ArticleBrain : a journal of neurology2018
A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.
Article in Brain : a journal of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 127 citations in OpenAlex.
- Spatial mapping of barcoded, brain-tropic AAVs using multiplexed RNAMolecular therapy. Advances · 2026Article
- Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease.Metabolic brain disease · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Current trends in gene therapy to treat inherited disorders of the brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside.Journal of translational medicine · 2024Review
- Enhanced AAV transduction across preclinical CNS models: A comparative study in human brain organoids with cross-species evaluations.Molecular therapy. Nucleic acids · 2024Article
- Rational evolution for altering the ligand preference of estrogen receptor alpha.Protein science : a publication of the Protein Society · 2024Article
- Development and characterization of a non-human primate model of disseminated synucleinopathy.Frontiers in neuroanatomy · 2024Article
- Identification and validation of novel engineered AAV capsid variants targeting human glia.Frontiers in neuroscience · 2024Article
- A Novel Retrograde AAV Variant for Functional Manipulation of Cortical Projection Neurons in Mice and Monkeys.Neuroscience bulletin · 2024Article
- Mucopolysaccharidosis type IIIC in chinese mainland: clinical and molecular characteristics of ten patients and report of six novel variants in the HGSNAT gene.Metabolic brain disease · 2023Article
- Structural and Biophysical Analysis of Adeno-Associated Virus Serotype 2 Capsid Assembly Variants.Journal of virology · 2023Article
- Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC.Journal of translational medicine · 2023Article
- Semi-automated workflows to quantify AAV transduction in various brain areas and predict gene editing outcome for neurological disorders.Molecular therapy. Methods & clinical development · 2023Article
- Review
- Lighting Up Neural Circuits by Viral Tracing.Neuroscience bulletin · 2022Review
- Mucopolysaccharidoses and the blood-brain barrier.Fluids and barriers of the CNS · 2022Review
- Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno-Associated Viral Vector rAAV9P1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Adeno-Associated Viral Vectors as Versatile Tools for Neurological Disorders: Focus on Delivery Routes and Therapeutic Perspectives.Biomedicines · 2022Review
- Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases.Frontiers in molecular neuroscience · 2022Review
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Authors and funding
31 authors at 10 institutions in 6 countries.
Funding
Abstract
Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.
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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.