Compounds for improved viral transduction

Inventors

Heffner, Garrett Collins • Bassan, Abraham Isaac

Assignees

Genetix Biotherapeutics Inc

Abstract

The present invention provides methods and compositions for improving efficacy of viral transduction of cells. More particularly, the present invention provides methods and materials useful for safely and reliably improving the efficiency of methods and materials useful for safely and reliably improving the efficiency of methods for transducing cells, such as human hematopoietic stem cells (HSC), with viruses and/or viral vectors. The compositions and methods are useful for therapeutic indications amenable to treatment with hematopoietic stem cell gene therapies.

Core Innovation

The invention relates to a method for increasing lentiviral vector transduction efficiency of human CD34+ hematopoietic stem or progenitor cells. The method comprises ex vivo contacting the human CD34+ cells with a culture medium comprising a lentiviral vector and prostaglandin E2 (PGE2) or 16,16-dimethyl PGE2, or an analogue thereof. The increased transduction efficiency is defined relative to contacting with a culture medium comprising the lentiviral vector in the absence of PGE2, 16,16-dimethyl PGE2, or the analogue.

The document further describes prostaglandin EP receptor signaling as the signaling component associated with PGE2 or an analogue, including EP1, EP2, EP3, and EP4 agonists. It is also described as compatible with optional inclusion of a histone deacetylase (HDAC) inhibitor in the culture medium.

The invention is applied in the context of lentiviral vectors used for gene therapy, including lentiviral SIN vectors and HIV-derived vector elements. The document provides vector and gene-cargo context for therapeutic corrected cells, including examples such as β-globin variants for hemoglobinopathies and an ABCD1 polypeptide for adrenoleukodystrophy/adrenomyeloneuropathy.

Claims Coverage

The independent claims cover three related methods for increasing lentiviral transduction efficiency of human CD34+ hematopoietic stem or progenitor cells ex vivo by adding prostaglandin E2 or 16,16-dimethyl PGE2, or analogues, to a lentiviral vector-containing culture medium. Each independent claim defines increased transduction efficiency compared to the corresponding medium lacking the prostaglandin component.

Across the independent claims, the core claim coverage is prostaglandin-containing culture media used ex vivo with lentiviral vectors to increase lentiviral transduction efficiency in human CD34+ hematopoietic stem or progenitor cells, as demonstrated by comparison to the corresponding culture media lacking PGE2 or 16,16-dimethyl PGE2. Dependent claims further define refinements such as transduction-efficiency thresholds, contact durations, and particular lentiviral vector features and gene cargo.

Stated Advantages

Documented Applications