A5064052127- Virus-based gene therapy research
- CRISPR and Genetic Engineering
- Viral Infectious Diseases and Gene Expression in Insects
- CAR-T cell therapy research
- Retinal Development and Disorders
- SARS-CoV-2 and COVID-19 Research
- Viral gastroenteritis research and epidemiology
- RNA Interference and Gene Delivery
- Agriculture and Rural Development Research
- Liver Disease and Transplantation
- Animal Virus Infections Studies
- Animal Genetics and Reproduction
- RNA and protein synthesis mechanisms
- RNA regulation and disease
- Biopolymer Synthesis and Applications
- Mechanical Circulatory Support Devices
- interferon and immune responses
- Milk Quality and Mastitis in Dairy Cows
- Organ Donation and Transplantation
- Probiotics and Fermented Foods
- Viral Infections and Immunology Research
- Retinal and Optic Conditions
- Organ Transplantation Techniques and Outcomes
- Cardiac Structural Anomalies and Repair
Massachusetts Eye and Ear Infirmary
2014-2023
Smith-Kettlewell Eye Research Institute
2015-2023
Broad Institute
2021-2022
Innovative Genomics Institute
2018-2022
Harvard University
2015-2022
Harvard Stem Cell Institute
2021-2022
Adeno-associated virus (AAV) vectors have emerged as a gene-delivery platform with demonstrated safety and efficacy in handful of clinical trials for monogenic disorders. However, limitations the current generation often prevent broader application AAV gene therapy. Efforts to engineer been hampered by limited understanding structure-function relationship complex multimeric icosahedral architecture particle. To develop additional reagents pertinent further our insight into AAVs, we inferred...
Adeno-associated virus (AAV) is a highly promising gene transfer vector, yet major cellular requirements for AAV entry are poorly understood. Using genome-wide CRISPR screen of evolutionarily divergent serotype AAVrh32.33, we identified GPR108, member the G protein-coupled receptor superfamily, as an factor. Of greater than 20 AAVs across all clades tested in human cell lines, only AAV5 transduction was unaffected GPR108 knockout (KO). dependency further shown murine and primary cells vitro....
The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity mouse non-human primates following single injection confers complete from challenge macaques. Peak neutralizing antibody...
The adeno-associated viral vector (AAV) provides a safe and efficient gene therapy platform with several approved products that have marked therapeutic impact for patients. However, major bottleneck in the development commercialization of AAV remains efficiency, cost, scalability production. Chromatographic methods potential to allow purification at increased scales lower cost but often require optimization specific each serotype. Here, we demonstrate POROS CaptureSelect AAVX affinity resin...
Gene therapy is a promising approach in the treatment of inherited and common complex disorders retina. Preclinical clinical studies have validated use adeno-associated viral vectors (AAV) as safe efficient delivery vehicle for gene transfer. Retinal pigment epithelium rods—and to lesser extent, cone photoreceptors—can be efficiently targeted with AAV. Other retinal cell types however are more challenging targets. The aim this study was characterize transduction profile efficiency silico...
Gene therapy is emerging as a modality in 21st-century medicine. Adeno-associated viral (AAV) gene transfer leading technology to achieve efficient and durable expression of therapeutic transgene. However, the structural complexity capsid has constrained efforts engineer particle toward improved clinical safety efficacy. Here, we generate curated library barcoded AAVs with mutations across variety functionally relevant motifs. We then screen this vitro vivo mice nonhuman primates, enabling...
Generation and screening of libraries adeno-associated virus (AAV) variants have emerged as a powerful method for identifying novel capsids gene therapy applications. For the majority libraries, vast population diversity requires multiplexed production, in which library inverted terminal repeat (ITR)-containing plasmid is transfected together into cells to generate viral library. This process has potential be confounded by cross-packaging mosaicism, particles are comprised genomes capsid...
Summary The SARS-CoV-2 pandemic has affected more than 70 million people worldwide and resulted in over 1.5 deaths. A broad deployment of effective immunization campaigns to achieve population immunity at global scale will depend on the biological logistical attributes vaccine. Here, two adeno-associated viral (AAV)-based vaccine candidates demonstrate potent immunogenicity mouse nonhuman primates following a single injection. Peak neutralizing antibody titers remain sustained 5 months are...
Gene therapy is a promising approach in the treatment of inherited and common complex disorders retina. Preclinical clinical studies have validated use adeno-associated viral vectors (AAV) as safe efficient gene delivery vehicle for subretinal transfer. AAV can efficiently target RPE cells rod cone photoreceptors but other retinal cell types are more challenging targets. Despite immune privileged status eye we still face some challenges with higher inflammation risks to vector or transgene...
A major limitation of vectors based on current AAVs is the wide prevalence memory B and T cells reactive to AAV capsid in human populations arisen following natural infection. The Neutralizing Antibody (NAB) assay guides experimentation determines inclusion or exclusion subjects clinical studies order predict vivo neutralization. Furthermore, evidence a B-cell response may correlate with anti-capsid T-cell implicated safety efficacy outcome liver studies. Based previously reported findings,...
Adeno-associated virus (AAV) vectors have emerged as therapy preferred clinical in vivo gene transfer system. Yet, their sensitivity to pre-existing immunity (PEI) and low carrying capacity remain major drawbacks that limit broad applications. We previously hypothesized shown ancestral species of AAV, which we inferred using statistical bio-informatic approaches, generated synthetically, reduced susceptibility PEI. Here, our ambition was study from a biophysical structural perspective the...
Study of naturally occurring isolates adeno-associated virus has revealed a wide range phenotypes across several viral characteristics relevant to gene therapy. These fundamental differences in properties such as receptor binding, particle assembly, and capsid stability are believed influence vector tissue tropism the efficiency transfer. Although well described, many these AAV capsids have proven difficult modulate with traditional biochemical molecular techniques, domain swapping....
Gene therapy is emerging as a modality in 21 st century medicine. Adeno-associated viral (AAV) gene transfer leading technology to achieve efficient and durable expression of therapeutic transgene. However, the structural complexity capsid has constrained efforts engineer particle towards improved clinical safety efficacy. Here, we generated curated library barcoded AAVs with mutations across variety functionally relevant motifs. We then screened this vitro vivo mice nonhuman primates,...