Biomedical subjects

Heather L Gray-Edwards

Publications and source records attributed to Heather L Gray-Edwards.

4 recordsLinked to original sources

PubMed2026

Cerebrospinal delivery of a bidirectional AAV9 vector improves optic nerve and retinal pathology in a sheep model of Tay-Sachs disease.

Tay-Sachs disease (TSD) is a fatal neurodegenerative lysosomal storage disease. The Jacob sheep is the only large-animal model of TSD, yet ocular pathology and the therapeutic potential of gene therapy remain poorly defined. Sheep cohorts included normal controls (n = 3); untreated TSD-affected (n = 4); intravenous AAV9-Bic_HexA/HexB-treated (n = 3); and intracerebroventricular, cisterna magna, and lumbar intrathecal AAV9- Bic_HexA/HexB-treated sheep (cerebrospinal fluid [CSF] therapy; n = 7). Retinal histopathology and immunohistochemistry, retinal whole-mount analyses for retinal ganglion cell (RGC) morphology and density, optic nerve evaluation with p-phenylenediamine (PPD )semi-thin sections, qPCR assessment for vector genomes, and RNAscope probes for transgene expression were performed. Untreated TSD sheep exhibited RGCs with abundant microvesicular cytoplasmic expansion and optic nerve spheroids, with storage material variably staining with periodic acid-Schiff. Marked astrocytosis, microgliosis, and GM2 accumulation within RGCs were present. Optic nerve axon counts and RGC density were significantly reduced, and optic nerve damage scores increased, in untreated and IV-treated sheep but were rescued with short-term CSF therapy. GM2 volume and signal intensity per RGC were significantly reduced following short-term CSF therapy. Minimal but detectable retinal vector genomes and transgene expression were observed. These findings demonstrate retinal and optic nerve pathology in Jacob sheep with TSD and AAV9 therapy.

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PubMed2025

Treatment of a severe vascular disease using a bespoke CRISPR-Cas9 base editor in mice.

Pathogenic missense mutations in the alpha actin isotype 2 (ACTA2) gene cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection and death in childhood. Here we perform mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the most common MSMDS-causative mutation ACTA2 R179H. To directly correct the R179H mutation, we screened dozens of configurations of base editors to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We create a murine model of MSMDS that shows phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this strategy. Delivery of the customized base editor via an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector substantially prolongs survival and rescues systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta and brain. Our results highlight how bespoke mutant-specific CRISPR-Cas9 enzymes can improve mutation correction with base editors.

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PubMed2025

Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial.

The dual rAAVrh8-HEXA and rAAVrh8-HEXB vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an n = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay-Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h-1 ml-1, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3-3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: NCT04669535 and NCT06614569 .

Humans↗

PubMed2016

In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy.

Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, β-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.

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