{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T04:17:53Z","timestamp":1784434673046,"version":"3.55.0"},"reference-count":201,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000098","name":"NIH","doi-asserted-by":"publisher","award":["RO1 1R01AR073908-01A1"],"award-info":[{"award-number":["RO1 1R01AR073908-01A1"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nationwide Children\u2019s Hospital","award":["RO1 1R01AR073908-01A1"],"award-info":[{"award-number":["RO1 1R01AR073908-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Neurodegenerative disorders (NDDs), such as Alzheimer\u2019s disease (AD) and Parkinson\u2019s Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NMDs) are a group of diseases in which patients show primary progressive muscle weaknesses, including Duchenne Muscular Dystrophy (DMD), Pompe disease, and Spinal Muscular Atrophy (SMA). NDDs and NMDs typically have a genetic component, which affects the physiological functioning of critical cellular processes, leading to pathogenesis. Currently, there is no cure or efficient treatment for most of these diseases. More than 200 clinical trials have been completed or are currently underway in order to establish safety, tolerability, and efficacy of promising gene therapy approaches. Thus, gene therapy-based therapeutics, including viral or non-viral delivery, are very appealing for the treatment of NDDs and NMDs. In particular, adeno-associated viral vectors (AAV) are an attractive option for gene therapy for NDDs and NMDs. However, limitations have been identified after systemic delivery, including the suboptimal capacity of these therapies to traverse the blood\u2013brain barrier (BBB), degradation of the particles during the delivery, high reactivity of the patient\u2019s immune system during the treatment, and the potential need for redosing. To circumvent these limitations, several preclinical and clinical studies have suggested intrathecal (IT) delivery to target the CNS and peripheral organs via cerebrospinal fluid (CSF). CSF administration can vastly improve the delivery of small molecules and drugs to the brain and spinal cord as compared to systemic delivery. Here, we review AAV biology and vector design elements, different therapeutic routes of administration, and highlight CSF delivery as an attractive route of administration. We discuss the different aspects of neuromuscular and neurodegenerative diseases, such as pathogenesis, the landscape of mutations, and the biological processes associated with the disease. We also describe the hallmarks of NDDs and NMDs as well as discuss current therapeutic approaches and clinical progress in viral and non-viral gene therapy and enzyme replacement strategies for those diseases.<\/jats:p>","DOI":"10.3390\/jpm12121979","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T07:10:27Z","timestamp":1669792227000},"page":"1979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders"],"prefix":"10.3390","volume":"12","author":[{"given":"Cintia","family":"Gomez Limia","sequence":"first","affiliation":[{"name":"Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Baird","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Saxena","sequence":"additional","affiliation":[{"name":"Department of Neurology, Inselspital, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Meyer","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5892-3639","authenticated-orcid":false,"given":"Nicolas","family":"Wein","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hardiman, O., and Doherty, C.P. (2011). Neurodegenerative Disorders a Clinical Guide, Infona. [2nd ed.].","DOI":"10.1007\/978-1-84996-011-3"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1474-4422(18)30499-X","article-title":"Global, regional, and national burden of neurological disorders, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Feigin","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S1474-4422(19)30411-9","article-title":"The global burden of neurological disorders: Translating evidence into policy","volume":"19","author":"Feigin","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_4","unstructured":"IQVIA Institute, and Parsippany, N. (2022, November 06). Understanding Neuromuscular Disease Care. October 2018. Available online: https:\/\/www.iqvia.com\/-\/media\/iqvia\/pdfs\/institute-reports\/understanding-neuromuscular-disease-care.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41580-021-00389-z","article-title":"Molecular and cellular basis of genetically inherited skeletal muscle disorders","volume":"22","author":"Dowling","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5835","DOI":"10.1007\/s12035-019-1478-5","article-title":"NeuroMuscleDB: A Database of Genes Associated with Muscle Development, Neuromuscular Diseases, Ageing, and Neurodegeneration","volume":"56","author":"Baig","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.tig.2019.12.002","article-title":"Omics in Neurodegenerative Disease: Hope or Hype?","volume":"36","author":"Ortiz","year":"2020","journal-title":"Trends Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.omtm.2021.01.009","article-title":"Preclinical biodistribution, tropism, and efficacy of oligotropic AAV\/Olig001 in a mouse model of congenital white matter disease","volume":"20","author":"Francis","year":"2021","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/gt.2012.101","article-title":"Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates","volume":"20","author":"Gray","year":"2013","journal-title":"Gene Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41573-020-0075-7","article-title":"Advances in oligonucleotide drug delivery","volume":"19","author":"Roberts","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3389\/fnagi.2019.00373","article-title":"Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain","volume":"11","author":"Pardridge","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1126\/science.aba4515","article-title":"RNA-targeted drugs for neuromuscular diseases","volume":"371","author":"Ferlini","year":"2021","journal-title":"Science"},{"key":"ref_13","first-page":"1","article-title":"Correction to: Neurodegenerative diseases: A hotbed for splicing defects and the