A5023594620- Hereditary Neurological Disorders
- Genetic Neurodegenerative Diseases
- Retinal Development and Disorders
- RNA Research and Splicing
- RNA regulation and disease
- Cellular Mechanics and Interactions
- Retinal Diseases and Treatments
- Cerebrovascular and genetic disorders
- Calcium signaling and nucleotide metabolism
- Genomics and Chromatin Dynamics
- Telomeres, Telomerase, and Senescence
- interferon and immune responses
- RNA Interference and Gene Delivery
- Neurological diseases and metabolism
- Adenosine and Purinergic Signaling
- Ubiquitin and proteasome pathways
- Neurogenetic and Muscular Disorders Research
- Cellular transport and secretion
- Folate and B Vitamins Research
- CRISPR and Genetic Engineering
- Signaling Pathways in Disease
- Retinoids in leukemia and cellular processes
- Retinal and Optic Conditions
- Migraine and Headache Studies
- Protist diversity and phylogeny
Massachusetts General Hospital
2020-2024
Massachusetts Eye and Ear Infirmary
2021-2024
Smith-Kettlewell Eye Research Institute
2017-2024
Harvard University
2020-2023
University of California, San Diego
2018-2023
University of Hyderabad
2011-2016
University Hospital Münster
2014
The scaffolding protein KIBRA (also called WWC1) is involved in the regulation of important intracellular transport processes and establishment cell polarity. Furthermore, KIBRA/WWC1 an upstream regulator Hippo signaling pathway that controls proliferation organ size animals. represents only one member WWC family also includes highly similar proteins WWC2 WWC3. Although function was studied intensively cells animal models, importance WWC3 not yet elucidated. Here, we describe evolutionary,...
Pre-mRNA splicing is a key controller of human gene expression. Disturbances in due to mutation lead dysregulated protein expression and contribute substantial fraction disease. Several classes modulator compounds (SMCs) have been recently identified establish that pre-mRNA represents target for therapy. We describe herein the identification BPN-15477, SMC restores correct ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells machine learning approach, we identify...
Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying course in mouse model MLIV human MCOLN1 gene transfer. Here, using primate-enabling capsid AAV.CPP.16 (CPP16), constructed new, clinic-oriented expression its efficacy preclinical MLIV. Systemic administration...
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This leads to the skipping of exon 20 and tissue-specific reduction ELP1, mainly central peripheral nervous systems. FD neurological disorder accompanied severe gait ataxia retinal degeneration. There currently no effective treatment restore ELP1 production individuals with FD, ultimately fatal. After identifying kinetin as small molecule able...
Abstract Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded CTRP5/C1QTNF5 gene . To understand mechanism underlying pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners CTRP5. Additionally, analyzed Bruch's membrane/choroid (BM‐Ch)...
Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This results tissue-specific reduction of ELP1 protein, with lowest levels central and peripheral nervous systems (CNS PNS, respectively). FD patients exhibit neurological phenotypes due to loss sensory autonomic neurons. Disease symptoms include decreased pain temperature perception, impaired or absent myotatic reflexes,...
Patients harboring homozygous c.498_499insC mutations in MFRP demonstrate hyperopia, microphthalmia, retinitis pigmentosa, retinal pigment epithelial atrophy, variable degrees of foveal edema, and optic disc drusen. The disease phenotype is variable, however, with some patients maintaining good central vision cone function till late the disease. A knock-in mouse model mutation Mfrp (Mfrp KI/KI) was developed to understand effects these retina. shares many features human clinical disease,...
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by mutation in the Elongator complex protein 1 (ELP1) gene that leads to tissue-specific reduction of ELP1 protein. Our work generate phenotypic mouse model for FD headed discovery homozygous deletion Elp1 embryonic lethality prior mid-gestation. Given reduction, not loss, ELP1, we generated two new models introducing different copy numbers human transgene into knockout (Elp1−/−) observed expression rescues...
Abstract Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This results tissue-specific skipping of exon 20 with corresponding reduction ELP1 protein, predominantly central and peripheral nervous system. Although FD patients have neurological phenotype continuous depletion sensory autonomic neurons, progressive visual decline leading to blindness one most...
Abstract Pre-mRNA splicing is a key control point in human gene expression. Disturbances due to mutation or aberrant regulatory networks lead dysregulated protein expression and contribute substantial fraction of disease. Several classes active selective modulator compounds have been recently identified, thus proving that pre-mRNA viable target for therapy. We describe herein the identification BPN-15477, novel compound, restores correct exon 20 Elongator complex 1 (ELP1) carrying major...
Abstract Familial dysautonomia (FD) is a fatal inherited congenital neuropathy characterized by both progressive neurological symptoms and systemic abnormalities, patients have reduced life expectancy. FD caused T-to-C mutation in intron 20 of the Elongator acetyltransferase complex subunit 1 ( ELP1 ) gene, which affects splicing process causing tissue-specific skipping exon 20. Here, we developed CRISPR base editor (BE) approach capable precisely correct this mutation. Using Cas9 variants...
Abstract Elongator is a highly conserved protein complex required for transcriptional elongation, intracellular transport and translation. 1 (ELP1) the scaffolding of essential its assembly stability. Familial dysautonomia (FD), hereditary sensory autonomic neuropathy, caused by mutation in ELP1 that lead to tissue-specific reduction protein. Our work generate phenotypic mouse model FD led discovery homozygous deletion Elp1 gene leads embryonic lethality prior mid-gestation. Given reduction,...
Abstract Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 ( ELP1 , also known as IKBKAP ). This results tissue-specific skipping of exon 20 with corresponding reduction protein, predominantly central and peripheral nervous system. Although FD patients have neurological phenotype continuous depletion sensory autonomic neurons, progressive visual decline leading to blindness one most...
Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by splice mutation in the Elongator acetyltransferase complex subunit 1 (
Abstract Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits and progressive vision loss. Using AAV9 AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying course in mouse model MLIV human MCOLN1 gene transfer. Here, using primate-enabling capsid AAV.CPP.16 (CPP16), constructed new, clinic-oriented expression vector its efficacy preclinical MLIV. Systemic administration CPP16- adult...