University of Massachusetts

Timothy F Kowalik

Marc E Uknis

Alexander Lagadinos

Xiaofei E

Mariluz Rodriguez-Gonzalez

Abraham L Brass

Bradford M Stadler

Paulo Martins

Methods for treating or reducing the risk of a cytomegalovirus infection in a subject that include administering one or more of an inhibitor of Deleted in Malignant Brain Tumors 1 (DMBT1), an inhibitor of OR14I1, or an inhibitor of adenylyl cyclases.

Targeting cell tropism receptors to inhibit cytomegalovirus infection

The invention provides methods for treating ischemia (such as ischemia repertusion injury (IRI)) in tissue (such as transplant donor tissue), comprising contacting the tissue during ex vivo perfusion with a therapeutically effective amount of RNAi (such as siRNA) that specifically hinds to at least a portion of a gene (such as p53) that mediates ischemic injury in the tissue. The invention's methods additionally decrease the risk of tissue rejection and/or or induce immunological tolerance to transplanted tissue.

Methods for preventing graft ischemia reperfusion injury during ex vivo machine perfusion preservation

The present invention, at least in part, relates to the discovery of efficacious delivery of an RNAi agent (in preferred aspects of the invention, an siRNA) to a transplantable tissue. Organ rejection, transplantation-mediated transmission of viral infection, and triggering of apoptosis in transplanted tissues can each be minimized by the methods and compositions of the instant invention. The RNAi agent(s) of the instant invention can be delivered as 'naked' molecules, or using liposomal and other modes of delivery, to transplantable tissues. Such delivery can occur via perfusion of the RNAi agent in solution through the vasculature of a whole or partial organ; or tissues including transplantable cells and cell lines may be bathed, injected or otherwise treated with RNAi agents. Preferred transplantable tissues include, for example, pancreas, liver, kidney, heart, lung, and all cells and cell lines derived from such tissues (e.g., pancreatic islet cells that may, e.g., be transplanted as a treated population).

Therapeutic alteration of transplantable tissues throughorexposure to RNA interference molecules

Therapeutic alteration of transplantable tissues through in situ or ex vivo exposure to RNA interference molecules

The present invention relates to miR145, miR132, miR212, and the genes or gene products regulated by these miRNAs. miR145 is downregulated in cells infected with HCMV. This downregulation modulates expression of miR145 target genes, including IRS-1. Transfection of cells with a miR145 agent, such as a miR145 mimetic, reduces HCMV replication and protein expression. miR132 and miR212 are upregulated in cells infected with HCMV. This upregulation modulates expression of miR132 and miR212 target genes, including MeCP2 and RICS. Transfection of cells with a miR132 and/or a miR212 antagonist reduces HCMV replication and protein expression. Accordingly, the invention provides methods of attenuating HCMV replication by modulating, for example, miR145, miR132, and/or miR212, and targets thereof. Also provided are methods of detecting an HCMV infection, and compositions and kits useful for attenuating HCMV replication.

Modulation of human cytomegalovirus replication by micro-RNA 132 (miR132), micro-RNA 145 (miR145) and micro-RNA 212 (miR212)

The present invention related to miR145, miR132, miR212, and the genes or gene products regulated by these miRNAs. miR145 is downregulated in cells infected with HCMV. This downregulation modulates expression of miR145 target genes, including IRS-1. Transfection of cells with a miR145 agent, such as a miR145 mimetic, reduces HCMV replication and protein expression. miR132 and miR212 are upregulated in cells infected with HCMV. This upregulation modulates expression of miR132 and miR212 target genes, including MeCP2 and RICS. Transfection of cells with a miR132 and/or a miR212 antagonist reduces HCMV replication and protein expression. Accordingly, the invention provides methods of attenuating HCMV replication by modulating, for example, miR145, miR132, and/or miR212, and targets thereof. Also provided are methods of detecting an HCMV infection, and compositions and kits useful for attenuating HCMV replication.

[object Object]

The present invention related to miR145, miR132, miR212, and the genes or gene products regulated by these miRNAs. miR145 is downregulated in cells infected with HCMV. This downregulation modulates expression of miR145 target genes, including IRS-I. Transfection of cells with a miR145 agent, such as a miR145 mimetic, reduces HCMV replication and protein expression. miR132 and miR212 are upregulated in cells infected with HCMV. This upregulation modulates expression of miR132 and miR212 target genes, including MeCP2 and RICS. Transfection of cells with a miR132 and/or a miR212 antagonist reduces HCMV replication and protein expression. Accordingly, the invention provides methods of attenuating HCMV replication by modulating, for example, miR145, miR132, and/or miR212, and targets thereof. Also provided are methods of detecting an HCMV infection, and compositions and kits useful for attenuating HCMV replication.

Modulation of human cytomegalovirus replication by micro-RNA 132 (miR132), micro-RNA 145 (mi145) and micro-RNA 212 (miR212)

The present invention, at least in part, relates to the discovery of efficacious delivery of an RNAi agent (e.g., an siRNA) to a transplantable tissue. The agent may be used to minimize organ rejection, transplantation-mediated transmission of viral infection, and triggering of apoptosis in transplanted tissues. The RNAi agent(s) can be delivered as 'naked' molecules, or using liposomal and other modes of delivery, to transplantable tissues. Such delivery can occur via perfusion of the RNAi agent in solution through the vasculature of a whole or partial organ; or tissues including transplantable cells and cell lines may be bathed, injected or otherwise treated with RNAi agents. Preferred transplantable tissues include, for example, pancreas, liver, kidney, heart, lung, and all cells and cell lines derived from such tissues (e.g., pancreatic islet cells that may, e.g., be transplanted as a treated population).

The present invention provides methods for identifying druggable targets in assays that feature compositions, cells and/or organisms having structured viral non-coding RNAs (svRNAs) and an RNA interference (RNAi) pathway. Methods for identifying antiviral agents and creating vaccines are also featured. The invention further provides methods for inhibiting RNAi involving svRNAs or inhibitory derivatives thereof. The invention also provides compositions for delivering siRNA and miRNA molecules derived from svRNA loci and methods of use thereof. Therapeutic methods are also featured.

Growing community of inventors

Princeton, MA, United States of America

Timothy F Kowalik