potential therapies","volume":"10","author":"Li","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1515\/jpm-2021-0435","article-title":"Postnatal gene therapy for neuromuscular diseases\u2013opportunities and limitations","volume":"49","author":"Kirschner","year":"2021","journal-title":"J. P\u00e9rinat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41593-020-00778-1","article-title":"Gene-based therapies for neurodegenerative diseases","volume":"24","author":"Sun","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1089\/hum.2020.105","article-title":"The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System","volume":"32","author":"Piguet","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2147\/IJN.S61288","article-title":"Current approaches to enhance CNS delivery of drugs across the brain barriers","volume":"9","author":"Lu","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.ymthe.2019.11.012","article-title":"A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna","volume":"28","author":"Taghian","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"580179","DOI":"10.3389\/fnins.2020.580179","article-title":"Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock","volume":"14","author":"Martier","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.3389\/fnins.2021.747726","article-title":"A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neu-rodegenerative Diseases","volume":"15","author":"Fischell","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"814174","DOI":"10.3389\/fneur.2021.814174","article-title":"Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence","volume":"12","author":"Manini","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1038\/sj.gt.3302133","article-title":"Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo","volume":"10","author":"Wang","year":"2003","journal-title":"Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nbt.1515","article-title":"Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes","volume":"27","author":"Foust","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/mt.2011.72","article-title":"Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman Primates","volume":"19","author":"Gray","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1089\/hum.2013.005","article-title":"Strong Cortical and Spinal Cord Transduction After AAV7 and AAV9 Delivery into the Cerebrospinal Fluid of Nonhuman Primates","volume":"24","author":"Samaranch","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3389\/fnmol.2014.00076","article-title":"Biology of adeno-associated viral vectors in the central nervous system","volume":"7","author":"Murlidharan","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1089\/hgtb.2016.133","article-title":"Impact of Inverted Terminal Repeat Integrity on rAAV8 Production Using the Baculovirus\/Sf9 Cells System","volume":"28","author":"Savy","year":"2017","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-associated virus vector as a platform for gene therapy delivery","volume":"18","author":"Wang","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1038\/sj.gt.3302615","article-title":"Current issues in adeno-associated viral vector production","volume":"12","author":"Merten","year":"2005","journal-title":"Gene Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1126\/science.149.3685.754","article-title":"Adenovirus-Associated Defective Virus Particles","volume":"149","author":"Atchison","year":"1965","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1073\/pnas.55.6.1467","article-title":"Studies of small DNA viruses found in various adenovirus preparations: Physical, biological, and immunological characteristics","volume":"55","author":"Hoggan","year":"1966","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16002","DOI":"10.1038\/mtm.2016.2","article-title":"Manufacturing of recombinant adeno-associated viral vectors for clinical trials","volume":"3","author":"Grieger","year":"2016","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2217\/fvl-2017-0011","article-title":"Understanding capsid assembly and genome packaging for adeno-associated viruses","volume":"12","author":"Bennett","year":"2017","journal-title":"Futur. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/sj.gt.3301514","article-title":"Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis","volume":"8","author":"Mccarty","year":"2001","journal-title":"Gene Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1128\/mr.54.3.316-329.1990","article-title":"Parvovirus replication","volume":"54","author":"Berns","year":"1990","journal-title":"Microbiol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/sj.mt.6300397","article-title":"Adeno-associated Virus of a Single-polarity DNA Genome Is Capable of Transduction In Vivo","volume":"16","author":"Zhou","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1038\/mt.2008.171","article-title":"Self-complementary AAV Vectors; Advances and Applications","volume":"16","author":"McCarty","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1586\/ehm.11.48","article-title":"Self-complementary adeno-associated viral vectors for gene therapy of hemophilia B: Progress and challenges","volume":"4","author":"Raj","year":"2011","journal-title":"Expert Rev. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41576-019-0205-4","article-title":"Engineering adeno-associated virus vectors for gene therapy","volume":"21","author":"Li","year":"2020","journal-title":"Nat. Rev. