On May 13, 2022, CblC APS, HCU Network America, and the Organic Acidemia Association announced the recipient of their first collaborative grant for cobalamin research. The grant was awarded to the Institute of Biophysics of the National Research Council in Palermo, Italy, to identify a potential treatment for cobalamin C (cblC) deficiency. The research, led by Dr. Silvia Vilasi, aims to identify compounds that could potentially correct the dysfunction of certain pathological variants of the MMACHC protein in the disease.
The project aims to characterize and classify some of the most common cblC variants of the MMACHC protein based on the impact a specific mutation has on MMACHC’s molecular characteristics, such as structure, stability, vitamin B12 binding properties, and function. Based on this classification, specific MMACHC molecules, potentially treatable with efficacy and safety, will be selected using a bioinformatics approach based on analysis of the protein’s structure. The idea is to find molecules capable of binding the mutants and stabilizing these protein variants in a conformation similar to the wild-type protein, thus restoring its function. Pharmacologically available protein sites will be identified using several virtual libraries of drug-like molecules, prioritizing the DrugBank library, which includes molecules approved by the EMA and FDA. 510 compounds resulting from the bioinformatics experiments will then be experimentally validated, evaluating their ability to restore protein function. The selected molecules could serve as precursors for further preclinical studies.
Leader the Institute of Biophysics, CNR (IBF-CNR), Dr. Silvia Vilasi
The protein has been characterized in many ways, both physically and functionally. The resulting data has led to the publication of several scientific studies, and this in-depth knowledge has allowed for a better understanding of the protein’s functional structure, which will also be useful for future applied studies, such as enzyme replacement therapy.
(Eur Biophys J. 2025 Jun 27. doi: 10.1007/s00249-025-01777-5.)
(Mol Genet Metab. 2025 Jul;145(3):109150. doi: 10.1016/j.ymgme.2025.109150.)
A doctoral thesis by Dr. Lisa Longo was also written, entitled: “Investigation on MMACHC pathological mtants involved in cblC disease, a rare metabolic disorder of vitamin B12”
The project is still ongoing and is analyzing some potential molecules
