Cardiolipin enhancing biodegradable nanoparticle for Barth syndrome
Shanta Dhar, PhD, Associate Professor, University of Miami Miller School Medicine, Miami, FL
Award: US $50,000 over 2-year period
Barth syndrome (BTHS) is a rare mitochondrial dysfunction related condition characterized by a group of symptoms which include dilated cardiomyopathy, skeletal myopathy, neutropenia, and short stature. Barth syndrome, which occurs almost exclusively in males, is a result of an X -linked genetic condition. Downstream of this genetic mutation results in inability of mitochondria to make adequate amounts of mature cardiolipin (CL) required for normal mitochondrial structure and energy production. Ongoing studies of BTHS mostly focus on the mechanistic and diagnostic level to understand the cause of this mitochondrial dysfunction related disease. Only a few therapeutic investigations were conducted by providing nutritional supplement to increase tetralinoleoyl-CL or delivery of antioxidant to prevent oxidation of CL.
The Principal Investigator’s laboratory recently developed a mitochondria-targeted nanoparticle (NP) with abilities to fuse with mitochondrial membrane and enhance CL content in the mitochondrial membrane of heart and liver tissues from different species ranging from mouse to dog. With this success, we now hypothesized that delivery of mature cardiolipin to this population of patients using a biodegradable synthetic nanoparticle can be an alternative way to manage BTHS associated symptoms. Further, patients with BTHS show inflammatory signals and enhanced levels of reactive oxygen species (ROS) which further worsen the symptoms by oxidizing the lipids. Thus, incorporation of a mitochondria-acting antioxidant in these NPs will further enhance the therapeutic outcome. The release of the anti-oxidant from the NP in a controlled release fashion over a period of time will enhance the therapeutic effects by preventing further lipid oxidation and reducing existing ROS.
To construct this NP platform and to demonstrate its potential, we have defined the following Specific Aims: (1) Development of a biodegradable nanoparticle for enrichment of mitochondrial cardiolipin; (2) Bio-distribution of T-CL-NPs and efficacy studies in Heart-On-Chip model; and (3) In vivo efficacy study in Barth syndrome model. Successful completion of this project will discover a potential therapeutic modality for reducing BTHS, a major unmet clinical need.