Compounds for improved viral transduction
Inventors
Heffner, Garrett Collins • Bassan, Abraham Isaac
Assignees
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Publication Number
US-9988644-B2
Publication Date
2018-06-05
Expiration Date
Abstract
The present invention provides methods and compositions for improving the 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 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 patent describes methods for increasing the transduction efficiency of CD34+ hematopoietic stem and/or progenitor cells cultured with a lentivirus. The approach comprises culturing the CD34+ hematopoietic stem and/or progenitor cells and the lentivirus in a culture medium that comprises a compound that increases prostaglandin EP receptor signaling, where the cells are cultured with the lentivirus during, or prior to, culture with the compound.
The compound that increases prostaglandin EP receptor signaling is selected from prostaglandin E2 (PGE2), 16,16-dimethyl PGE2, and analogues thereof. The transduction efficiency is increased compared to culturing with the lentivirus in the absence of the compound, and the disclosure includes culturing CD34+ hematopoietic stem and/or progenitor cells with lentivirus in the presence of prostaglandin EP receptor signaling to improve viral delivery.
The disclosure further relates to optional addition of an HDAC inhibitor as a culture component to enhance transduction efficiency. It also encompasses engineered lentiviral vector features, including HIV-1-based vector backbones with regulatory element modifications such as self-inactivating (SIN) designs, LTR modifications, and packaging/accessory elements, as well as optional VSV-G pseudotyping.
Claims Coverage
The independent claims are clm-00001, clm-00019, and clm-00038. Across these claims, the core coverage centers on culturing CD34+ hematopoietic stem and/or progenitor cells with lentivirus in a medium comprising prostaglandin EP receptor signaling compounds, with specific embodiments for PGE2 and 16,16-dimethyl PGE2.
Prostaglandin EP receptor signaling compound-mediated lentiviral transduction
Culturing CD34+ hematopoietic stem and/or progenitor cells and the lentivirus in a culture medium that comprises a compound that increases prostaglandin EP receptor signaling, wherein the cells are cultured with the lentivirus during, or prior to, culture with the compound, and wherein transduction efficiency is increased compared to the absence of the compound.
PGE2-containing culture medium for enhanced lentiviral transduction
Culturing the CD34+ hematopoietic stem and/or progenitor cells and the lentivirus in a culture medium that comprises PGE2, with increased transduction efficiency compared to the absence of PGE2.
16,16-dimethyl PGE2-containing culture medium for enhanced lentiviral transduction
Culturing the CD34+ hematopoietic stem and/or progenitor cells and the lentivirus in a culture medium that comprises 16,16-dimethyl PGE2, with increased transduction efficiency compared to the absence of 16,16-dimethyl PGE2.
The independent claims collectively cover increasing lentiviral transduction efficiency of CD34+ hematopoietic stem and/or progenitor cells by culturing them with lentivirus in a culture medium that includes prostaglandin EP receptor signaling compounds, specifically PGE2 and 16,16-dimethyl PGE2 as separately emphasized embodiments.
Stated Advantages
Increases the transduction efficiency of CD34+ hematopoietic stem and/or progenitor cells cultured with a lentivirus compared to the absence of the prostaglandin EP receptor signaling compound.
Documented Applications
Therapeutic applications for hemoglobinopathies including β-thalassemia and sickle cell disease using β-globin gene delivery.
Therapeutic applications for adrenoleukodystrophy and adrenomyeloneuropathy using ABCD1 gene delivery.
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