A5014115936- Virus-based gene therapy research
- Retinal Development and Disorders
- Viral Infectious Diseases and Gene Expression in Insects
- Viral Infections and Immunology Research
- Neurogenetic and Muscular Disorders Research
- CRISPR and Genetic Engineering
- Retinal Diseases and Treatments
- Metabolism and Genetic Disorders
- RNA Interference and Gene Delivery
- Viral gastroenteritis research and epidemiology
- Lysosomal Storage Disorders Research
- Retinal and Optic Conditions
- Biochemical and Molecular Research
- Muscle Physiology and Disorders
- Ruminant Nutrition and Digestive Physiology
- Mitochondrial Function and Pathology
- Herpesvirus Infections and Treatments
- Crop Yield and Soil Fertility
- Bioenergy crop production and management
- Rangeland and Wildlife Management
- CAR-T cell therapy research
- Child Nutrition and Feeding Issues
- Turfgrass Adaptation and Management
- Cytomegalovirus and herpesvirus research
- Algal biology and biofuel production
Institute of Technology Sligo
2021-2025
Children's Hospital of Philadelphia
2017-2024
University of Pennsylvania
2024
Atlantic Technological University
2023-2024
University of Florida
2010-2023
Scientific Consulting Group
2018-2020
Florida College
2005-2016
Pediatrics and Genetics
2000-2011
Vector (United States)
2010
University of California, Davis
2006
Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry human gene (rAAV2-CBSB-hRPE65), restored vision animal models with deficiency. clinical trial was designed assess safety rAAV2-CBSB-hRPE65 subjects RPE65-LCA. Three young adults (ages 21–24 years)...
Heart disease is often the end result of inherited genetic defects, which may potentially be treatable using a gene-transfer approach. Recombinant adeno-associated virus (rAAV)-mediated gene delivery has emerged as realistic method for treatment such disorders. Here, we demonstrate and compare natural affinity specific AAV serotype capsids transduction cardiac tissue. We compared previously accepted optimal rAAV skeletal muscle, rAAV2/1, with rAAV2/8 newer rAAV2/9 vectors carrying CMV-lacZ...
Human gene therapy with rAAV2-vector was performed for the RPE65 form of childhood blindness called Leber congenital amaurosis. In three contemporaneous studies by independent groups, procedure deemed safe and there evidence visual gain in short term. At 12 months after treatment, our young adult subjects remained healthy without vector-related serious adverse events. Results immunological assays to identify reaction AAV serotype 2 capsid were unchanged from baseline measurements. clinical...
Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed phase 1, open-label, dose-escalation clinical trial of recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts 3 each at doses 6.9 x 10(12), 2.2 10(13), and 6.0 10(13) genome particles per patient. Four receiving protein augmentation...
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, membrane-stabilizing protein encoded DMD gene. Although mouse models provide insight into potential corrective therapy, data from genetically homologous large animals, such as dystrophin-deficient golden retriever (GRMD) model, may more readily translate to humans. To evaluate clinical translatability an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5)...
ABSTRACT Adeno-associated virus type 2 (AAV2) has proven to be a valuable vector for gene therapy. Characterization of the functional domains AAV capsid proteins can facilitate our understanding viral tissue tropism, immunoreactivity, entry, and DNA packaging, all which are important issues generating improved vectors. To obtain comprehensive genetic map gene, we have constructed 93 mutants at 59 different positions in by site-directed mutagenesis. Several types were studied, including...
Abstract Objective: The aim of this study was to attain long‐lasting alpha‐sarcoglycan gene expression in limb‐girdle muscular dystrophy, type 2D (LGMD2D) subjects mediated by adeno‐associated virus (AAV) transfer under control a muscle specific promoter (tMCK). Methods: rAAV1.tMCK.hSGCA (3.25 × 10 11 vector genomes) delivered the extensor digitorum brevis 3 with documented SGCA mutations via double‐blind, randomized, placebo controlled trial. Control sides received saline. blind not broken...
AAV2 delivery of the RPE65 gene to retina blind RPE65-deficient animals restores vision. This strategy is being considered for human trials in RPE65-associated Leber congenital amaurosis (LCA), but toxicity and dose efficacy have not been defined. We studied ocular AAV-2/2.RPE65 RPE65-mutant dogs. There was no systemic toxicity. Ocular examinations showed mild or moderate inflammation that resolved over 3 months. Retinal histopathology indicated traumatic lesions from injection were common,...
