HDL-replacement therapy: From traditional to emerging clinical applications

The unique and multifaceted properties of high-density lipoproteins (HDL)—ranging from cholesterol efflux to anti-inflammatory, anti-oxidant, and immunomodulatory effects—have prompted their direct use, particularly in cardiovascular ischemic conditions. Recent advances have extended the interest in HDL-based treatments to novel applications, from improving stent biocompatibility, to treatment of heart failure to central nervous system (CNS) disorders. Strategies to harness HDL’s therapeutic potential have evolved from the direct use of isolated HDL in animal models to reconstituted HDL (rHDL) in humans. For these latter, the use of isolated apoA-I associated with different phospholipids has been the most frequent approach, also involving apparently beneficial mutants, such as the apo A-I Milano (AIM). From the initial very promising results, particularly with this mutant in coronary patients, later studies have mostly been non-confirmatory, although issues such as possible inadequate dose/response and unexpected immunological properties have come to light. Most recently a study on isolated plasma HDL in coronary patients (AEGIS-II) provided overall negative findings, but a clear fall of major cardiovascular events was recorded when restricting analysis to hypercholesterolemic patients. Emerging approaches, including gene therapy and plant-derived recombinant HDL formulations, hold promise for enhancing the accessibility and efficacy of HDL-based interventions. At this time, an improved approach to heart failure treatment also appears feasible, and a better understanding of the role played by HDL in the CNS may lead to significant improvements in the handling of some dramatic diseases at this level. While challenges persist, the evolving landscape of HDL replacement therapies offers hope for significant progress in addressing both cardiovascular and non-cardiovascular conditions.