A feasibility study for the in vitro development of an enzyme replacement therapy targeted to the treatment of cblC type methylmalonic acidemia with homocystinuria. The project, led by researcher Laura Tinti, was financed by Telethon as part of the “2013 exploratory projects call” dedicated to the support of hitherto neglected diseases of a genetic origin.
MMACHC, a rare disease. cblC-type methylmalonic acidemia with homocystinuria is the most frequent congenital defect of the metabolism of vitamin B12. There are two forms of this disease: a more serious one that develops within the first year of life and another that arises during adolescence. Patients with the more serious form present a multisystemic disease with serious neurological, ocular, hematological, renal, gastrointestinal, cardiac and pulmonary manifestations. The therapies currently available are not effective, especially over the long term, during which there is an inexorable progression of the neurological and ocular symptoms.
The research project. The objective of this project is to understand how the defective protein in these patients, MMACHC, can be replaced with a properly functioning version. The research conducted in the last two years has led to the development of a method to produce significant quantities of active MMACHC protein. As part of this project the studies that have already begun will be continued, and the therapeutic potential of the protein developed will be evaluated by analyzing its activity on primary fibroblast cultures obtained from patients. The protein will be conveyed into diseased cells through various transport methods. Once effective entry into cells has been verified, the protein’s effective function will be tested by measuring variations over time of the levels of homocysteine and methylmalonic acid, the two metabolites regulated by the activity of MMACHC that tend to accumulate as a consequence of the enzymatic defect. The results obtained from this project will allow the investigators to pass, in the case of success, to subsequent stages in the development of this therapy.