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1038\/s41467-019-11668-x","article-title":"Divergent engagements between adeno-associated viruses with their cellular receptor AAVR","volume":"10","author":"Zhang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Large, E., Silveria, M., Zane, G., Weerakoon, O., and Chapman, M. (2021). Adeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions upon Cell Entry. Viruses, 13.","DOI":"10.3390\/v13071336"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.omtm.2022.05.009","article-title":"Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors","volume":"26","author":"Xu","year":"2022","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/jnc.13861","article-title":"Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells","volume":"140","author":"Merkel","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1038\/mt.2011.98","article-title":"Several rAAV Vectors Efficiently Cross the Blood\u2013brain Barrier and Transduce Neurons and Astrocytes in the Neonatal Mouse Central Nervous System","volume":"19","author":"Zhang","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1038\/mt.2009.71","article-title":"Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons","volume":"17","author":"Duque","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.cardiores.2006.09.021","article-title":"Targeting the heart with gene therapy-optimized gene delivery methods","volume":"73","author":"Katus","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.cardiores.2005.12.017","article-title":"Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors","volume":"70","author":"Leuchs","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ymthe.2006.03.014","article-title":"Robust systemic transduction with AAV9 vectors in mice: Efficient global cardiac gene transfer superior to that of AAV8","volume":"14","author":"Inagaki","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1038\/mt.2008.207","article-title":"A Single Intravenous Injection of Adeno-associated Virus Serotype-9 Leads to Whole Body Skeletal Muscle Transduction in Dogs","volume":"16","author":"Yue","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41587-019-0103-5","article-title":"Duchenne muscular dystrophy awaits gene therapy","volume":"37","author":"Jones","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"eaan8081","DOI":"10.1126\/scitranslmed.aan8081","article-title":"Single-cut genome editing restores dystrophin expression in a new mouse model of muscular dystrophy","volume":"9","author":"Amoasii","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/j.ymthe.2018.07.011","article-title":"Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy","volume":"26","author":"Duan","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/mus.25658","article-title":"Long-term effects of systemic gene therapy in a canine model of myotubular myopathy","volume":"56","author":"Elverman","year":"2017","journal-title":"Muscle Nerve"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"695937","DOI":"10.3389\/fnmol.2021.695937","article-title":"Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord","volume":"14","author":"Jensen","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2418","DOI":"10.1016\/j.ymthe.2018.07.008","article-title":"Extensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS","volume":"26","author":"Naidoo","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.neuron.2016.09.021","article-title":"A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons","volume":"92","author":"Tervo","year":"2016","journal-title":"Neuron"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1172\/JCI66778","article-title":"Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy","volume":"123","author":"Haurigot","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1083\/jcb.111.3.1027","article-title":"Brain dynein (MAP1C) localizes on both anterogradely and retrogradely transported membranous organelles in vivo","volume":"111","author":"Hirokawa","year":"1990","journal-title":"J. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.omtm.2019.11.012","article-title":"Adeno-Associated Viral Vectors in Neuroscience Research","volume":"17","author":"Haggerty","year":"2019","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/sj.gt.3302126","article-title":"CMV enhancer\/human PDGF-\u03b2 promoter for neuron-specific transgene expression","volume":"11","author":"Liu","year":"2003","journal-title":"Gene Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/jnc.14124","article-title":"Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: The impact of serotypes and promoters","volume":"142","author":"Haenraets","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.neures.2005.08.001","article-title":"Neuronal cell type-specific promoter of the \u03b1 CaM kinase II gene is activated by Zic2, a Zic family zinc finger protein","volume":"53","author":"Sakurada","year":"2005","journal-title":"Neurosci. Res."},{"key":"ref_63","first-page":"1317","article-title":"U7 snRNA, a Small RNA with a Big Impact in Gene Therapy","volume":"32","author":"Lesman","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Castle, M.J., Turunen, H.T., Vandenberghe, L.H., and Wolfe, J.H. (2016). Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids. Gene Therapy for Neurological Disorders, Humana Press.","DOI":"10.1007\/978-1-4939-3271-9_10"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41593-021-00969-4","article-title":"AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset","volume":"25","author":"Goertsen","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nbt.1599","article-title":"Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle","volume":"28","author":"Asokan","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/mt.2011.22","article-title":"Engineering Liver-detargeted AAV9 Vectors for Cardiac and Musculoskeletal Gene Transfer","volume":"19","author":"Pulicherla","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1038\/mt.2016.84","article-title":"In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy","volume":"24","author":"Choudhury","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/mt.2015.231","article-title":"Widespread Central Nervous System Gene Transfer and Silencing After Systemic Delivery of Novel AAV-AS Vector","volume":"24","author":"Choudhury","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3946","DOI":"10.1073\/pnas.0813207106","article-title":"A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection","volume":"106","author":"Yang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-63559-7","article-title":"Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: Implications for disease modeling and therapeutic development","volume":"10","author":"Weiss","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41434-018-0017-8","article-title":"Rationally designed AAV2 and AAVrh8R capsids provide improved transduction in the retina and