| [Background]: Lipoprotein lipase (LPL) is the principal enzyme involved in the clearance of triglycerides. Total loss of LPL function causes severely elevated plasma triglyceride levels. LPL deficient patients usually present with repetitive bouts of colicky pain, failure to thrive, and growth retardation. The most severe complication, however, is acute life-threatening pancreatitis. Treatment currently consists of a severe reduction of dietary fat. For adolescents in Western societies it is almost impossible to comply with such a lifestyle and accordingly they experience pancreatitis. Of more general interest is the notion that high LPL is associated with a beneficial lipoprotein phenotype, and a reduced risk of cardiovascular disease. LPL is a good candidate to explore the clinical use of gene therapy: 1) There are thousands of LPL deficient patients suffering from severe clinical complications. 2) There is no effective clinical therapy. 3) An accurate diagnosis at the molecular level is available. 4) There exists a low probability that patients will develop an immune response against exogenous LPL. 5) Proof of principle that viral-mediated LPL gene delivery induces 90% decreases of triglycerides in LPL deficient animal models. 6) The existence of a Lipid Clinic Network enables quick tracing of LPL deficient patients. 7) Since LPL deficiency is associated with a poor quality of life, no problems in obtaining informed consent are anticipated. 8) Last but not least: this therapy can be studied to improve lipoprotein profiles to ultimately prevent cardiovascular disease. [Hypothesis]: Adeno-associated (AAV) virus is a suitable vector for LPL delivery to establish an efficient and safe therapy to treat genetic LPL deficiency. [Primary study objectives]: 1) Use LPL gene therapy to correct the biochemical phenotype of LPL deficient animals, and to ameliorate the clinical phenotype of human LPL deficiency. 2) Investigate the effects of enhancing LPL gene function to correct an atherogenic lipoprotein profile, and to ultimately prevent atherosclerosis. When successful in animals, these studies will be followed by patient studies. [Methods]: For long-term expression, AAV-LPL will be delivered through intramuscular injections. Monitoring LPL function, studying effects on lipids and lipoproteins, and the assessment of atherosclerotic disease, in animal models and humans will be performed with established methods. [Expected results]: Intramuscular delivery of AAV-LPL will result in clinically significant triglyceride lowering in patients with genetic LPL deficiency. This result may kick off studies into enhanced LPL function, by means of gene therapy, to reduce progression or even induce regression of (coronary) atherosclerosis. [Relevance for cardiovascular diseases]: Both animal studies and epidemiological studies provide convincing data that enhancing LPL gene function ameliorates an atherogenic lipoprotein profile and helps to prevent coronary heart disease. In addition to the treatment of genetic LPL deficiency, LPL gene therapy could therefore prove to be a means to improve lipoprotein profiles to ultimately prevent cardiovascular ischemia and cardiovascular disease. |
