Novel in vitro and in vivo enrichment strategy targeting lymphocytes derived from vector transduced hscs for therapy of disorders
AssigneesThe Medical College of Wisconsin, Inc., University Health Network, Washington University in St. Louis
InventorsJeffrey A. Medin, John F. Dipersio, Murtaza S. Nagree
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Abstract
The present invention is related to a dual promoter lentiviral vector and methods of use for the treatment of diseases and disorders, specifically lysosomal storage disorders.
Claims40
A dual promoter lentivirus vector that expresses a protein of interest encoded by a transgene and a mutant form of inosine-5′-monophosphate dehydrogenase 2 (IMPDH2(IY)) when transduced into a host cell.
The dual promoter lentivirus vector of any one of the preceding claims, wherein the host cell is a hematopoietic cell.
The dual promoter lentivirus vector of any one of the preceding claims, wherein a first promoter is hPGK promoter and a second promoter is EF1α promoter.
The dual promoter lentivirus vector of any one of the preceding claims, wherein the mutant form of inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) contains T333I and S351Y mutations in the IMPDH2 transgene.
The dual promoter lentivirus vector of any one of the preceding claims, wherein the protein of interest is a protein or an enzyme associated with a lysosomal storage disorder.
A host cell expressing the dual promoter lentivirus vector of any one of the preceding claims.
A method of treating a subject having a disease or disorder associated with a defect in a single protein, the method comprising the steps of
- i) obtaining hematopoietic stem cells (HSCs) from the subject and/or HSCs from a suitable donor,
- ii) transducing the HSCs in vitro or ex vivo with a dual promoter lentivirus vector that expresses a functional form of the protein of interest and a mutant form of inosine-5′-monophosphate dehydrogenase 2 (IMPDH2(IY)) encoded by SEQ ID NO:7 in the transduced cells,
- iii) introducing the transduced HSCs into the subject, and
- iv) administering to the subject an amount of mycophenolate mofetil (MMF) sufficient to enrich the population of lentivirus vector transduced HSCs engrafted in the subject, wherein the method treats one or more symptoms of the disease or disorder.
Dependencies are inferred from the claim text.