brain","volume":"25","author":"Sullivan","year":"2018","journal-title":"Gene Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1038\/gt.2009.82","article-title":"Isolation and evaluation of novel adeno-associated virus sequences from porcine tissues","volume":"16","author":"Bello","year":"2009","journal-title":"Gene Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/hum.2015.29017.asr","article-title":"Adeno-Associated Virus: The Naturally Occurring Virus Versus the Recombinant Vector","volume":"27","author":"Srivastava","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.omtm.2019.05.014","article-title":"Prevalence of Anti-Adeno-Associated Virus Immune Responses in International Cohorts of Healthy Donors","volume":"14","author":"Kruzik","year":"2019","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"753467","DOI":"10.3389\/fimmu.2021.753467","article-title":"Adeno-Associated Viruses (AAV) and Host Immunity\u2014A Race Between the Hare and the Hedgehog","volume":"12","author":"Rapti","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1086\/595830","article-title":"Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses","volume":"199","author":"Calcedo","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.omtm.2018.09.003","article-title":"Adeno-Associated Virus Neutralizing Antibodies in Large Animals and Their Impact on Brain Intraparenchymal Gene Transfer","volume":"11","author":"Wang","year":"2018","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3389\/fnmol.2020.00129","article-title":"Intramuscular Delivery of Gene Therapy for Targeting the Nervous System","volume":"13","author":"Tosolini","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"17553","DOI":"10.1523\/JNEUROSCI.3258-13.2013","article-title":"The Choroid Plexus and Cerebrospinal Fluid: Emerging Roles in Development, Disease, and Therapy","volume":"33","author":"Lehtinen","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1089\/hum.2017.026","article-title":"Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals","volume":"29","author":"Hinderer","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"618360","DOI":"10.3389\/fnmol.2021.618360","article-title":"Comparative Effectiveness of Intracerebroventricular, Intrathecal, and Intranasal Routes of AAV9 Vector Administration for Genetic Therapy of Neurologic Disease in Murine Mucopolysaccharidosis Type I","volume":"14","author":"Belur","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/mt.2014.210","article-title":"Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose\u2013response Study in Mice and Nonhuman Primates","volume":"23","author":"Meyer","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5257","DOI":"10.1007\/s11033-019-04983-5","article-title":"Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: Results of a 3-year phase 1 study of 113 injections in 31 patients","volume":"46","author":"Duma","year":"2019","journal-title":"Mol. Biol. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.molmed.2021.09.007","article-title":"Delivery of therapeutic AAV9 vectors via cisterna magna to treat neurological disorders","volume":"28","author":"Marchi","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/hum.2022.29196.hrb","article-title":"Adeno-Associated Virus Delivery Limitations for Neurological Indications","volume":"33","author":"Benatti","year":"2022","journal-title":"Hum. Gene Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"eaau9859","DOI":"10.1126\/sciadv.aau9859","article-title":"Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion","volume":"4","author":"Castle","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1177\/0883073815627882","article-title":"Intrathecal Injections in Children With Spinal Muscular Atrophy","volume":"31","author":"Swoboda","year":"2016","journal-title":"J. Child Neurol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s40263-019-00656-w","article-title":"An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials","volume":"33","author":"Darras","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.ymthe.2017.10.017","article-title":"Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier","volume":"26","author":"Albright","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s40259-017-0234-5","article-title":"Adeno-Associated Virus (AAV) as a Vector for Gene Therapy","volume":"31","author":"Naso","year":"2017","journal-title":"BioDrugs"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1006\/mthe.2001.0246","article-title":"Combined Injection of rAAV with Mannitol Enhances Gene Expression in the Rat Brain","volume":"3","author":"Mastakov","year":"2001","journal-title":"Mol. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jneumeth.2010.10.010","article-title":"Convection-enhanced delivery and systemic mannitol increase gene product distribution of AAV vectors 5, 8, and 9 and increase gene product in the adult mouse brain","volume":"194","author":"Carty","year":"2010","journal-title":"J. Neurosci. Methods"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1177\/0271678X16637881","article-title":"Direct brain infusion can be enhanced with focused ultrasound and microbubbles","volume":"37","author":"Wang","year":"2016","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"989","DOI":"10.3171\/2017.8.JNS17790","article-title":"Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound","volume":"130","author":"Stavarache","year":"2019","journal-title":"J. Neurosurg."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrneurol.2017.188","article-title":"Blood\u2013brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders","volume":"14","author":"Sweeney","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"734878","DOI":"10.3389\/fgene.2021.734878","article-title":"GM1 Gangliosidosis\u2014A Mini-Review","volume":"12","author":"Nicoli","year":"2021","journal-title":"Front. