Time: Wednesday, 14/June/2023: 10:45am - 12:15pm Session Chair: Caterina Garone Session Chair: Chiara La Morgia |
Location: Bologna Congress Center - Sala Europa Address: Piazza della Costituzione, 4/a, Bologna (BO), Italy |
ID: 166
Invited Speakers
Clinical trials for Leber hereditary optic neuropathy
Emory University School of Medicine, United States of America
Newman NJ, Yu-Wai-Man P, Subramanian PS, et al. Bilateral injection of lenadogene nolparvovec for m.11778G>A MT-ND4 Leber hereditary optic neuropathy. Brain 2023;awac421.doi: 10.1093/brain/awac421.
Carelli V, Newman NJ, Yu-Wai-Man P, et al. Indirect comparison of lenadogene nolparvovec gene therapy versus natural history in Leber hereditary optic neuropathy patients carrying the m.11778G>A MT-ND4 mutation. Ophthalmol Ther, 2022, https://doi.org/10.007/s40123-022-0061-x .
Newman NJ, Yu-Wai-Man P, Biousse V. Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management. Lancet Neurol 2023;S1474-4422(22)00174-0. doi: 10.1016/S1474-4422(22)00174-0.
Sahel JA, Newman NJ, Yu-Wai-Man P, Vignal-Clermont C, Carelli V, Biousse V, Moster ML, Sergott R, Klopstock T, Sadun AA, Blouin L, Katz B, Taiel M. Gene therapies for the treatment of Leber hereditary optic neuropathy. Int Ophthalmol Clin 61:195-208 2021.
Newman NJ, Yu-Wai-Man P, Carelli V, et al, for the LHON Study Group. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology 128:649-660, 2021.
Yu-Wai-Man P, Newman NJ, Carelli V, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med 2020 Dec 9;12(573):eaaz7423.
Catarino C, von Livonious B, Gallenmuller C, Banik R, Matloob S, Tamhankar M, Castillo Campillo LC, Dahlgren N, Friedburg C, Halfpenny C, Lincoln J, Traber G, Acaroglu G, Black G, Doncel C, Fraser C, Jakubaszko J, Landau K, Langenegger S, Munoz Negrete F, Newman N, Poulton J, Scoppettuolo E, Subramanian P, Toosy A, Vidal M, Vincent A, Votruba M, Zarowski M, Zermansky A, Lob F, Rudolph G, Mikazans O, Silva M, Lloria X, Metz G, Klopstock T. Real world clinical experience with idebenone in the treatment of Leber’s hereditary optic neuropathy. J Neuro-ophthalmol 40: 558–565, 2020.
ID: 2104
Invited Speakers
Development of deoxynucleoside therapy for mitochondrial DNA depletion/deletions syndrome
1Columbia University Irving Medical Center, New York, USA, United States of America; 2University of Bologna, Bologna, Italy; 3Univerity of Malaga, Malaga, Spain; 4University Hospital, 12 de Octubre, Madrid, Spain; 5Vall d’Hebron Institut de Recerca, Barcelona, Spain
1.Lopez-Gomez C, Camara Y, Hirano M, Marti R, nd EWP. 232nd ENMC international workshop: Recommendations for treatment of mitochondrial DNA maintenance disorders. 16 - 18 June 2017, Heemskerk, The Netherlands. Neuromuscul Disord. 2022;32(7):609-20. Epub 20220514. doi: 10.1016/j.nmd.2022.05.008. PubMed PMID: 35641351.
2.Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet. 2001;29(3):342-4. PubMed PMID: 11687801.
3.Garone C, Taylor RW, Nascimento A, Poulton J, Fratter C, Dominguez-Gonzalez C, Evans JC, Loos M, Isohanni P, Suomalainen A, Ram D, Hughes MI, McFarland R, Barca E, Lopez Gomez C, Jayawant S, Thomas ND, Manzur AY, Kleinsteuber K, Martin MA, Kerr T, Gorman GS, Sommerville EW, Chinnery PF, Hofer M, Karch C, Ralph J, Camara Y, Madruga-Garrido M, Dominguez-Carral J, Ortez C, Emperador S, Montoya J, Chakrapani A, Kriger JF, Schoenaker R, Levin B, Thompson JLP, Long Y, Rahman S, Donati MA, DiMauro S, Hirano M. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018;55(8):515-21. Epub 20180330. doi: 10.1136/jmedgenet-2017-105012. PubMed PMID: 29602790; PMCID: PMC6073909.
4.Wang J, Kim E, Dai H, Stefans V, Vogel H, Al Jasmi F, Schrier Vergano SA, Castro D, Bernes S, Bhambhani V, Long C, El-Hattab AW, Wong LJ. Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect. Mol Genet Metab. 2018;124(2):124-30. Epub 20180428. doi: 10.1016/j.ymgme.2018.04.012. PubMed PMID: 29735374.
5.Hidago-Gutierrez A, Shintaku J, Barriocanal-Casado E, Saneto R, Ramon J, Garrabou G, Tort F, Millsenda JC, Gort L, Pesini A, Tadesse S, King M-C, Martí R, Ribes A, Hirano M, editors. Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Form of Mitochondrial DNA Depletion/Deletions Syndrome. Euromit 2023; 2023; Bologna, Italy.
