Diet controlled expression of a nucleic acid encoding a pro-apoptotic protein

Inventors

FAFOURNOUX, Pierre • Mallet, Jacques

Assignees

Centre National de la Recherche Scientifique CNRS • Assistance Publique Hopitaux de Paris APHP • Institut National de la Sante et de la Recherche Medicale INSERM • Sorbonne Universite • Institut du Cerveau et de La Moelle Epiniere ICM • Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement

Abstract

A nucleic acid for the controlled expression of a nucleic acid encoding a pro-apoptotic protein in an individual, including: a regulatory polynucleotide including a minimal promoter and at least one AARE (amino acid response element) nucleic acid, the regulatory polynucleotide being activated in an individual upon consumption of a diet deficient in at least one essential amino acid; and a nucleic acid encoding a pro-apoptotic protein, which is placed under the control of the regulatory polynucleotide.

Core Innovation

The invention relates to a method for eliminating infused cells using a regulatory polynucleotide that is activated in a human individual upon consumption of a diet deficient in at least one essential amino acid. The regulatory polynucleotide comprises a minimal promoter and at least one AARE (amino acid response element) nucleic acid, and controls a suicide safety gene, thereby coupling cell elimination to an essential amino acid deficiency.

The method specifies that the suicide safety gene is selected from the group consisting of BCL2 modifying factor, Apoptosis inducer NBK, Apoptotic protease-activating factor 1 (APAF1, CED4), BAX, Endophilin B1, FADD, CRADD, FAS, Modulator of apoptosis 1, SMAC, Endonuclease G, HRK, Serine protease HTRA2, p53, NOXA, RIPK1, Bcl2 binding component 3, PMAIP1, Tumor necrosis factor receptor superfamily member 10A Precursor (Death receptor 4), caspase 1, caspase 3, caspase 7, caspase 8, and caspase 9. The elimination is achieved by administering infused cells to a human individual in need of cancer treatment or regenerative medicine and then inducing programmed cellular death by submitting the human individual to a diet deficient in at least one essential amino acid.

The disclosed system supports inducible on/off expression through the use of an AARE-containing regulatory polynucleotide, including embodiments in which the AARE nucleic acid has a sequence selected from SEQ ID No: 1 through SEQ ID No: 5 and embodiments in which the regulatory polynucleotide contains at least two AARE nucleic acids. Documented embodiments also include nucleic acid vectors and delivery particles whose surfaces carry ligands that can bind to a target receptor on the membrane of a targeted cell.

Claims Coverage

The partial content includes one independent claim and multiple dependent claims. Across these claims, the inventive coverage centers on diet-activated regulation via a minimal promoter plus AARE, paired with a selected suicide safety gene whose expression induces programmed cellular death in infused cells.

Across the independent and dependent claims provided, the core claim coverage is directed to a diet-deficiency-activated regulatory polynucleotide (minimal promoter plus AARE) controlling a selected suicide safety gene, followed by eliminating infused cells by inducing programmed cellular death through essential amino acid deficiency. Dependent claim coverage narrows the AARE to SEQ ID No: 1 through SEQ ID No: 5, requires at least two AARE nucleic acids, and adds vector-based control and targeted delivery using surface ligands and a target receptor.

Stated Advantages

Documented Applications