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.bbadis.2011.03.018","article-title":"GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical find-ings","volume":"1812","author":"Caciotti","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.bbamcr.2008.12.001","article-title":"Lysosomal disorders: From storage to cellular damage","volume":"1793","author":"Ballabio","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"115142","DOI":"10.1016\/j.bone.2019.115142","article-title":"The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention","volume":"131","author":"Ferreira","year":"2019","journal-title":"Bone"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/B978-0-444-59565-2.00039-3","article-title":"Gangliosidoses","volume":"113","author":"Patterson","year":"2013","journal-title":"Handb Clin. Neurol."},{"key":"ref_103","unstructured":"Regier, D.S., Tifft, C.J., and Rothermel, C.E. (2021). GLB1-Related Disorders, University of Washington."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Singer, H.S., Mink, J.W., Gilbert, D.L., and Jankovic, J. (2016). Inherited Metabolic Disorders with Associated Movement Abnormalities, Academic Press.","DOI":"10.1016\/B978-0-12-411573-6.00017-6"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1007\/s11011-017-0044-y","article-title":"The treatment of juvenile\/adult GM1-gangliosidosis with Miglustat may reverse disease progression","volume":"32","author":"Deodato","year":"2017","journal-title":"Metab. Brain Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s10545-005-0089-7","article-title":"Bone marrow transplantation correcting \u03b2-galactosidase activity does not influence neurological outcome in juvenile GM1-gangliosidosis","volume":"28","author":"Shield","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ymgme.2015.12.002","article-title":"Enzyme replacement for GM1-gangliosidosis: Uptake, lysosomal activation, and cellular disease correction using a novel \u03b2-galactosidase:RTB lectin fusion","volume":"117","author":"Condori","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"13532","DOI":"10.1074\/jbc.RA119.009811","article-title":"Intracerebroventricular enzyme replacement therapy with \u03b2-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice","volume":"295","author":"Chen","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"100513","DOI":"10.1016\/j.ymgmr.2019.100513","article-title":"Human GLB1 knockout cerebral organoids: A model system for testing AAV9-mediated GLB1 gene therapy for reducing GM1 ganglioside storage in GM1 gangliosidosis","volume":"21","author":"Latour","year":"2019","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"352","DOI":"10.2174\/1566523222666220304092732","article-title":"AAV9-coGLB1 Improves Lysosomal Storage and Rescues Central Nervous System Inflammation in a Mutant Mouse Model of GM1 Gangliosidosis","volume":"22","author":"Liu","year":"2022","journal-title":"Curr. Gene Ther."},{"key":"ref_111","unstructured":"(2022, October 28). Issue: Molecular Therapy. Available online: https:\/\/www.cell.com\/molecular-therapy-family\/molecular-therapy\/issue?pii=S1525-0016(21)X0004-4."},{"key":"ref_112","unstructured":"Passage Bio, Inc. (2022, October 17). Passage Bio Presents New Interim Clinical and Biomarker Data for Patients with GM1 Gangliosidosis in Imagine-1 Study at ASGCT 25th Annual Meeting. Available online: https:\/\/www.passagebio.com\/investors-and-news\/press-releases-and-statements\/news-details\/2022\/Passage-Bio-Presents-New-Interim-Clinical-and-Biomarker-Data-for-Patients-with-GM1-Gangliosidosis-in-Imagine-1-Study-at-ASGCT-25th-Annual-Meeting\/default.aspx."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1177\/0883073813494268","article-title":"Classification and Natural History of the Neuronal Ceroid Lipofuscinoses","volume":"28","author":"Mink","year":"2013","journal-title":"J. Child Neurol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1126\/science.277.5333.1802","article-title":"Association of Mutations in a Lysosomal Protein with Classical Late- Infantile Neuronal Ceroid Lipofuscinosis Published by: American Association for the Advancement of Science Stable","volume":"277","author":"Sleat","year":"1997","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.bbadis.2015.05.011","article-title":"Genetics of the neuronal ceroid lipofuscinoses (Batten disease)","volume":"1852","author":"Mole","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1023\/A:1005564509027","article-title":"The neuronal ceroid-lipofuscinoses (Batten disease): A new class of lysosomal storage diseases","volume":"22","author":"Bennett","year":"1999","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1086\/302427","article-title":"Mutational Analysis of the Defective Protease in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis, a Neurodegenerative Lysosomal Storage Disorder","volume":"64","author":"Sleat","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/S2352-4642(18)30179-2","article-title":"Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: An observational cohort study","volume":"2","author":"Nickel","year":"2018","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/j.bbadis.2013.04.008","article-title":"NCL diseases\u2014Clinical perspectives","volume":"1832","author":"Schulz","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1056\/NEJMoa1712649","article-title":"Study of Intraventricular Cerliponase Alfa for CLN2 Disease","volume":"378","author":"Schulz","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s40265-017-0771-8","article-title":"Cerliponase Alfa: First Global Approval","volume":"77","author":"Markham","year":"2017","journal-title":"Drugs"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3171\/2010.4.PEDS09507","article-title":"Gene therapy for late infantile neuronal ceroid lipofuscinosis: Neurosurgical considerations","volume":"6","author":"Souweidane","year":"2010","journal-title":"J. Neurosurg. Pediatr."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"eabb5413","DOI":"10.1126\/scitranslmed.abb5413","article-title":"Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2","volume":"12","author":"Sondhi","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_124","unstructured":"(2022). 51st Annual Meeting of the Child Neurology Society. Ann. Neurol., 92, S1\u2013S211."