Acute Kidney Injury
Acute Kidney Injury (AKI) affects over 1 million patients per year in the US and is a major risk factor for developing chronic kidney disease. Despite these sobering statistics, there are currently no effective treatments for preventing the progression of AKI. We are tackling this unmet medical need via two approaches. We have previously shown that the administration of a pro-drug of 4-(phenylthiol) butanoic acid (PTBA) enhances renal recovery, increases renal epithelial cell proliferation, and displays a reduction in renal fibrosis in multiple mouse models of AKI. The use of a pro-drug, in this case, the 2-hydroxyphenyl amide of PTBA, was required, as direct administration of the carboxylic acid was ineffective. However, pro-drugs can prove to be challenging to develop due to differences in metabolism across species. In order to identify compounds which would not require a pro-drug for delivery, we designed and synthesized novel PTBA analogs containing carboxylic acid bioisosteres, and assessed them in zebrafish, human kidney organoids, and rodent AKI models.
Kidney Disease: Focal Segmental Glomerosclerosis
We have found that active site inhibitors of HDAC are efficacious in models of kidney disease characterized by focal segmental glomerulosclerosis (FSGS). Unfortunately, currently known HDAC inhibitors contain a hydroxamic acid moiety, whose toxicity is unacceptable in the FSGS patient population. We are working on designing several different scaffolds as novel HDAC inhibitors that using molecular modelling to guide synthesis. From there we hope to build the structure activity relationships of these new potential inhibitors to better inform future synthetic endeavors.
Duchenne Muscular Dystrophy
DMD is a severe muscle-wasting condition affecting 1 in 3,600 live-born males. It results from mutations in the dystrophin gene, leading to a lack of the dystrophin protein, which is essential for muscle integrity. Utilizing high-throughput screening, we have identified multiple compounds that result in the increased expression of utrophin. In animal models of DMD, one of the compounds improved the DMD phenotype. Our preliminary studies have identified two promising compounds, ‘Utro 6’ and ‘Utro 88,’ which show significant potential in upregulating utrophin expression. These compounds are currently undergoing further optimization and testing to confirm their efficacy and safety.
Another approach we are investigating for the treatment of DMD is increasing the quantity of NAD (nicotinamide adenine dinucleotide) in muscle cells. Our collaboration with the Baur and Khurana labs has shown that the dystrophic phenotype can be mimicked by reducing NAD+ levels in skeletal muscle. In addition, studies from the Auwerx group have demonstrated that methods of increasing NAD+ levels in muscle of the mdx mouse model of DMD, such as treating mice with NAD+ biosynthetic precursors, lead to an improvement in the dystrophic phenotype. Through high-throughput screening, we have identified several hit compounds which lead to an increase in NAD+ levels. Investigations into the targets of these compounds, as well as their optimization, are ongoing.