A5000705491- RNA Research and Splicing
- RNA regulation and disease
- Muscle Physiology and Disorders
- Genetics and Neurodevelopmental Disorders
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Lysosomal Storage Disorders Research
- RNA and protein synthesis mechanisms
- Virus-based gene therapy research
- Congenital heart defects research
- Hereditary Neurological Disorders
- Adipose Tissue and Metabolism
- Cancer-related molecular mechanisms research
- Cardiomyopathy and Myosin Studies
- Cellular transport and secretion
- interferon and immune responses
- Viral Infections and Immunology Research
- Adrenal Hormones and Disorders
Nationwide Children's Hospital
2015-2024
Office of Infectious Diseases
2024
University of California, Davis
2024
Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, feasibility these for dominantly inherited diseases — where treatment may require reduction in a toxic mutant protein resulting from gain-of-function allele is unclear. Here we show efficacy allele-specific RNAi as potential Charcot-Marie-Tooth disease type 2D (CMT2D), caused dominant mutations glycyl-tRNA synthetase (GARS). A de novo mutation GARS was...
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There currently no pharmacological treatment. The emergence enabled development cell and animal models that could be used for basic translational research. Since toxic, model has been challenging, but progress made, revealing tight regulation expression critical creating viable animals develop myopathy. Here, we report such a —...
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based for remained largely in the pre-clinical realm, limited clinical safety efficacy data to date. We are developing approach treat autosomal-dominant disorder facioscapulohumeral muscular...
Developmental and epileptic encephalopathy (DEE) associated with de novo variants in the gene encoding dynamin-1 (DNM1) is a severe debilitating disease no pharmacological remedy. Like most genetic DEEs, majority of DNM1 patients suffer from therapy-resistant seizures comorbidities such as intellectual disability, developmental delay, hypotonia. We tested RNAi therapy Dnm1 fitful mouse model DEE using Dnm1-targeted therapeutic microRNA delivered by self-complementary adeno-associated virus...
The DUX4 gene, encoded within D4Z4 repeats on human chromosome 4q35, has recently emerged as a key factor in the pathogenic mechanisms underlying Facioscapulohumeral muscular dystrophy (FSHD). This recognition prompted development of animal models expressing open reading frame (ORF) alone or embedded repeats. In first published model, we used adeno-associated viral vectors (AAV) and strong control elements (CMV promoter, SV40 poly A) to demonstrate that cDNA caused dose-dependent toxicity...
OBJECTIVES/GOALS: Vanishing White Matter Disease (VWM), is a childhood neurodegenerative leukodystrophy that presents with motor deficits, neurologic decline, and seizures leading to death.There are no treatments. Herein we investigate adeno-associated virus serotype 9 (AAV9) gene addition therapy for VWM. METHODS/STUDY POPULATION: To serve as baseline disease correction, characterized the severe VWM Eif2b5 I98M murine model clinically relevant readouts including function, gait mapping...