This disclosure concerns an engineered polynucleotide that interacts with a pre-mRNA and a spliceosome to regulate gene expression. The engineered polynucleotide may have stem-loop structure that recruits the spliceosome and targeting sequences that are complementary to a target sequence at an exon-intron splice junction and may include nucleotides with 2′ modifications and phorphorothioate linkages.

The invention relates to a combination and its use for the treatment of diseases. The instant disclosure provides a combination of a so-called T-cell regulator selected from the group comprising PD1, PD-L1, OX40, TIM-3, LAG3, CD137(4-1BB) and a non-coding immunomodulating DNA.

Oligonucleotides are provided herein that inhibit NR1H3 expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with NR1H3 expression.

The present invention is related to a ribonucleic acid comprising a double stranded structure whereby the double-stranded structure comprises a first strand and a second strand, whereby the first strand comprises a first stretch of contiguous nucleotides and whereby said first stretch is at least partially complementary to a target nucleic acid, and the second strand comprises a second stretch of contiguous nucleotides whereby said second stretch is at least partially identical to a target nucleic acid, and whereby the double stranded structure is blunt ended.

The emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). LSCs are heterogeneous for their phenotypes and their sensitivity to chemotherapeutic agents in vivo. Using in silico and functional approaches, the inventors uncovered that CALCRL is overexpressed in LSCs compared with normal hematopoietic cells. They further demonstrated that the CALCRL ligand adrenomedullin (ADM) is highly expressed in AML cells and that increased transcript level was markedly associated with decreased complete remission rates, 5-year overall and event7free survival. The inventors also showed that CALCRL depletion strongly affected leukemic growth in vivo and increased mice survival. Targeting ADM phenocopies the biological and anti-leukemic effects of the CALCRL depletion. These data highlight the critical role of ADM and disclose a promising therapeutic target to specifically eradicate R-LSCs and overcome relapse in AML.

Disclosed herein are compositions that comprise engineered polynucleotides, pharmaceutical compositions comprising the same, methods of making the same, and methods of treatment comprising the compositions that comprise the engineered polynucleotides.

Provided are methods, compositions, and cells for use in adoptive cell therapy for the treatment of cancer. The methods involve administering an effective amount of cells to a subject, wherein the cells are modified ex vivo to suppress endogenous Zbtb20 expression and/or activity within the modified cells. The cells may comprise a dominant negative Zbtb20 capable of suppressing endogenous Zbtb20 activity, at least one shRNA capable of suppressing endogenous Zbtb20 expression, or at least one sgRNA capable of suppressing endogenous Zbtb20 expression. The cells may further comprise an exogenous TCR and/or CAR suitable for treating cancer. The method can further involve administering one or more additional cancer therapies, such as cells which express at least one exogenous TCR and/or CAR suitable for treating cancer. The method can provide various advantages, such as a reduction and/or elimination of an amount of cancer cells in the subject.

Provided are methods, compositions, and cells for use in adoptive cell therapy for the treatment of cancer. The methods involve administering an effective amount of cells to a subject, wherein the cells are modified ex vivo to suppress endogenous Zbtb20 expression and/or activity within the modified cells. The cells may comprise a dominant negative Zbtb20 capable of suppressing endogenous Zbtb20 activity, at least one shRNA capable of suppressing endogenous Zbtb20 expression, or at least one sgRNA capable of suppressing endogenous Zbtb20 expression. The cells may further comprise an exogenous TCR and/or CAR suitable for treating cancer. The method can further involve administering one or more additional cancer therapies, such as cells which express at least one exogenous TCR and/or CAR suitable for treating cancer. The method can provide various advantages, such as a reduction and/or elimination of an amount of cancer cells in the subject.

Methods and systems to reduce neurotoxicity associated with the treatment of CD19.sup.+ B-cell hyperproliferative disorders are disclosed. Neurotoxicity is reduced by the use of agents that protect CD19.sup.+ neurovascular pericytes and/or CD19.sup.+ vSMCs from attack by CD19-targeted therapy, and by modification of CD19-targeted therapy to avoid CD19.sup.+ pericytes and/or CD19.sup.+ vSMCs.

The present disclosure provides methods of treating subjects having psoriasis, and methods of identifying subjects having an increased risk of developing psoriasis.