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1159\/000445751","article-title":"The Incidence of Parkinson\u2019s Disease: A Systematic Review and Meta-Analysis","volume":"46","author":"Hirsch","year":"2016","journal-title":"Neuroepidemiology"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"218","DOI":"10.3389\/fneur.2019.00218","article-title":"Parkinson\u2019s Disease and the Environment","volume":"10","author":"Ball","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/mds.27344","article-title":"Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies","volume":"33","author":"Palma","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_128","first-page":"419","article-title":"A new look at levodopa based on the ELLDOPA study","volume":"70","author":"Fahn","year":"2006","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/jnc.13649","article-title":"Deep brain stimulation mechanisms: The control of network activity via neurochemistry modulation","volume":"139","author":"McIntyre","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s00415-016-8314-x","article-title":"Impulse control behaviors and subthalamic deep brain stimulation in Parkinson disease","volume":"264","author":"Merola","year":"2016","journal-title":"J. Neurol."},{"key":"ref_131","first-page":"S71","article-title":"Neuropathological Staging of Brain Pathology in Sporadic Parkinson\u2019s disease: Separating the Wheat from the Chaff","volume":"7","author":"Braak","year":"2017","journal-title":"J. Park. Dis."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Lemkau, L.R., Comellas, G., Lee, S.W., Rikardsen, L.K., Woods, W.S., George, J., and Rienstra, C.M. (2013). Site-Specific Perturbations of Alpha-Synuclein Fibril Structure by the Parkinson\u2019s Disease Associated Mutations A53T and E46K. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0049750"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.neulet.2019.05.026","article-title":"Alpha-synuclein gene polymorphism affects risk of dementia in Han Chinese with Parkinson\u2019s disease","volume":"706","author":"Zheng","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_134","first-page":"1","article-title":"\u03b1-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson\u2019s disease","volume":"6","author":"Cole","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.neuron.2015.03.002","article-title":"Moving Stem Cells to the Clinic: Potential and Limitations for Brain Repair","volume":"86","author":"Steinbeck","year":"2015","journal-title":"Neuron"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41536-020-00106-y","article-title":"Challenges and translational considerations of mesenchymal stem\/stromal cell therapy for Parkinson\u2019s disease","volume":"5","author":"Korchak","year":"2020","journal-title":"npj Regen. Med."},{"key":"ref_137","first-page":"251","article-title":"Clinical Trial Highlights: 1. Gene Therapy for Parkinson\u2019S, 2. Phase 3 Study in Focus-Intec Pharma\u2019S Accordion Pill, 3. Clinical Trials Resources","volume":"9","author":"McFarthing","year":"2019","journal-title":"J. Park. Dis."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s10020-021-00279-2","article-title":"Novel targeted therapies for Parkinson\u2019s disease","volume":"27","author":"Ntetsika","year":"2021","journal-title":"Mol. Med."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1002\/mds.26354","article-title":"Disease-modifying strategies for Parkinson\u2019s disease","volume":"30","author":"Kalia","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_140","unstructured":"(2022, October 16). VY-AADC01 Gene Therapy in Parkinson\u2019s Disease: Interim Results of the On-Going Phase 1b PD-1101 Trial-MDS Abstracts. Available online: https:\/\/www.mdsabstracts.org\/abstract\/vy-aadc01-gene-therapy-in-parkinsons-disease-interim-results-of-the-on-going-phase-1b-pd-1101-trial."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S1474-4422(11)70039-4","article-title":"AAV2-GAD gene therapy for advanced Parkinson\u2019s disease: A double-blind, sham-surgery controlled, randomised trial","volume":"10","author":"LeWitt","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"19559","DOI":"10.1073\/pnas.0706006104","article-title":"Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson\u2019s disease","volume":"104","author":"Feigin","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1212\/WNL.0b013e3182904faa","article-title":"Safety\/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients","volume":"80","author":"Bartus","year":"2013","journal-title":"Neurology"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/S1474-4422(10)70254-4","article-title":"Gene delivery of AAV2-neurturin for Parkinson\u2019s disease: A double-blind, randomised, controlled trial","volume":"9","author":"Marks","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1089\/hum.2015.134","article-title":"The CERE-120 Study Group Long-Term Safety of Patients with Parkinson\u2019s Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer","volume":"27","author":"Marks","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 17, 327\u2013406.","DOI":"10.1002\/alz.12328"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"103691","DOI":"10.1016\/j.ebiom.2021.103691","article-title":"Antisense oligonucleotides for Alzheimer\u2019s disease therapy: From the mRNA to miRNA paradigm","volume":"74","author":"Want","year":"2021","journal-title":"eBioMedicine"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s40035-018-0117-9","article-title":"Impact of the biological definition of Alzheimer\u2019s disease using amyloid, tau and neurodegeneration (ATN): What about the role of vascular changes, inflammation, Lewy body pathology?","volume":"7","author":"Gauthier","year":"2018","journal-title":"Transl. Neurodegener."