EXploring therapeutic strategies for cblC Disease: Italy-Turkey collaboration

CblC disease is a rare genetic disorder that disrupts vitamin B12 metabolism leading to severe clinical outcomes including pulmonary complications, neuro-cognitive impairment, and degenerative maculopathy. Currently, the only existing therapy for the cblC (betaine, folic acid, L-carnitine and hydroxocobalamin) is unsatisfactory on the long-term. The disease is caused by a broad spectrum of mutations in the gene coding for MMACHC, that converts dietary cobalamin from an inactive to active co-enzyme forms MeCbl and AdoCbl. The most common allelic variant found in cblC patients, c.271dupA, suggested to cause nonsense-mediated mRNA decay (NMD), would result in a truncated protein with a frameshift of 14 ammino acids before the stop codon. For this mutation, gene therapy or enzyme replacement appears to be the only viable option. However, if the MMACHC protein resulted effectively produced by a certain mutated gene, or the nonsense mutation caused protein synthesis failure, like seems to occur for some nonsense mutations, different pharmacological approaches, never implemented for cblC treatment, could be contemplated. The focus of this project is on identifying small molecules (SMs) that can correct protein misfolding defects and/or induce readthrough of premature stop codons to restore the function of the MMACHC protein and to test these drug candidates in human disease specific in vitro cellular models