ArticleHuman gene therapy methods2012
Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis.
Article in Human gene therapy methods, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01801709 (A Phase I/II, Open Labeled, Monocentric Study of Direct Intracranial Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human ARSA cDNA to Children With Metachromatic Leukodystrophy.), which is not on this map. Cited by 54 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase I/II, Open Labeled, Monocentric Study of Direct Intracranial Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human ARSA cDNA to Children With Metachromatic Leukodystrophy.
Who cites it
54 citing papers in PubMed, 91 citations in OpenAlex.
- Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressingScience translational medicine · 2020Trial
- Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications.Advanced drug delivery reviews · 2024Review
- State-of-the-art therapies for fragile X syndrome.Developmental medicine and child neurology · 2024Review
- Neurosurgical gene therapy for central nervous system diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Adeno-associated virus as a delivery vector for gene therapy of human diseases.Signal transduction and targeted therapy · 2024Review
- Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A.Cellular and molecular life sciences : CMLS · 2023Article
- Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease.Human gene therapy · 2023Article
- Gene Therapy of Sphingolipid Metabolic Disorders.International journal of molecular sciences · 2023Review
- Transduction characteristics of alternative adeno-associated virus serotypes in the cat brain by intracisternal delivery.Molecular therapy. Methods & clinical development · 2022Article
- Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy.Human gene therapy · 2021Article
- AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord.Frontiers in molecular neuroscience · 2021Review
- Review
- Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement.Frontiers in molecular biosciences · 2021Review
- Quantitative Whole-Body Imaging of I-124-Labeled Adeno-Associated Viral Vector Biodistribution in Nonhuman Primates.Human gene therapy · 2020Article
- AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains.Molecular therapy. Methods & clinical development · 2020Article
- A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise.Medical research archives · 2020Article
- AAVrh-10 transduces outer retinal cells in rodents and rabbits following intravitreal administration.Gene therapy · 2019Article
- Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema.Allergy · 2019Article
- Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal, lysosomal storage disorder caused by mutations in the CLN2 gene, results in a deficiency of tripeptidyl-peptidase I (TPP-I) activity in neurons. Our prior studies showed that delivery of the human CLN2 cDNA directly to the CNS, using an adeno-associated virus serotype 2 (AAV2) vector, is safe in children with LINCL. As a second-generation strategy, we have demonstrated that AAVrh.10hCLN2, a rhesus-derived AAV vector, mediates wide distribution of TPP-I through the CNS in a murine model. This study tests the hypothesis that direct administration of AAVrh.10hCLN2 to the CNS of rats and nonhuman primates at doses scalable to humans has an acceptable safety profile and mediates significant CLN2 expression in the CNS. A dose of 10(11) genome copies (GC) was administered bilaterally to the striatum of Sprague Dawley rats with sacrifice at 7 and 90 days with no significant impact except for mild vector-related histopathological changes at the site of vector administration. A dose of 1.8×10(12) GC of AAVrh.10hCLN2 was administered to the CNS of 8 African green monkeys. The vector-treated monkeys did not differ from controls in any safety parameter except for mild to moderate white matter edema and inflammation localized to the administration sites of the vector. There were no clinical sequelae to these localized findings. TPP-I activity was >2 SD over background in 31.7±8.1% of brain at 90 days. These findings establish the dose and safety profile for human clinical studies for the treatment of LINCL with AAVrh.10hCLN2.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.