Exploring therapeutic approaches to treat Inborn Errors of Metabolism

Scientists in the School of Pharmacy and Pharmaceutical Sciences have teamed up with an industry collaborator to leverage their platform chemistry toward developing new therapies for rare pediatric diseases with no available treatment.

Inborn Errors of Metabolism (IEMs) are a group of inherited disorders caused by genetic defects that hinder production of vital metabolic intermediates, eventually leading to tissue myopathy and organ failure. In some cases, mortality rates are higher than 50% in early childhood.

Previous attempts at treating these diseases using a substrate replacement approach have generated proof-of-concept in in vitro models, demonstrating the ability to rescue depletion of key metabolites and salvage cell viability. However, the prospects of such approaches as pharmaceuticals have been complicated by a lack of optimal ‘drug-like’ properties.

Now, the medicinal chemistry group at Cardiff hopes to successfully apply knowledge gained transforming the treatment of anti-viral diseases to developing treatments for rare disorders in collaboration with Ichorion Therapeutics, a New York-based biopharmaceutical company focused on IEMs. Building upon the ProTide strategy originally conceptualized by Cardiff’s own Professor Chris McGuigan, the collaboration takes a fresh look at a prodrug approach balancing the capability to directly address a monogenic deficiency of the disease state with a small molecule possessing suitable chemical properties to become a medicine.

One such disease state is the mitochondrial DNA depletion syndrome (MDS) known as Deoxyguanosine Kinase (DGUOK) Deficiency. MDS patients have difficulty synthesizing mitochondrial DNA (mtDNA), which compromises the cell’s powerhouse. Cardiff and Ichorion have worked closely over the past year to optimize lead compounds shown to rescue mtDNA depletion in multiple models of DGUOK Deficiency. What they’ve learned is being applied to others MDSs and to IEMs more broadly.

Dr. Fabrizio Pertusati of Cardiff University’s School of Pharmacy and Pharmaceutical Sciences, who leads the chemistry efforts, added, ‘This work may represent an important step forward toward hope for patients with unmet medical needs. We’ve learned a lot applying our chemistry to anti-viral and anti-cancer drug development, and we’re excited to extend our scientific platform with the hope of helping under-served patient populations with rare metabolic diseases.’