University of Pittsburgh researchers have identified a novel therapy for Medium Chain Acyl-CoA Dehydrogenase Deficiency in Humans (MCADD), one of the most frequent inborn errors of metabolism. A single point mutation in the medium chain acyl-CoA dehydrogenase (MCAD) gene which encodes for the MCAD enzyme, is generally the cause of this lifelong condition. Using small molecules, it is possible to increase MCAD enzyme activity in the presence of this mutation and may be a novel treatment for this potentially life-threatening condition.
Description
MCADD is the most frequently inherited defect of fatty acid oxidation. While patients may be asymptomatic at birth, MCADD can be detected from the ﾓheel-prickﾔ test. Defective fatty acid oxidation can lead to a variety of complications including ketogenesis, hypoglycemia, hyperammonemia, and hepatic steatosis. Physiological stress such as infection, strenuous exercise or fasting can lead to episodes of acute, potentially life-threatening metabolic decompensation. Currently, no medication exists to overcome the metabolic deficiencies caused by MCADD and it remains an unmet clinical need for patients and their caregivers.
Applications
1. Medium Chain Acyl-CoA Dehydrogenase (MCAD) deficiency
Advantages
Current approaches to manage MCADD involve lifelong dietary management with hospitalizations and IV glucose therapy in times of illness. Given this condition first presents in the initial 24 months of life, dietary management and monitoring of children can place a substantial burden on families and caregivers. Research has identified a point mutation in the MCAD gene (A985G) in 90% of alleles in patients with MCADD. This mutation leads to a glutamic acid (Glu) instead of a Lysine (Lys) at position 304 (K304E), resulting in protein instability and inefficient binding with subsequent ?, -dehydrogenation of acyl-CoA esters and transfer of electrons to electron transferring flavoprotein (ETF). This novel approach has identified methods of stabilizing the mutated MCAD enzyme using chaperones for the substrates at key docking sites. The resulting increased protein stability and improved enzyme activity leads to oxidation of fatty acids and could restore normal metabolic balance in patients.
Invention Readiness
In silico screening identified several potential substrates that may stabilize the mutated MCAD enzyme (MCAD K304E). In experiments, phenylbutyryl-CoA ﾖ a CoA-ester of the existing drug Buphenyl (sodium phenylbutyrate) ﾖ could stabilize MCAD K304E. In vitro testing has found phenylbutyryl-CoA enhanced MCAD activity of both wild type and patient cells. Further work is required but this novel approach could substantially improve the lives of patients with MCADD.
IP Status
https://patents.google.com/patent/US9283200B2