6.Akman HO, Dorado B, Lopez LC, Garcia-Cazorla A, Vila MR, Tanabe LM, Dauer WT, Bonilla E, Tanji K, Hirano M. Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance. Hum Mol Genet. 2008;17(16):2433-40. Epub 20080508. doi: 10.1093/hmg/ddn143. PubMed PMID: 18467430; PMCID: PMC3115590.
7.Zhou X, Solaroli N, Bjerke M, Stewart JB, Rozell B, Johansson M, Karlsson A. Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice. Hum Mol Genet. 2008;17(15):2329-35. Epub 20080422. doi: 10.1093/hmg/ddn133. PubMed PMID: 18434326.
8.Blazquez-Bermejo C, Molina-Granada D, Vila-Julia F, Jimenez-Heis D, Zhou X, Torres-Torronteras J, Karlsson A, Marti R, Camara Y. Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice. EBioMedicine. 2019;46:342-55. Epub 20190724. doi: 10.1016/j.ebiom.2019.07.042. PubMed PMID: 31351931; PMCID: PMC6711114.
9.Garone C, Garcia-Diaz B, Emmanuele V, Lopez LC, Tadesse S, Akman HO, Tanji K, Quinzii CM, Hirano M. Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med. 2014;6(8):1016-27. doi: 10.15252/emmm.201404092. PubMed PMID: 24968719; PMCID: PMC4154130.
10.Lopez-Gomez C, Levy RJ, Sanchez-Quintero MJ, Juanola-Falgarona M, Barca E, Garcia-Diaz B, Tadesse S, Garone C, Hirano M. Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency. Ann Neurol. 2017;81(5):641-52. doi: 10.1002/ana.24922. PubMed PMID: 28318037.
11.Lopez-Gomez C, Sanchez-Quintero MJ, Lee EJ, Kleiner G, Tadesse S, Xie J, Akman HO, Gao G, Hirano M. Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency. Ann Neurol. 2021;90(4):640-52. Epub 20210813. doi: 10.1002/ana.26185. PubMed PMID: 34338329; PMCID: PMC9307066.
12.Dominguez-Gonzalez C, Madruga-Garrido M, Mavillard F, Garone C, Aguirre-Rodriguez FJ, Donati MA, Kleinsteuber K, Marti I, Martin-Hernandez E, Morealejo-Aycinena JP, Munell F, Nascimento A, Kalko SG, Sardina MD, Alvarez Del Vayo C, Serrano O, Long Y, Tu Y, Levin B, Thompson JLP, Engelstad K, Uddin J, Torres-Torronteras J, Jimenez-Mallebrera C, Marti R, Paradas C, Hirano M. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy. Ann Neurol. 2019;86(2):293-303. Epub 20190617. doi: 10.1002/ana.25506. PubMed PMID: 31125140; PMCID: PMC7586249.
ID: 110
Therapy 2: clinical trials
Histopathological and molecular characterization in ocular post-mortem analyses following AAV2 gene therapy for LHON
1IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 2Doheny Eye Institute, UCLA School of Medicine, Los Angeles, CA, USA; 3IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 4Departments of Ophthalmology, Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, GA, USA; 5Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; 6Charles River Laboratories, Evreux, France; 7Gensight Biologics, Paris, France
Carelli V, Newman NJ, Yu-Wai-Man P, Biousse V, Moster ML, Subramanian PS, Vignal-Clermont C, Wang AG, Donahue SP, Leroy BP, Sergott RC, Klopstock T, Sadun AA, Rebolleda Fernández G, Chwalisz BK, Banik R, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA; theLHON Study Group. Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation. Ophthalmol Ther. 2022 Nov 30. doi: 10.1007/s40123-022-00611-x. Epub ahead of print. PMID: 36449262.
Newman NJ, Schniederjan M, Mendoza PR, Calkins DJ, Yu-Wai-Man P, Biousse V, Carelli V, Taiel M, Rugiero F, Singh P, Rogue A, Sahel JA, Ancian P. Absence of lenadogene nolparvovec DNA in a brain tumor biopsy from a patient in the REVERSE clinical study, a case report. BMC Neurol. 2022 Jul 12;22(1):257. doi: 10.1186/s12883-022-02787-y. PMID: 35820885; PMCID: PMC9277876.
Calkins DJ, Yu-Wai-Man P, Newman NJ, Taiel M, Singh P, Chalmey C, Rogue A, Carelli V, Ancian P, Sahel JA. Biodistribution of intravitreal lenadogene nolparvovec gene therapy in nonhuman primates. Mol Ther Methods Clin Dev. 2021 Oct 1;23:307-318. doi: 10.1016/j.omtm.2021.09.013. PMID: 34729378; PMCID: PMC8526752.