Abstract Objective α‐Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb‐girdle type 2D [LGMD2D]) without treatment. Gene replacement represents strategy for correcting the underlying defect. Questions related to this approach were addressed clinical trial, particularly need immunotherapy and persistence gene expression. Methods A double‐blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into extensor digitorum brevis muscle was conducted. Control...
Reliable measurements are needed to document the natural history of ALS and determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive change—the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists following four major categories: pulmonary function, oropharyngeal timed functional activities, isometric strength using an electronic strain gauge. 29-item exam takes about 1 hour administer has excellent test-retest reliability.
A phase I trial of intramuscular injection a recombinant adeno-associated virus serotype 2 (rAAV2) α1- antitrypsin (AAT) vector was performed in 12 AAT-deficient adults, 10 whom were male. All subjects either homozygous for the most common AAT mutation (a missense designated PI*Z) or compound heterozygous PI*Z and another known to cause disease. There four dose cohorts, ranging from 2.1 × 1012 genomes (VG) 6.9 1013 VG, with three per cohort. Subjects injected sequentially dose-escalating...
Pompe disease is an inherited neuromuscular caused by deficiency of lysosomal acid alpha-glucosidase (GAA) leading to glycogen accumulation in muscle and motoneurons. Cardiopulmonary failure infancy leads early mortality, GAA enzyme replacement therapy (ERT) results improved survival, reduction cardiac hypertrophy, developmental gains. However, many children have progressive ventilatory insufficiency need additional support. Preclinical work shows that gene transfer restores phrenic neural...
A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome infectious titer AAV2 gene transfer vectors. Production purification material were carried out by helper virus–free transient transfection chromatographic purification. The purified bulk was vialed, confirmed negative microbial contamination, then distributed characterization along...
A first-in-human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease was conducted. The primary objective this study assess the safety rAAV1-CMV-hGAA vector delivered diaphragm muscle subjects with ventilatory insufficiency. Safety assessed by measurement change serum chemistries hematology, urinalysis, immune response GAA AAV, as well level health. data demonstrate that AAV treatment safe there were no adverse events...
Using a quantitative, reliable, sensitive and valid measurement technique, we analyzed the rate pattern of motor deterioration in 50 strictly defined ALS patients for up to 67 months. We observed that motoneuron loss was linear symmetric. Bulbar function deteriorated more slowly than respiratory, arm, leg function. The strength slower arm. No correlation between age at onset deterioration, or with different regions onset. Arm changed women, but other functions showed no male-female...
Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision restored subretinal delivery of AAV-RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies AAV-2/2.RPE65 RPE65-mutant dogs showed evidence modest photoreceptor loss the injection region some animals at higher vector doses. We now test hypothesis there can be vectorrelated toxicity...
The Tufts Quantitative Neuromuscular Exam (TQNE) consists of 28 items that were designed to measure voluntary motor deficit in amyotrophic lateral sclerosis (ALS) and related diseases. Individual raw data converted Z scores for standardization then grouped into five megascores with statistical clinical relevance. derived Mega 1, pulmonary function; 2, bulbar 3, timed hand activities; 4, isometric arm strength; 5, leg strength. Megascores should enhance the usefulness testing therapeutic...
Adeno-associated virus (AAV) has proven an effective gene delivery vehicle for the treatment of retinal disease. Ongoing clinical trials using a serotype 2 AAV vector to express RPE65 in pigment epithelium have safe and effective. While many proof-of-concept studies animal models disease suggested that transfer neural retina will also be effective, photoreceptor-targeting yet used clinic, principally because efficiently but exclusively targets all primate photoreceptors demonstrated. Here,...
Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College Surgeon (RCS) rat, a well characterized model recessive retinitis pigmentosa that contains mutation Mertk gene. plays key role renewal photoreceptor outer segments (OS) by phagocytosis shed OS tips. Mutations cause impaired phagocytic activity and accumulation debris interphotoreceptor space ultimately leads to cell death. In present study, we conducted series...
A recombinant serotype 9 adeno-associated virus (rAAV9) vector carrying a transgene that expresses codon-optimized human acid alpha-glucosidase (hGAA, or GAA) driven by desmin (DES) promoter (i.e., rAAV9-DES-hGAA) has been generated as clinical candidate for Pompe disease. The rAAV9-DES-hGAA is being developed treatment both early- and late-onset disease, in which patients lack sufficient lysosomal leading to glycogen accumulation. In young patients, the therapy may need be readministered...