Neurosciences
Neuromuscular and Mitochondrial Pathology
Ramon Martí
Researchers
Yolanda Cámara Navarro, Elena García Arumí, Xavier Ortega Gonzalez, Tomas Pinós Figueras, Antoni Andreu
Researchers in training
Albert Blanco Grau, Astrid Brull Cañagueral, Raquel Cabrera Perez, Lidia Carreño Gago
Investigadors predoctorals
Àstrid Brull Cañagueral, Raquel Cabrera Pérez, Albert Blanco Grau, Josep Maria Guiu Segura
Nursing, technical and administrative staff
Maria Jesús Melià Grimal
Project Manager
Noemi Baruch
SUMMARY
Three important achievements have been reached during 2014 by our group. First, we obtained very good results in our preclinical studies to investigate a Gene Therapy approach for MNGIE, a rare mitochondrial disease, using an adeno-associated vector (AAV) carrying the TYMP gene (Torres-Torronteras et al, Mol Ther 2014). The use of this vector in a murine model of MNGIE prevented the biochemical imbalances observed in this disorder, confirming the proof of concept study that we had published 3 years ago, using a different vector (Torres-Torronteras et al, Gene Ther 2011). Based on these results, Orphan Drug Designation of this AAV vector was achieved from the EMA (EU/3/14/1326) in August 2014, and from the FDA (14-4410) in September 2014.
Second, we have obtained also results that allowed us to propose a new strategy to treat the mitochondrial DNA depletion/deletions syndrome, based on the supply of substrates of the enzymes which are defective in these disorders (Cámara et al, Hum Mol Genet, 2014). This milestone will serve as base to propose new projects to advance towards in vivo evidence that this strategy of treatment is feasible in patients.
And third, framed in our EUROMAC project (European registry of patients with McArdle Disease and other glycogenoses), we reached one of its main milestones, which is to finish the design and implementation of the functional platform to introduce patients, which will allow all partners of the consortium we coordinate to initiate the registering activity.
PUBLICATIONS
- Cámara Y, González-Vioque E, Scarpelli M, Torres-Torronteras J, Caballero A, Hirano M, Martí R. Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome. Hum Mol Genet. 2014 May 1;23(9):2459-67. doi: 10.1093/hmg/ddt641. Epub 2013 Dec 20. PubMed PMID: 24362886.
- Torres-Torronteras J, Viscomi C, Cabrera-Pérez R, Cámara Y, Di Meo I, Barquinero J, Auricchio A, Pizzorno G, Hirano M, Zeviani M, Martí R. Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE. Mol Ther. 2014 May;22(5):901-7. doi: 10.1038/mt.2014.6. Epub 2014 Jan 22. PubMed PMID: 24448160; PubMed Central PMCID: PMC4015233.
- Nogales-Gadea G, Santalla A, Brull A, de Luna N, Lucia A, Pinós T. The pathogenomics of McArdle disease-genes, enzymes, models, and therapeutic implications. J Inherit Metab Dis. 2015 Mar;38(2):221-30. doi: 10.1007/s10545-014-9743-2. Epub 2014 Jul 23. PubMed PMID: 25053163.
- Meseguer S, Martínez-Zamora A, García-Arumí E, Andreu AL, Armengod ME. The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet. 2015 Jan 1;24(1):167-84. doi: 10.1093/hmg/ddu427. Epub 2014 Aug 22. PubMed PMID: 25149473.
- Santalla A, Nogales-Gadea G, Ørtenblad N, Brull A, de Luna N, Pinós T, Lucia A. McArdle disease: a unique study model in sports medicine. Sports Med. 2014 Nov;44(11):1531-44. doi: 10.1007/s40279-014-0223-5. PubMed PMID: 25028051.
MAIN RESEARCH PROJECTS
View- PI: Tomàs Pinós Figueras
Title: Avances en la enfermedad de McArdle: Nuevas aproximaciones terapéuticas y desarrollo de un nuevo método diagnóstico no invasivos
Funder Entity: Instituto de Salud Carlos III
Reference: PI13/00855
Funding: 162.140 €
Duration: from 2014 to 2016 - PI: Ramon Martí (project coordinator)
Title: EUROMAC – European registry of patients with McArdle disease and very rare muscle glycogenolytic disorders (MGD) with exercise intolerance as the major symptom (PR-MDMGD)
Funder Entity: European Comission (DG-SANCO)
Reference: Agreement number 2012 12 14
Funding: Provided by EC (60% of total budget): 911,578 € for the whole project (220,556 € for our group)
Duration: 40 months (23/03/2013 – 22/09/2016) - PI: Javier Torres Torronteras
Title: Gene therapy preclinical studies for neurogastrointestinal Mitochondrial encephalomyopathy (MNGIE). Long-term monitoring and use of adeno-associated viral vectors.
Funder Entity: United Mitochondrial Disease Foundation (UMDF)
Reference: UMDF-12-029
Funding: 95.000 $
Duration: 2 years, from July 2012 to June 2014 - PI: García Arumí, Elena
Title: Medicina mitocondrial: configuración de una estrategia para la identificación genético-molecular de pacientes OXPHOS
Funder Entity: Instituto de Salud Carlos III
Reference: PI12/02149
Funding: 260,513 €
Duration: from 2013 to 2015 - PI: Martí Seves, Ramon
Title: Aproximaciones terapeúticas para el tratamiento de los síndromes de depleción del DNA mitocondrial.
Funder Entity: Instituto de Salud Carlos III
Reference: PI12/00322
Funding: 263,477 €
Duration: from 2013 to 2015
PATENTS
- Designation by the EMA:
Vector based on an adeno-associated virus serotype 2 backbone, pseudoserotyped with a type 8 capsid, which carries the coding sequence of the human TYMP gene under the control of the human thyroxine binding globulin promoter for the treatment of mitochondrial neurogastrointestinal encephalomyopathy
Ramón Martí - Designation by the FDA:
AAV Vector containing TYMP, the gene encoding thymidine phosporilase
Ramon Martí