Trial readiness for LCAT deficiency

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY Genetic bi-allelic deficiency of LCAT (LCAT-D) is an ultra-rare, autosomal recessive condition that manifests as two different syndromes, familial LCAT deficiency (FLD) and fish-eye disease (FED). Both syndromes are characterized by excess of unesterified cholesterol (UC), significantly reduced HDL-C levels and corneal opacities. In addition, FLD patients develop chronic progressive renal disease, which represents the main cause of morbidity and mortality in this condition. Additional manifestations of FLD include anemia, increased levels of triglycerides and the presence of an abnormal lipoprotein called LpX. While the consequences of LCAT-D on lipoprotein metabolism have been extensively characterized, much less in known about the natural history of LCAT-D. Clinical presentation and progression of disease appear to be heterogeneous across individuals, and we still lack a clear understanding of the factors contributing to such variability, not only between FED and FLD, but also within each syndrome. Current treatment for FLD is limited to symptomatic management of its sequelae. Novel therapeutics targeting LCAT are at different stages of development, including an AAV-hLCAT gene therapy approach at the University of Pennsylvania. Unfortunately, their further development is limited by inadequate understanding of the natural history of LCAT-D. Identification of suitable biomarkers to determine eligibility and assess efficacy is urgently needed. The overarching goal of this proposal is to: 1. Identify biomarkers that can guide enrollment criteria, including diagnostic biomarkers to distinguish FLD from FED, and prognostic biomarkers to enrich enrollment with FLD patients that have a higher risk of rapid CKD progression (Aim 1). 2. Identify pharmacodynamic and efficacy biomarkers to aid the identification of target response and the efficacy of the intervention tested (Aim 2). 3. Identify comorbidities and concomitant medications that may impact pharmacodynamic measurements (Aim 3). We will achieve these goals by performing unbiased retrospective long-term deep data extraction from medical records of FED and FLD patients that will enroll in our ongoing natural history study (NCT06217588). These data will be complemented by laboratory assays assessing LCAT mass and activities, and other markers of esterification, including %CE, done in samples obtained from the patients enrolled in the study and from pre-existing samples and data from selected cohorts of LCAT-D patients and patients with secondary LCAT deficiency. The successful completion of this study will provide key diagnostic biomarkers and needed information on the rate of decline of key markers of disease, as well as the effect of concomitant medications or co-morbidity that may affect the primary pharmacodynamic parameters. Overall, these data will be pivotal for the refinement of the inclusion and exclusion criteria and be instrumental to identify the primary clinical efficacy endpoints and establish the duration of the clinical trial.