Lentiviral vector for dopamine synthesis

A lentiviral vector using a tricistronic expression cassette for tyrosine hydroxylase, GTP-cyclohydrolase 1, and aromatic L-amino acid decarboxylase under the PGK-1 promoter addresses the challenge of optimal dopamine synthesis in gene therapy, enhancing treatment efficacy for dopamine deficiency diseases.

WO2024251679A1PCT designated stage expired Publication Date: 2024-12-12CENT DETUD DES CELLULES SOUCHES CECS +1
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Patent Information

Application Number
PCT/EP2024/065237
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-06-06
Filing Date
2024-06-03
Publication Date
2024-12-12

AI Technical Summary

Technical Problem

Current gene therapy approaches for treating dopamine deficiency-related diseases, such as Parkinson's and pediatric genetic disorders, face challenges in achieving optimal stoichiometry of enzyme expression for dopamine synthesis and suffer from adverse effects of oral pharmacological treatments.

Method used

A lentiviral vector constructed from human immunodeficiency virus 1 (HIV-1) with a tricistronic expression cassette encoding tyrosine hydroxylase, GTP-cyclohydrolase 1, and aromatic L-amino acid decarboxylase under the control of the human PGK-1 promoter, allowing for optimal dopamine synthesis and expression in target tissues.

Benefits of technology

The vector effectively transduces human neurons, inducing neosynthesis and secretion of dopamine, demonstrating improved expression profiles and therapeutic potential for diseases like Lesch-Nyhan disease and Parkinson's.

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Abstract

The invention relates to a lentiviral vector comprising a tricistronic expression cassette encoding: - tyrosine hydroxylase of SEQ ID NO 1; - GTP cyclohydrolase I of SEQ ID NO 2; and - aromatic L-amino acid decarboxylase of SEQ ID NO 3, or a functional variant of said enzymes having a nucleic sequence that is at least 80% identical to SEQ ID NOs 1, 2 and 3. The vector is characterised in that the three enzymes are expressed under the control of the same human PGK-1 promoter, or a functional variant of said human PGK-1 promoter having a nucleic sequence that is at least 80% identical to SEQ ID NO 4.
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Citation Information

Patent Citations

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    EP3937985A1

  • Nucleic acid construct

    CN113388642A

  • Gene therapeutic compositions and methods for treating Parkinson's disease

    CN115835887A

  • Catecholamine enzyme fusions

    US20130116311A1

  • Lentiviral vectors for delivery of PKLR to treat pyruvate kinase deficiency

    WO2019079338A1