibody natalizumab.2 Natalizumab is highly efficacious for relapsing MS, although it has also been associated with risk of developing progressive multifocal leukoencephalopathy.3–5 As an antisense agent, ATL1102 targets the same CD49d molecule but through inhibition of protein expression. The present study was insufficiently powered to assess long-term risks of progressive multifocal leukoencephalopathy and other infectious complications.
In the study by Limmroth et al., 77 patients with relapsing-remitting MS were enrolled in a trial of 200 mg of ATL1102 given subcutaneously twice weekly for 7 weeks, following an initial induction week of 3 injections. Patients were randomized 1:1 to either ATL1102 or to placebo for the 8 weeks. Brain MRIs were obtained at baseline and weeks 4, 8, 12, and 16. Based upon MRIs performed at 4, 8, and 12 weeks, ATL1102 was associated with a 54% reduction in cumulative new active lesions compared to placebo and a 68% reduction in gadolinium-enhancing lesions. The number of relapses in the 2 groups was not significantly different, but the study was not powered to detect a difference. The ATL1102 trial is remarkable for its beneficial imaging effects after 8 weeks of treatment, and that this study is one of the first reports of an antisense oligonucleotide used to successfully treat a neurologic condition. As of this writing, the Food and Drug Administration has approved 2 drugs based on antisense technology: fomivirsen (used for treatment of cytomegalovirus retinitis but now withdrawn from the market for commercial reasons) and mipomersen (targets the mRNA for apolipoprotein B-100; used to treat homozygous familial hypercholesterolemia).6,7 A survey of ClinicalTrials.gov revealed that dozens more drugs based on antisense technology are at various stages in human clinical trials. The potential uses for antisense agents could include anti-infectious treatments, therapy of genetic or degenerative disorders in which abnormal proteins are produced,8 as well as to block production of normal proteins that represent critical steps in pathophysiology of diseases, as in the present study. MRI in MS is established as a sensitive and powerful biomarker of a clinical response to anti-inflammatory treatments.9 The present proof-of-concept trial is encouraging in that positive MRI results were obtained within only 2 months in 77 patients. However, validation that ATL1102 works through its intended effects will be important. This is because some antisense therapies can provoke a generalized and nonspecific “antiviral” or anti-inflammatory response. Further human studies to
See page XXX 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. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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fully clarify the mechanism of action of ATL1102 should be done. Antisense RNA-based therapies have potential to provide precise effects in MS and other neurologic and neurodegenerative disorders. In comparison to monoclonal antibodies, these therapies might provide improved means of delivery and safety. Antisense oligonucleotides have for decades been a valuable tool in laboratory research to understand biological systems. Now, with advances in the understanding of the molecular pathophysiology of neurologic disorders, the goal of using highly specific therapies such as antisense therapies to meet the imminent needs of our patients is becoming within reach. STUDY FUNDING No targeted funding reported.
DISCLOSURE R. Naismith serves on a Scientific Advisory Board for Acorda Therapeutics; has received funding for travel or speaker honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, Genzyme Corporation, National MS Society, Consortium MS Centers, EMD Serono, Questcor Therapeutics, Genentech, and Novartis; serves as an Associate Editor for Journal Watch; serves on speakers’ bureaus for Acorda Therapeutics, Bayer Healthcare, Biogen Idec, and Genzyme Corporation; and receives research support from Acorda Therapeutics and the National MS Society. A. Cross serves/has served on scientific advisory boards for Hoffman–la Roche, Genzyme, GlaxoSmithKline, Novartis, and the National MS Society; has received funding for travel or speaker honoraria from Projects in Knowledge, Inc., Sanofi-Aventis (Genzyme), WebMD 2014, CMEducation, and Med-IQ; serves on editorial boards for Brain Pathology and Journal of Neuroimmunology and Associate Editor of Annals Clinical Translational Neurology; serves/has served as a consultant for BiogenIdec, Sanofi- Aventis, Novartis, Teva Neuroscience, Gerson Lehrman Group, Guidepoint Global, LLC, and Frankel Group; has served on speakers’ bureaus for Genzyme and Novartis; and receives/has received research support from Sanofi-Aventis, Hoffman–La Roche, Teva Neuroscience, EMD-Serono, NIH/National Institute of Neurological Disorders
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and Stroke, National MS Society, Missouri Spinal Cord Injuries Research Program, Barnes-Jewish Hospital Foundation, and Consortium of MS Centers. Go to Neurology.org for full disclosures.
REFERENCES 1. Limmroth V, Barkhof F, Desem N, Diamond MP, Tachas G, for the ATL1102 Study Group. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology 2014;83:xx–xx. 2. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15–23. 3. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369–374. 4. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353:375–381. 5. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368. 6. Fattal E, Bochot A. Ocular delivery of nucleic acids: antisense oligonucleotides, aptamers and siRNA. Adv Drug Deliv Rev 2006;58:1203–1223. 7. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebocontrolled trial. Lancet 2010;375:998–1006. 8. Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435–442. 9. Sormani MP, Bruzzi P. MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol 2013;12:669–676.
November 11, 2014
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Antisense therapy: Potential tool to reduce activity in MS via protein expression inhibition Robert T. Naismith and Anne H. Cross Neurology published online September 19, 2014 DOI 10.1212/WNL.0000000000000927 This information is current as of September 19, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/09/19/WNL.00000 00000000927.full.html
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