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一种罕见遗传病的患者定制寡核苷酸疗法
Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease


Jinkuk Kim ... 其他 • 2019.10.24
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摘要


基因组测序通常是诊断罕见病的关键,但许多罕见病缺乏特异性治疗方法。我们在本文中介绍了对一种罕见致死性神经退行性疾病的分子诊断是如何促使我们合理设计、检测和制造出milasen,即为1例患者定制的,用于调节剪接的反义寡核苷酸药物。在该患者细胞系中进行的概念验证实验成为首次接触患者后1年内启动milasen“单一患者”(N-of-1)研究的基础。本试验未发生严重不良事件,且治疗与癫痫发作的客观减少相关(通过脑电图和家长报告确定)。本研究为针对患者快速开发出定制治疗提供了一个可能的模板(由Mila的奇迹基金会[Mila's Miracle]等资助)。





作者信息

Jinkuk Kim, Ph.D., Chunguang Hu, M.D., Ph.D., Christelle Moufawad El Achkar, M.D., Lauren E. Black, Ph.D., Julie Douville, Ph.D., Austin Larson, M.D., Mary K. Pendergast, J.D., Sara F. Goldkind, M.D., Eunjung A. Lee, Ph.D., Ashley Kuniholm, B.S., Aubrie Soucy, B.A., Jai Vaze, B.A., Nandkishore R. Belur, M.S., Kristina Fredriksen, B.S., Iva Stojkovska, B.S., Alla Tsytsykova, Ph.D., Myriam Armant, Ph.D., Renata L. DiDonato, B.S., Jaejoon Choi, Ph.D., Laura Cornelissen, Ph.D., Luis M. Pereira, Ph.D., Erika F. Augustine, M.D., Casie A. Genetti, M.S., Kira Dies, Sc.M., Brenda Barton, R.N., Lucinda Williams, D.N.P., Benjamin D. Goodlett, Ph.D., Bobbie L. Riley, M.D., Amy Pasternak, D.P.T., P.C.S., Emily R. Berry, D.P.T., Kelly A. Pflock, D.P.T., P.C.S., Stephen Chu, Pharm.D., Chantal Reed, Ph.D., Kimberly Tyndall, B.A., Pankaj B. Agrawal, M.B., B.S., M.M.Sc., Alan H. Beggs, Ph.D., P. Ellen Grant, M.D., David K. Urion, M.D., Richard O. Snyder, Ph.D., Susan E. Waisbren, Ph.D., Annapurna Poduri, M.D., M.P.H., Peter J. Park, Ph.D., Al Patterson, Pharm.D., Alessandra Biffi, M.D., Joseph R. Mazzulli, Ph.D., Olaf Bodamer, M.D., Ph.D., Charles B. Berde, M.D., Ph.D., and Timothy W. Yu, M.D., Ph.D.
From the Divisions of Genetics and Genomics (J.K., C.H., E.A.L., A.S., J.V., R.L.D., J.C., P.B.A., A.H.B., S.E.W., O.B., T.W.Y.), Newborn Medicine (P.B.A., P.E.G.), and Neuroradiology (P.E.G.), the Departments of Neurology (C.M.E.A., D.K.U., A. Poduri), Anesthesiology, Critical Care and Pain Medicine (L.C., C.B.B.), Physical and Occupational Therapy (A. Pasternak, E.R.B., K.A.P.), and Pharmacy (S.C., A. Patterson), the Institutional Centers for Clinical and Translational Research (A.K., B.B., L.W.), and the Manton Center for Orphan Disease Research (C.A.G., P.B.A., A.H.B.), Boston Children’s Hospital (A.K., A.T., M.A., L.M.P., K.D., B.B., L.W., B.D.G., B.L.R., A.B.), the Department of Biomedical Informatics (J.K., P.J.P.), Harvard Medical School (J.K., C.M.E.A., E.A.L., L.C., B.D.G., B.L.R., P.B.A., A.H.B., P.E.G., D.K.U., S.E.W., P.J.P., A. Patterson, A.B., O.B., C.B.B., T.W.Y.), and the Gene Therapy Program (A.B.), Boston Children’s and Dana–Farber Cancer and Blood Disorders Center (A.K., B.B., L.W.), Boston, Charles River Laboratories, Wilmington (L.E.B.), and Broad Institute of MIT and Harvard (E.A.L., O.B., T.W.Y.), Cambridge — all in Massachusetts; Charles River Laboratories, Montreal (J.D.); University of Colorado School of Medicine, Aurora (A.L.); Pendergast Consulting, Washington, DC (M.K.P.); Goldkind Consulting, Potomac, MD (S.F.G.); the Department of Neurology Feinberg School of Medicine, Northwestern University, Chicago (N.R.B., K.F., I.S., J.R.M.); the Department of Neurology, University of Rochester Medical Center, Rochester, NY (E.F.A.); Brain Hz Consulting, Del Mar, CA (C.R.); Tyndall Consulting, Wake Forest, NC (K.T.); and Brammer Bio, Alachua, FL (R.O.S.). Address reprint requests to Dr. Yu at the Division of Genetics and Genomics, Boston Children’s Hospital, 300 Longwood Ave., Mailstop BCH3150, Boston, MA 02115, or at timothy.yu@childrens.harvard.edu.

 

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