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Scientists from the University of Granada develop a new pharmacological therapy to fight a rare disease that affects mainly children and for which there is no effective treatment

Scientists from the University of Granada (UGR) have developed a new pharmacological therapy, based on a type of phenolic acid, which is effective against a severe kind of deficiency in Coenzyme Q10 (CoQ10), a rare mitochondrial disease. 

Scientists from the University of Granada (UGR) have developed a new pharmacological therapy using a molecule that presents similarities with one of the precursors of coenzyme Q10 (CoQ10). The therapy is effective against a severe type of deficiency in Coenzyme Q10 (CoQ10), a rare mitochondrial disease that targets mostly children and for which there is currently no effective treatment.

EMBO Molecular Medicine just published this study, demonstrating the effectiveness of this experimental treatment in an animal model with severe deficiency in CoQ, encephalomyopathy and premature death, through the chronic administration of an analogue of one of the precursors that eukaryotic cells use to synthesize CoQ.

CoQ10 is a molecule synthesized in body cells with key functions in the cellular metabolism. Deficiency in CoQ10 is a syndrome featuring very diverse clinical manifestations. Usually, cases that present neurological symptoms or those that manifest the multisystem variant do not respond to the conventional treatment with high doses of exogenous CoQ10, due to the low capacity of this molecule to cross biological obstacles and reach the nervous system.

In this regard, the focus of this research has been to assess a therapeutic option that is effective for severe cases of deficiencies in CoQ10. The working hypothesis of the researchers was based on recent studies in yeasts and cell cultures generated by some international groups, including the UGR group.

The results indicate that the therapeutic molecule is capable of modulating the multiprotein complex for CoQ biosynthesis, so that endogenous CoQ synthesis is stimulated. “But we have also seen, and this is even more striking, that the therapeutic molecule is capable of reducing the levels of intermediary metabolites of CoQ that can be toxic to the power plant of the cells” explains Luis Carlos López García, a researcher of the UGR Biomedical Research Center and one of the article authors.

Consequently, these metabolic changes induce an increase in the capability of cells to produce energy, together with a reduction in the molecular and histopathological markers characteristic of mitochondrial encephalomyopathies.

The final result is an improvement of the phenotypic characteristics of the animal model with a very significant increase in life expectancy: while the untreated mutant mice reach a maximum of 7 months of life, the treated mutant mice are able to reach up to 25 months of life, approaching the survival curve characteristic of healthy mice.

“The therapeutic results we have obtained are very important, so one of the medium-term objectives is to apply it into the clinic,” Prof. López observes. On the other hand, from an intellectual point of view “there are some response mechanisms to the treatment that we still do not understand, so we are working on new experimental approaches that will help us to figure out these aspects, which should contribute to better understand the pathophysiology of mitochondrial diseases and to generate new therapeutic advances, for this and other mitochondrial disorders. At the same time, we are testing other molecules, with very interesting characteristics, that may be important not only for the treatment of severe diseases but also as nutraceuticals for the healthy population or for people without severe pathological conditions”.

Agustín Hidalgo and Eliana Barriocanal, hired by FPU program and the Junta de Andalucía, respectively, in the CTS-101 group of the UGR Biomedical Research Center, have developed most of the experimental work. Other significant collaborations are: Prof. Mohammed Bakkali from the Department of Genetics of the UGR and of Profs. Juan Duarte and Miguel Romero, as members of the Unit of Excellence “UNETE”.

Reference:

Hidalgo-Gutiérrez A, Barriocanal-Casado E, Bakkali M, Díaz-Casado ME, Sánchez-Maldonado L, Romero M, Sayed RK, Prehn C, Escames G, Duarte J, Acuña-Castroviejo D, López LC. β-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice. EMBO Mol Med, 2018, e9466. DOI: 10.15252/emmm.201809466

http://embomolmed.embopress.org/cgi/doi/10.15252/emmm.201809466

 

A picture of the member of the group that has developed this study. From the left to the right: Luis C. López, Agustín Hidalgo, Eliana Barriocanal, Laura Sánchez and Pilar González.

Video in which is easy to distinguish the phenotypic differences between a treated mouse and an untreated mouse.

 

Contact:

Luis Carlos López García

Centro de Investigación Biomédica

Tel.: +34958241000 – ext. 20197

Correo electrónico: luisca@ugr.es

http://wpd.ugr.es/~luisca/