IEMTX

Therapies for inborn errors of metabolism

Coordinatore	FONDAZIONE TELETHON    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Italy [IT]
Totale costo	1˙491˙520 €
EC contributo	1˙491˙520 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2012-StG_20111109
Funding Scheme	ERC-SG
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-11-01   -   2017-10-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	FONDAZIONE TELETHON  Organization address address: VIA VARESE 16/B city: ROMA postcode: 185 contact info Titolo: Dr. Nome: Nicola Cognome: Brunetti-Pierri Email: send email Telefono: +39 081 6132361 Fax: +39 0644202032	IT (ROMA)	hostInstitution	1˙491˙520.00
2	FONDAZIONE TELETHON  Organization address address: VIA VARESE 16/B city: ROMA postcode: 185 contact info Titolo: Mrs. Nome: Irene Cognome: Mearelli Email: send email Telefono: +39 06 440151 Fax: +39 06 44015521	IT (ROMA)	hostInstitution	1˙491˙520.00

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 Obiettivo del progetto (Objective)

'We discovered that phenylbutyrate, prevents both in vitro and in vivo the inactivation by phosphorylation of the branched chain ketoacid dehydrogenase complex (BCKDC) and pyruvate dehydrogenase complex (PDHC). We show that phenylbutyrate is effective for treatment of maple syrup urine disease (MSUD) due to deficiency of branched chain ketoacid dehydrogenase complex (BCKDC), and has potential for therapy of deficiency of pyruvate dehydrogenase complex (PDHC). We propose to investigate phenylbutyrate for PDHC deficiency in a zebrafish model and in PDHC-deficient patients. We have recently developed a systems biology tool for prediction of drug mode of action starting from their gene expression profiles. This tool has a significant potential for drug discovery and repositioning. Through this approach, we found several FDA-approved drugs sharing with phenylbutyrate a similar mode of action. We propose to investigate the efficacy of these drugs for increasing the enzymatic activity of both BCKDC and PDHC and their therapeutic potential. While useful for proof-of-concept studies animal models are not suited to predict patient response to drugs which depends upon multiple factors including type of mutation and affected enzyme subunit. We propose to develop PDHC deficient neurons and MSUD hepatocytes from induced pluripotent stem cells (iPSCs) derived from patients’ fibroblasts. Drug response in these disease-relevant cell types will better predict clinical response of patients. Human iPSCs will be generated through a novel system based on high cloning capacity, non-integrating helper-dependent adenoviral (HDAd) vector expressing a combination of reprogramming factors. We will investigate altered metabolic pathways in PDHC deficient neurons and MSUD hepatocytes to search for effective drugs by an innovative systems biology approach. In summary, the results of the proposed study have the potential to provide novel and effective treatments for MSUD and PDHC deficiency.'