ID: 546
Therapy 2: clinical trials
Combatting myopathy in m.3243A>G mutation carriers: first in human transplantation of autologous mesoangioblasts
1Department of Toxicogenomics, Maastricht University Medical Centre+, Maastricht, The Netherlands; 2School for Mental Health and Neurosciences (MHeNS), Maastricht University Medical Centre+, Maastricht, The Netherlands; 3Department of Neurology, Maastricht University Medical Centre+, Maastricht, The Netherlands; 4Department of Radiology, Maastricht University Medical Centre+, Maastricht, The Netherlands; 5School for Developmental Biology and Oncology (GROW), Maastricht University Medical Centre+, Maastricht, The Netherlands; 6Center for Cell and Gene Therapy (CCG), Leiden University Medical Center, Leiden, The Netherlands; 7Department of Rehabilitation Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands; 8SMRC – Sports Medicine Research Center, BIOMED - Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; 9Neuromuscular and Mitochondrial research center (NeMo), Rotterdam/Maastricht, The Netherlands
ID: 573
Therapy 2: clinical trials
PHEMI: Phenylbutyrate Therapy in Mitochondrial Diseases with lactic acidosis: an open label clinical trial in MELAS and PDH deficiency patients.
1Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Experimental Neuroscience, Unit of Medical Genetics and Neurogenetics, Milan, Italy; 2Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Pediatric Neurosciences, Milan, Italy; 3Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis.
Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N.
Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.
PMID: 23467562
ID: 355
Therapy 2: clinical trials
Niacin treatment improves metabolic changes in early-stage mitochondrial myopathy
1Research Program for Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 3Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland; 4Department of Clinical Physiology and Nuclear Medicine, Laboratory of Clinical Physiology, Helsinki University Hospital, Helsinki, Finland; 5HUS Diagnostic Center, Radiology, Helsinki University and Helsinki University Hospital, Helsinki, Finland; 6Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; 7Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 8Healthy Weight Hub, Abdominal Center, Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 9Helsinki University Hospital Diagnostic Centre, Helsinki, Finland
Eija Pirinen, Mari Auranen, Nahid A. Khan, Virginia Brilhante, Niina Urho, Alberto Pessia, Antti Hakkarainen, Juho Kuula, Ulla Heinonen, Mark S. Schmidt, Kimmo Haimilahti, Päivi Piirilä, Nina Lundbom, Marja-Riitta Taskinen, Charles Brenner, Vidya Velagapudi, Kirsi H. Pietiläinen, Anu Suomalainen. Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab 2020;31(6):1078-1090.e5.
ID: 102
Therapy 2: clinical trials
Use of lenadogene nolparvovec gene therapy for Leber hereditary optic neuropathy in early access programs
1IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 2Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France; 3Centre Hospitalier National d’Ophtalmologie des Quinze Vingts, Paris, France; 4Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA; 5Department of Ophthalmology, Neurology, and Pediatrics, Vanderbilt University, and Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA; 6Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 7Institut de Génétique Médicale d’Alsace, CHU de Strasbourg, Strasbourg, France; 8Friedrich-Baur-Institute, University Hospital, Ludwig-Maximilians-University, Munich, Germany; 9University Hospital, Ludwig-Maximilians-University, Munich, Germany; 10Service Explorations de la Vision et Neuro-Ophtalmologie, CHU de Lille, Lille, France; 11Service d'Ophtalmologie, CHU de Rennes, Rennes, France; 12Service d'Ophtalmologie, CHU de Bordeaux, Groupe Hospitalier Pellegrin, Bordeaux, France; 13Service d'Ophtalmologie, CHU de Nantes, Nantes, France; 14Service de Neuro-Cognition et Neuro-Ophtalmologie, CHU de Lyon, Lyon, France; 15Service d'Ophtalmologie, Centre Hospitalier de Valence, Valence, France; 16Service d'Ophtalmologie, CHU de Caen, Caen, France; 17Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas, USA; 18Retina Consultants, P.C, Hartford, Connecticut, USA; 19Service d'Ophtalmologie, Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; 20Centre Hospitalier de Wallonie Picarde, Tournai, Belgium; 21GenSight Biologics, Paris, France; 22Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France; 23Department of Biomedical and Neuromotor Sciences, DIBINEM, Bologna, Italy
Yu-Wai-Man P, Newman NJ, Carelli V, Moster ML, Biousse V, Sadun AA, Klopstock T, Vignal-Clermont C, Sergott RC, Rudolph G, La Morgia C, Karanjia R, Taiel M, Blouin L, Burguière P, Smits G, Chevalier C, Masonson H, Salermo Y, Katz B, Picaud S, Calkins DJ, Sahel JA. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. 2020 Dec 9;12(573):eaaz7423. doi: 10.1126/scitranslmed.aaz7423. PMID: 33298565.
Newman NJ, Yu-Wai-Man P, Carelli V, Biousse V, Moster ML, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Front Neurol. 2021 May 24;12:662838. doi: 10.3389/fneur.2021.662838. PMID: 34108929; PMCID: PMC8181419.
Biousse V, Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Esposti S, La Morgia C, Priglinger C, Karanja R, Blouin L, Taiel M, Sahel JA; LHON Study Group. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study. J Neuroophthalmol. 2021 Sep 1;41(3):309-315. doi: 10.1097/WNO.0000000000001367. PMID: 34415265; PMCID: PMC8366761.