This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Familial hypercholesterolemia (FH) is a heritable disease that is believed to be an excellent candidate for gene therapy. SFBR maintains a unique colony of rhesus monkeys (Macacca mulatta) that carry a defective gene for the low density lipoprotein (LDL) receptor and provide a naturally occurring model of human familial hypercholesterolemia. The defect in LDL receptor of these monkeys has been identified as a nonsense mutation in exon 6 that results in the production of a protein truncated at a position corresponding to amino acid 284 of the human LDL receptor. This defect has segregated with the phenotype of spontaneous hypercholesterolemia through four generations. This is the only nonhuman primate model for FH and proof of efficacy and safety of gene therapy in this model would be a major accomplishment toward human gene therapy for this disease. The objective of the program project is to examine the effect of the hepatic transfer of rhesus and human LDL receptor genes to LDL receptor defective rhesus monkeys. The goal is to demonstrate that transgenes increase hepatic expression of LDL receptor, reduce plasma LDL levels, slow development of arterial lesions and are safe during a 24-month period. Three methods were used for hepatic delivery of helper-dependent adenoviral vector with LDL-R (HDAd-LDLR). First, a single injection of 5 x 10E12 vp/kg HDAd-LDLR was given intravenously (IV). The treatment lowered the plasma cholesterol level from 578 mg/dl to 276 mg/dl at 21 days after injection;however, cholesterol returned to the pretreatment level by 42 days. Treatment was associated with elevated liver enzymes. Second, the efficiency of hepatocyte transduction was increased by a direct HDAd injection into the hepatic artery while transiently raising intrahepatic pressure by a balloon catheter inserted in the inferior vena cava (IVC), blocking hepatic venous drainage, which was released immediately before HDAd injection.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR013986-12
Application #
8172640
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2010-05-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
12
Fiscal Year
2010
Total Cost
$110,863
Indirect Cost
Name
Texas Biomedical Research Institute
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78245
Shelton, Elaine L; Waleh, Nahid; Plosa, Erin J et al. (2018) Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data. Pediatr Res 84:458-465
Perminov, Ekaterina; Mangosing, Sara; Confer, Alexandra et al. (2018) A case report of ovotesticular disorder of sex development (OT-DSD) in a baboon (Papio spp.) and a brief review of the non-human primate literature. J Med Primatol 47:192-197
Jensen, Jeffrey T; Hanna, Carol; Mishler, Emily et al. (2018) Effect of menstrual cycle phase and hormonal treatments on evaluation of tubal patency in baboons. J Med Primatol 47:40-45
Confer, Alexandra; Owston, Michael A; Kumar, Shyamesh et al. (2018) Multiple endocrine neoplasia-like syndrome in 24 baboons (Papio spp.). J Med Primatol 47:434-439
Mustonen, Allison; Gonzalez, Olga; Mendoza, Elda et al. (2018) Uremic encephalopathy in a rhesus macaque (Macaca mulatta): A case report and a brief review of the veterinary literature. J Med Primatol :
Koistinen, Keith; Mullaney, Lisa; Bell, Todd et al. (2018) Coccidioidomycosis in Nonhuman Primates: Pathologic and Clinical Findings. Vet Pathol 55:905-915
Mahaney, Michael C; Karere, Genesio M; Rainwater, David L et al. (2018) Diet-induced early-stage atherosclerosis in baboons: Lipoproteins, atherogenesis, and arterial compliance. J Med Primatol 47:3-17
Mangosing, Sara; Perminov, Ekaterina; Gonzalez, Olga et al. (2018) Uterine Tumors Resembling Ovarian Sex Cord Tumors in Four Baboons ( Papio spp.). Vet Pathol 55:753-758
Joganic, Jessica L; Willmore, Katherine E; Richtsmeier, Joan T et al. (2018) Additive genetic variation in the craniofacial skeleton of baboons (genus Papio) and its relationship to body and cranial size. Am J Phys Anthropol 165:269-285
Kumar, Shyamesh; Laurence, Hannah; Owston, Michael A et al. (2017) Natural pathology of the captive chimpanzee (Pan troglodytes): A 35-year review. J Med Primatol 46:271-290

Showing the most recent 10 out of 444 publications