AAV gene therapy for Tay-Sachs disease.

  title={AAV gene therapy for Tay-Sachs disease.},
  author={Terence R. Flotte and Oguz Cataltepe and A.S. Puri and Ana Rita Batista and Richard P. Moser and Diane M. McKenna-Yasek and Catherine L Douthwright and Gwladys Gernoux and Meghan Blackwood and Christian Mueller and Phillip W. L. Tai and Xuntian Jiang and Scot T. Bateman and Spiro G. Spanakis and Julia Parzych and Allison M. Keeler and Aly H Abayazeed and Saurabh Rohatgi and Laura L. Gibson and Robert Finberg and Bruce Barton and Zeynep Vardar and Mohammed Salman Shazeeb and Matthew J. Gounis and Cynthia J. Tifft and Florian S. Eichler and Robert H Brown and Douglas R Martin and Heather L. Gray-Edwards and Miguel Sena-Esteves},
  journal={Nature medicine},
Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 1014 vector genomes (vg)) in… 

Tay-Sachs Disease: From Molecular Characterization to Ethical Quandaries and the Possibility of Genetic Medicine

Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by mutations in the HEXA gene, which encodes the ɑ subunit of the enzyme β-hexosaminidase A, which results in the progressive deterioration of the central nervous system.

A versatile toolkit for overcoming AAV immunity

Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy and has been widely used in >200 clinical trials globally. There are already several approved gene

Approaches to Gene Modulation Therapy for ALS

The latest clinical and preclinical advances in gene modulation approaches for ALS are reviewed, including gene silencing, gene correction, and gene augmentation, which have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease.

CRISPR/nCas9-Based Genome Editing on GM2 Gangliosidoses Fibroblasts via Non-Viral Vectors

Results show the remarkable potential of CRISPR/nCas9 as a new alternative for treating GM2 gangliosidoses, as well as the superior performance of non-viral vectors in enhancing the potency of this therapeutic approach.

Acoustically Targeted Noninvasive Gene Therapy in Large Brain Regions

This study provides a brain-wide map of transduction efficiency and the first example of gene editing after site-specific noninvasive gene delivery to a large brain region and found effective gene editing but also a loss of neurons at the targeted sites.

Gene therapy for lysosomal storage diseases: Current clinical trial prospects

The administration of viral vectors has achieved good therapeutic outcomes in animal models of LSDs, and subsequent human clinical trials are expected to promote the practical application of gene therapy for LSDs.

CNS gene therapy: present developments and emerging trends accelerating industry-academia pathways.

The recent success of first central nervous system gene therapies has reinvigorated the growing community of gene therapy researchers and strengthened the field's market position and the latest improvements of vector design and targeting are outlined.

Towards gene therapy for Tay-Sachs disease.

  • D. Clyde
  • Medicine
    Nature reviews. Genetics
  • 2022



Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay-Sachs Disease.

This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.

Therapeutic response in feline sandhoff disease despite immunity to intracranial gene therapy.

These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.

Effective gene therapy in an authentic model of Tay-Sachs-related diseases

Gene delivery of β-hexosaminidase A by using adeno-associated viral vectors has realistic potential for treating the human Tay-Sachs-related diseases.

Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I.

This first demonstration of the efficacy of intrathecal gene therapy in a large animal model of a LSD should pave the way for translation into the clinic.

AAV-Mediated Gene Delivery in a Feline Model of Sandhoff Disease Corrects Lysosomal Storage in the Central Nervous System

This study demonstrates the therapeutic potential of AAV for feline SD and suggests a similar potential for human SD patients.

Direct Intracranial Injection of AAVrh8 Encoding Monkey β-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain.

Most monkeys receiving AAVrh8-cmHexα/β intracranial injection developed dyskinesias, ataxia, and loss of dexterity, with higher dose animals eventually becoming apathetic, and this study demonstrates the variations in safety profiles of AAV rh8-Hex α- and β-subunits among different species, despite encoding for self-proteins.

Widespread correction of central nervous system disease after intracranial gene therapy in a feline model of Sandhoff disease

Sandhoff disease (SD) is caused by deficiency of N-acetyl-β-hexosaminidase (Hex) resulting in pathological accumulation of GM2 ganglioside in lysosomes of the central nervous system (CNS) and

Gene transfer corrects acute GM2 gangliosidosis--potential therapeutic contribution of perivascular enzyme flow.

It is argued that infusion of rAAV into CSF space and intraparenchymal administration by convection-enhanced delivery at a few strategic sites will optimally treat neurodegeneration in many diseases affecting the nervous system.

B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study

A key finding of this single subject case report is the observation that B-cell ablation with rituximab prior to AAV vector exposure results in non-responsiveness to both capsid and transgene, therefore allowing the possibility of repeat administration in the future.

AAV-Mediated Gene Delivery in Adult GM1-Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survival

The studies show that the AAV-modified thalamus can be used as a ‘built-in’ central node network for widespread distribution of lysosomal enzymes in the mouse cerebrum and indicates that thalamic delivery of AAV vectors should be combined with additional targets to supply the cerebellum and spinal cord with therapeutic levels of enzyme necessary to achieve complete correction of the neurological phenotype in GM1 mice.