AAV-mediated liver-directed gene therapy for gyrate atrophy of the choroid and retina
AAV-mediated liver-directed gene therapy for gyrate atrophy of the choroid and retina
Research Summary
Dr. Nicola Brunetti-Pierri
Telethon Institute of Genetics and Medicine in Italy
Conquering Gyrate Atrophy has awarded $50,000 to support research on safety elements of liver-directed gene therapy. They have recently shown that adeno-associated virus (AAV)-mediated liver-directed gene transfer of OAT corrects systemic ornithine increase and prevents the retinal degeneration in two independent mouse models of GACR1. As liver‐directed gene therapy by AAV vectors is showing safety and efficacy in a growing number of clinical trials3-5, GACR is an attractive disease candidate. However, previous studies were performed using the hepatocyte-specific thyroxine-binding globulin (TBG) promoter to drive OAT expression and there are concerns about expression of OAT in hepatocytes not physiologically expressing OAT (i.e., periportal hepatocytes). The goals of this research are to investigate whether ectopic expression of OAT in periportal hepatocytes results in defective ureagenesis and hyperammonemia (specific aim 1) and to investigate the efficacy of an AAV vector expressing OAT under the control of the natural OAT promoter at correction of GACR phenotype in mice (specific aim 2).
Researcher Profiles
Dr. Brunetti-Pierri is a physician-scientist whose research goals are to elucidate the pathogenetic mechanisms and to develop new and more effective therapies for genetic diseases. He has defined the clinical phenotypes and identified the molecular bases of several genetic diseases (lathosterolosis, 1q21.1 deletion and duplication syndromes, FOXG1 duplication syndrome, blepharophimosis intellectual disability syndrome [BIS]). He developed proof-of-concept data supporting the efficacy of small molecule drugs for maple syrup urine disease, pyruvate dehydrogenase deficiency, urea cycle disorders, and Myhre syndrome. He has a long-standing interest in liver-directed gene therapy for inborn errors of metabolism
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