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1002\/alz.12321","article-title":"Visualization of neurofibrillary tangle maturity in Alzheimer\u2019s disease: A clinicopathologic perspective for biomarker research","volume":"17","author":"Moloney","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.nbd.2018.05.012","article-title":"TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities","volume":"122","author":"Cortes","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1212\/WNL.0000000000000596","article-title":"Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis","volume":"83","author":"Ryman","year":"2014","journal-title":"Neurology"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.3233\/JAD-131883","article-title":"Central and Peripheral Administration of Antisense Oligonucleotide Targeting Amyloid-\u03b2 Protein Precursor Improves Learning and Memory and Reduces Neuroinflammatory Cytokines in Tg2576 (A\u03b2PPswe) Mice","volume":"40","author":"Farr","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.ymthe.2018.02.029","article-title":"Targeting Amyloid-\u03b2 Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-\u03b2 Production","volume":"26","author":"Chang","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41582-018-0013-z","article-title":"Tau-targeting therapies for Alzheimer disease Erin","volume":"14","author":"Congdon","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1755-5949.2010.00177.x","article-title":"The Role of Tau in Alzheimer\u2019s Disease and Related Disorders","volume":"17","author":"Medeiros","year":"2010","journal-title":"CNS Neurosci. Ther."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.jalz.2013.09.004","article-title":"A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer\u2019s disease","volume":"10","author":"Rafii","year":"2014","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1093\/ilar\/ilx021","article-title":"Nonhuman Primate Models of Neurodegenerative Disorders","volume":"58","author":"Emborg","year":"2017","journal-title":"ILAR J."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1089\/hum.2019.367","article-title":"Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer\u2019s Disease Identifies a Need for Improved Vector Delivery","volume":"31","author":"Castle","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41434-018-0010-2","article-title":"MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates","volume":"25","author":"Nagahara","year":"2018","journal-title":"Gene Ther."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/emmm.201200245","article-title":"Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer","volume":"4","author":"Vera","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/ana.24864","article-title":"Emerging therapies and challenges in spinal muscular atrophy","volume":"81","author":"Farrar","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_162","unstructured":"NORD (2021). Spinal Muscular Atrophy, National Organization for Rare Disorders."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0092-8674(00)81632-3","article-title":"A Novel Function for SMN, the Spinal Muscular Atrophy Disease Gene Product, in Pre-mRNA Splicing","volume":"95","author":"Pellizzoni","year":"1998","journal-title":"Cell"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1128\/MCB.06077-11","article-title":"A Role for SMN Exon 7 Splicing in the Selective Vulnerability of Motor Neurons in Spinal Muscular Atrophy","volume":"32","author":"Ruggiu","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/13543784.2022.2056836","article-title":"Risdiplam: An investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)","volume":"31","author":"Markati","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s40265-019-01162-5","article-title":"Onasemnogene Abeparvovec: First Global Approval","volume":"79","author":"Hoy","year":"2019","journal-title":"Drugs"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1358\/dot.2021.57.6.3264117","article-title":"Onasemnogene abeparvovec-xioi: A gene replacement strategy for the treatment of infants diagnosed with spinal muscular atrophy","volume":"57","author":"Schwartz","year":"2021","journal-title":"Drugs Today"},{"key":"ref_168","unstructured":"(2022, October 16). Zolgensma\u00ae Data Shows Rapid, Significant, Clinically Meaningful Benefit in SMA including Prolonged Event-Free Survival, Motor Milestone Achievement and Durability Now Up to 5 Years Post-Dosing|Novartis. Available online: https:\/\/www.novartis.com\/news\/media-releases\/zolgensma-data-shows-rapid-significant-clinically-meaningful-benefit-sma-including-prolonged-event-free-survival-motor-milestone-achievement-and-durability-now-5-years-post-dosing."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ejpn.2020.07.001","article-title":"European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy","volume":"28","author":"Kirschner","year":"2020","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_170","unstructured":"(2022, October 16). Novartis Announces Lift of Partial Clinical Trial Hold and Plans to Initiate a New, Pivotal Phase 3 Study of Intrathecal OAV-101 in Older Patients with SMA|Novartis. Available online: https:\/\/www.novartis.com\/news\/media-releases\/novartis-announces-lift-partial-clinical-trial-hold-and-plans-initiate-new-pivotal-phase-3-study-intrathecal-oav-101-older-patients-sma."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0960-8966(91)90039-U","article-title":"Population frequencies of inherited neuromuscular diseases\u2014A world survey","volume":"1","author":"Emery","year":"1991","journal-title":"Neuromuscul. Disord."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.pcl.2015.03.008","article-title":"Genetics and Emerging Treatments for Duchenne and Becker Muscular Dystrophy","volume":"62","author":"Wein","year":"2015","journal-title":"Pediatr. Clin. North Am."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fgene.2019.00114","article-title":"Genotypes and Phenotypes of DMD Small Mutations in Chinese Patients With Dystrophinopathies","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Genet."},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Lim, K.R.Q., Nguyen, Q., and Yokota, T. (2020). Genotype\u2013Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040241"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fgene.2020.00131","article-title":"The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study","volume":"11","author":"Neri","year":"2020","journal-title":"Front. Genet."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-021-00248-3","article-title":"Duchenne muscular dystrophy","volume":"7","author":"Duan","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Flanigan, K.M., Waldrop, M.A., Martin, P.T., Dunn, D.M., Alfano, L.N., and Simmons, T.R. (2021). A genome-wide association analysis of loss of ambulation in dystrophinopathy patients suggests multiple candidate modifiers of disease severity. medRxiv Yale, 1\u201330.","DOI":"10.1101\/2021.11.03.21265887"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"16006","DOI":"10.1038\/npjregenmed.2016.6","article-title":"Targeting muscle stem cell intrinsic defects to treat Duchenne muscular dystrophy","volume":"1","author":"Dumont","year":"2016","journal-title":"NPJ Regen. Med."