Gene Therapy for Lipoprotein Lipase Deficiency: Working Toward Clinical Application

Abstract

Lipoprotein lipase (LPL) deficiency causes hypertriglyceridemia and recurrent, potentially life-threatening pancreatitis. There currently is no adequate treatment for this disease. Previously, we showed that intramuscular administration of an adeno-associated virus serotype 1 (AAV1) vector encoding the human LPL(S447X) variant cDNA (AAV1-LPL(S447X)) normalized the dyslipidemia of LPL-/- mice for more than 1 year. In preparation for a clinical trial, we evaluated the safety and biodistribution of AAV1-LPL(S447X) in wild-type mice and fully characterized six LPL-deficient patients. Toxicological analysis in mice showed that intramuscular administration was well tolerated. Acute inflammatory response markers were transiently increased, and anti- AAV1 antibodies were generated. Histological analyses indicated a dose-dependent reversible spleen hyperplasia, and myositis at the injection sites. Biodistribution data showed short-term vector leakage from injection sites into the circulation, followed by liver-mediated clearance. Persistence of vector DNA was limited to the injected muscle and draining lymph nodes, and spread to reproductive organs was limited. Characterization of LPL-deficient patients showed that all patients presented with hypertriglyceridemia and recurrent pancreatitis. LPL catalytic activity was absent, but LPL protein levels were 20-100% of normal. Myoblasts derived from skeletal muscle biopsies of these patients were efficiently transduced by AAV1-LPL(S447X) and secreted active LPL. These data support the initiation of a clinical trial in LPL-deficient patients, for which regulatory approval has been granted.

Lessons Learned from the Clinical Development and Market Authorization of Glybera

“…This not only allows for a large portion of the AAV genome to be replaced with a therapeutic transgene but also the packaging of an AAV2-derived genome by capsid (Cap) proteins from other serotypes, resulting in AAV2 with altered tropism and immunogenicity. The recombinant vector used for this study, AAV1-LPL S447X , was produced in this way, using Cap proteins from AAV serotype 1 and ITRs from AAV2 (Rip et al, 2005).…”

“…In addition to the lower seroprevalence, AAV1 vectors transduce skeletal muscle with substantially higher efficiency than is observed with AAV2. Given that skeletal muscle is a site for physiological expression of LPL, the efficiency of transduction in this tissue made AAV1 an attractive vector for delivery of the LPL transgene (Rip et al, 2005).…”

“…Formal assessments of safety were conducted in preparation for the first clinical trial under conditions of Good Laboratory Practices (GLP) (Rip et al, 2005). Wild-type mice in a C57BL/6 background were selected for an evaluation of maximally tolerated dose (MTD) and dose-limiting toxicities.…”

Potential of AAV vectors in the treatment of metabolic disease

“…These include Canavan disease, 94 a-1-antitrypsin deficiency, 95 late infantile neuronal ceroid lipofuscinosis 96 and lipoprotein lipase deficiency. 97 All are phase I or I/II. Two of these conditions, Canavan disease and late infantile neuronal ceroid lipofuscinosis, involve targeting of the central nervous system and necessitate the enrolment of children.…”

An update on gene therapy for the treatment of lipoprotein lipase deficiency

“…20 It was found that muscle is well-suited to dose-dependent LPL expression and that skeletal muscle is tolerant to high viral loads. 18 Additionally, acute inflammatory elements are only transiently elevated post-injection in mice.…”