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Therapies for inborn errors of metabolism

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.
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Principal Investigator

Nicola Brunetti-Pierri (Dr.)

Host institution

FONDAZIONE TELETHON

Address

Via Varese 16/B
00185 Roma

Italy

Activity type

Research Organisations

EU Contribution

€ 1 491 520

Principal Investigator

Nicola Brunetti-Pierri (Dr.)

Administrative Contact

Raffaella Pettorruso

Beneficiaries (1)

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FONDAZIONE TELETHON

Italy

EU Contribution

€ 1 491 520

Project information

Grant agreement ID: 311596

Status

Closed project

  • Start date

    1 November 2012

  • End date

    31 October 2018

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 491 520

  • EU contribution

    € 1 491 520

Hosted by:

FONDAZIONE TELETHON

Italy