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s43440-020-00134-x","article-title":"Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: Past, present, and future","volume":"72","author":"Dulak","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.nmd.2015.08.005","article-title":"The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development","volume":"25","author":"Vulin","year":"2015","journal-title":"Neuromuscul. Disord."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1089\/nat.2021.0043","article-title":"Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1\/2 Trial","volume":"32","author":"Servais","year":"2022","journal-title":"Nucleic Acid Ther."},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Fortunato, F., Rossi, R., Falzarano, M., and Ferlini, A. (2021). Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040820"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"S102","DOI":"10.1016\/j.nmd.2022.07.248","article-title":"132 Casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: Interim results from the Phase 3 ESSENCE trial","volume":"32","author":"Iannaccone","year":"2022","journal-title":"Neuromuscul. Disord."},{"key":"ref_184","unstructured":"(2022, October 16). Solid Biosciences Reports Efficacy and Safety Data from the Ongoing IGNITE DMD Clinical Trial and Resumption of Patient Dosing in the 2E14 vg\/kg Cohort Solid Biosciences. Available online: https:\/\/www.solidbio.com\/about\/media\/press-releases\/solid-biosciences-reports-efficacy-and-safety-data-from-the-ongoing-ignite-dmd-clinical-trial-and-resumption-of-patient-dosing-in-the-2e14-vg-kg-cohort."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1001\/jamaneurol.2020.1484","article-title":"Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy","volume":"77","author":"Mendell","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_186","first-page":"91","article-title":"Sarepta\u2019s DMD gene therapy falls flat","volume":"20","author":"Mullard","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"289","DOI":"10.21037\/atm.2019.04.49","article-title":"An emerging phenotype of central nervous system involvement in Pompe disease: From bench to bedside and beyond","volume":"7","author":"Korlimarla","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1007\/s13311-018-0655-y","article-title":"Pompe Disease: From Basic Science to Therapy","volume":"15","author":"Kohler","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1042\/bj0860011","article-title":"\u03b1-Glucosidase deficiency in generalized glycogen-storage disease (Pompe\u2019s disease)","volume":"86","author":"Hers","year":"1963","journal-title":"Biochem. J."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1002\/ana.20807","article-title":"Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease","volume":"59","author":"Fukuda","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"283","DOI":"10.21037\/atm.2019.04.70","article-title":"Long-term outcome and unmet needs in infantile-onset Pompe disease","volume":"7","author":"Hahn","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.jpeds.2005.11.033","article-title":"A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease","volume":"148","author":"Kishnani","year":"2006","journal-title":"J. Pediatr."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/brain\/awh384","article-title":"Clinical manifestation and natural course of late-onset Pompe\u2019s disease in 54 Dutch patients","volume":"128","author":"Hagemans","year":"2005","journal-title":"Brain"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"e1756","DOI":"10.1212\/WNL.0000000000008441","article-title":"Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease","volume":"93","author":"Harlaar","year":"2019","journal-title":"Neurology"},{"key":"ref_195","first-page":"729","article-title":"The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: Lessons learned from infantile Pompe disease","volume":"13","author":"Banugaria","year":"2011","journal-title":"Anesthesia Analg."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1042\/BJ20050364","article-title":"Carbohydrate-remodelled acid \u03b1-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice","volume":"389","author":"Zhu","year":"2005","journal-title":"Biochem. J."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1172\/JCI1722","article-title":"Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail","volume":"101","author":"Kikuchi","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.nmd.2018.12.004","article-title":"Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-na\u00efve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study","volume":"29","author":"Pena","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"9462","DOI":"10.1021\/acs.jmedchem.7b00646","article-title":"N-Butyl-l-deoxynojirimycin (l-NBDNJ): Synthesis of an Allosteric Enhancer of \u03b1-Glucosidase Activity for the Treatment of Pompe Disease","volume":"60","author":"Porto","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s40478-017-0464-2","article-title":"Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease","volume":"5","author":"Hordeaux","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_201","unstructured":"(2022, October 28). MDA2022\u2014Pompe Gene Therapy ACT-101 Boosts GAA Levels in Trial. Available online: https:\/\/pompediseasenews.com\/news\/mda-2022-gene-therapy-act-101-well-tolerated-boosts-gaa-levels-early-trial\/."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/12\/1979\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:30:28Z","timestamp":1760146228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/12\/1979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,30]]},"references-count":201,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["jpm12121979"],"URL":"https:\/\/doi.org\/10.3390\/jpm12121979","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,30]]}}}