According to the principal investigator, Dr. Silvia Vilasi, the project aims to characterize and classify some of the most common cblC variants of MMACHC protein based on the impact that specific mutation has on MMACHC molecular features, such as structure, stability, B12 binding properties, and function. Based on this classification, MMACHC-specific molecules with potential therapeutic benefit and safety will be screened exploiting a structure-based bioinformation approach. The idea is to find molecules able to bind the mutants and stabilize these protein variants in a conformation similar to the unmutated protein (wild type), recovering their function. The protein druggable sites will be targeted with several virtual libraries of drug-like molecules, giving priority to DrugBank library that includes EMA and FDA-approved molecules. 5-10 compounds from the bioinformatic experiments will be then experimentally validated, assessing their ability to restore functionality of proteins. The selected molecules could be precursors for further preclinical studies. Dr. Silvia Vilasi says “I am very happy and honoured to have the possibility to contribute to homocystinuria research and I am grateful to CblC Onlus, HCU Network America, and the Organic Acidemia Association for the trust they have placed in the project. The team I will coordinate with at IBF can leverage a wealth of facilities, multidisciplinary skills, and backgrounds of the members participating in the project, from experimental biophysics, chemistry, cell biology, structural biology, and structure-based drug screening. Moreover, to achieve the proposed goals we will collaborate with Prof. Carlo Dionisi Vici, Head of Clinical and Research Unit of Metabolic Diseases at the Ospedale Pediatrico Bambino Gesù in Rome, who will have an important role in mentoring and guiding the experimental activities as the project is designed to be ‘patient-centered’”.

Rossella Brindisi, President of CblC Onlus says, “It is a great pleasure to collaborate with HCU Network America and Organic Acidemia Association on this project. It is a good example of cooperation among different organizations spread out in different countries to support scientific research and family community. We hope it will pave the way for further common initiatives.”

President of HCU Network America, Margie McGlynn says, “While HCU Network America’s prior grants were awarded for research projects for potential new therapies for classical homocystinuria, we are pleased to collaborate with cblC Onlus and the Organic Acidemia Association to support a grant-focused on potential new therapies for cobalamin C disorder, which is consistent with the expanded focus of HCU Network America. We also hope this project will generate insights that can be applied in the future to other cobalamin disorders.”

Organic Acidemia Executive Director, Kathy Stagni says, “The Organic Acidemia Association is happy to collaborate with HCU America and CblC Onlus on this grant request. We feel fortunate and hopeful that researchers work toward the goal of better treatments for our cobalamin C families.”