2022 Cbl C Research Grant

Identification of Compounds to Rescue MMACHC Functional Deficiency in CBLC Disease
Principal Investigator: Silvia Vilasi, PhD


May 13, 2022

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CblC Onlus, HCU Network America and the Organic Acidemia Association have awarded funding to a research project to identify potential treatment for cobalamin C (cblC) deficiency. The research, entitled Identification of Compounds to Rescue MMACHC Functional Deficiency in cblC Disease, will be carried out by Dr. Silvia Vilasi at Institute of Biophysics (IBF) in the National Research Council in Palermo, Italy.

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.”

About Dr. Silvia Vilasi

Throughout her career, starting from a hard science such as Physics, (Master Degree in Physics in 2002, at the University of Naples “Federico II”, Naples, Italy), Silvia Vilasi has focused on Life Sciences and human health. Since her Ph.D. thesis (Ph.D. in “Fundamental and applied Physics” in 2006, Biophysics specialization at Perugia University), she has studied the mechanisms (due to mutations or environment), by which a protein folds incorrectly and reaches non-functional conformations and aggregates, causing severe neurodegenerative diseases. She has thus acquired significant expertise in a wide variety of biophysical tools, from microscopic techniques (e.g. atomic force microscopy) to spectroscopy (fluorescence, absorption, and circular dichroism) and light scattering on which she continued getting experience during several postdoc fellows (2005-2009, Department of Biochemistry and Biophysics, Second University of Naples, Italy; 2009-2011, Department of Pharmaceutical Sciences, Salerno University, Italy; 2011-2012 Biophysics Institute (IBF), National Research Council (CNR), Italy). From 2012 to 2015 she was a fixed-term researcher at IBF-CNR. The position was self-financed since she led one of the research units of the FIRB MIUR project “MIND: Multidisciplinary Investigations for the development of Neuroprotective Drugs” (awarded 845.090 euros), focused on the identification of chemical compounds or molecular chaperones able to counteract the pathological consequences of protein misfolding. The participation to Third International Patient Expert Homocystinurias Meeting in 2019 (Roma, Italy) fueled her involvement with cblC victims and she started working on proteins resulting from cblC mutations, investigating the effect of mutation c.394C>T on MMACHC structure and properties, as evidenced by a recent publication in “Biochimica and Biophysica Acta, Proteins and Proteomics” (https://doi.org/10.1016/j.bbapap.2022.140793).