57 results about "Gain of function" patented technology

The present invention provides compositions and methods for modulating smoothened-dependent pathway activation. The present invention provides analogs of cyclopamine that can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, Ptc loss-of-function or smoothened gain-of-function mutations. The compounds of the present invention are particularly useful in treating cancers.

The present invention provides methods for enhancing discriminatory RNA silencing by RNA silencing agents. In particular, the invention provides methods for generating RNA silencing agents which can discriminate between target and non-target mRNAs that differ in sequence by only one nucleotide. Also provided are improved RNA silencing agents with enhanced discriminatory RNA silencing, e.g., single nucleotide discriminatory RNA silencing. The compositions and methods of the invention are useful in therapeutic strategies for treating genetic disorders associated with dominant, gain-of-function gene mutations.

An embodiment of the present invention is a method for subjecting a hematopoetic cell to a JAK / STAT inhibitor, determining the activity of gain-of-function mutations of a Jak family kinase, determining the expression levels and activity of JAK / STAT regulatory proteins, correlating the expression levels and the activity of JAK / STAT regulatory proteins with the activity of gain-of-function mutations of a Jak family kinase and with a response to the JAK / STAT inhibitor, and then classifying the cells. A further embodiment of the invention includes determining the clinical outcome based on the cell classification, determining a method of treatment, determining dosing and scheduling of at least one of the JAK / STAT inhibitors or other compounds.

The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.

The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington's disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease.

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity. Such methods and reagents may also inhibit the hedgehog pathway in normal cells, e.g., where normal levels of hedgehog signalling are unwanted.

The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington's disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease.

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

Formation of nitrogen fixing root nodules in legumes is induced by perception of lipochitin-oligosaccharide signal molecules secreted by compatible Rhizobium bacteria, which triggers a common symbiotic pathway. The present invention provides a spontaneous nodule formation (snf2) mutant, in which the formation of symbiotic nodules is spontaneous, leading to nodule development in the absence as well as in the presence of Rhizobium bacteria and / or exogenous rhizobial signals. The invention further provides an isolated DNA sequence encoding a mutant cytokinin-independent histidine kinase whose activity results in this ‘gain of function’ dominant phenotype of spontaneous nodule formation. Furthermore the snf2 gene is shown to confer a phenotype, characterised by regulated organogenesis of spontaneous nodules, to plants having a nodulation deficient genetic background. A gene of the invention, that confers this spontaneous nodulation phenotype, has 15 utility for the transfer and establishment of nitrogen fixing capability in non-nodulating plants, and thereby reducing the nitrogen fertiliser dependence of non-nodulating crop plants.

The present invention relates to a method for detection and interpretation of loss-of-function or gain-of-function mutations for test genes of interest. The genes of interest include those associated with inherited genetic disorders. The present invention involves the process of obtaining a sample of genetic material from an individual in the form of tissue or cells, separation of the genetic material from the cells of the individuals into haploid sets by transferring the individual chromosomal entities into a population of target cells, and monitoring the target cell population for successful transfer and expression of the test genes of interest using various functional, immunological and structural assays.

The present invention provides methods related to the treatment of head and neck squamous cell carcinoma (HNSCC) and its associated premalignant lesions. In particular, the invention features methods which may specifically target HNSCC-associated genes and alter gene expression to treat or alleviate a symptom of HNSCC, or its related premalignant lesions. These methods may involve decreasing the function of an HNSCC-associated gene with aberrant gain-of-function; or increasing the function of an HNSCC-associated gene with aberrant loss-of-function.

The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington's disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease.

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g.,to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

The orphan nuclear receptors TR2 and TR4 together constitute the DNA binding core of the 540 kDa DRED complex, a putative repressor of the human embryonic ε- and fetal γ-globin genes. Here the functional consequences of TR2 and TR4 germ line loss of function were examined, transgenic gain of function and dominant negative gain of function on human and murine β-type globin gene expression throughout development. ε-globin transcription responded in a manner consistent with the hypothesis that TR2 / TR4 is a constitutive erythroid ε-globin repressor. In contrast, parallel experiments show that TR2 / TR4 is a definitive stage-selective γ-globin repressor. This developmental stage-specific, gene-selective repression of the ε- and γ-globin genes by TR2 / TR4 establishes, when considered in concert with the competition hypothesis, a coherent molecular rationale for hemoglobin switching (temporally specific, sequential activation of all the β-type globin genes) during vertebrate development.

The present invention provides methods related to the treatment of head and neck squamous cell carcinoma (HNSCC) and its associated premalignant lesions. In particular, the invention features methods which may specifically target HNSCC-associated genes and alter gene expression to treat or alleviate a symptom of HNSCC, or its related premalignant lesions. These methods may involve decreasing the function of an HNSCC-associated gene with aberrant gain-of-function; or increasing the function of an HNSCC-associated gene with aberrant loss-of-function.

Mutations in the leucine-rich repeat kinase (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD) with pleiomorphic pathology. Previously, we and others found that expression of mutant LRRK2 causes neuronal degeneration in cell culture. Here we used the GAL4 / UAS system to generate transgenic Drosophila expressing either wild-type (WT1) human LRRK2 or LRRK2-G2019S, the most common mutation associated with PD. Expression of either WT1 human LRRK2 or LRRK2-G2019S in the photoreceptor cells caused retinal degeneration. Expression of WT1 LRRK2 or LRRK2-G2019S in neurons produced adult-onset selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Expression of mutant G2019S-LRRK2 caused a more severe parkinsonism-like phenotype than expression of equivalent levels of WT1 LRRK2. Treatment with L-DOPA improved mutant LRRK2-induced locomotor impairment but did not prevent the loss of tyrosine hydroxylase (TH)-positive neurons. To our knowledge, this is the first in vivo “gain-of-function” model which recapitulates several key features of LRRK2-linked human parkinsonism. These flies may provide a useful model for studying LRRK2-linked pathogenesis and for future therapeutic screens for PD intervention.

The invention provides methods for modulating, e.g., antagonizing, the activity of the Hedgehog signaling pathway, and for treating Hedgehog related disorders such as cancers (e.g., medulloblastoma). In particular, the invention provides methods for inhibiting aberrant growth states resulting from phenotypes such as Ptch loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function by administering to a mammal combinations of Smoothened inhibitors (e.g., a compound of Formula I, Formula II, or Formula III, or any of the compounds listed herein or incorporated by reference) and cholesterol biosynthesis pathway inhibitors (e.g., statins), Gli inhibitors, and / or Phosphatidylinositol 3-kinase (PI3K) inhibitors.

The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.

The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.

The present invention relates to cardiac performance, in particular to regulating cardiac performance via recombinant troponin I (TnI) protein and nucleic acids encoding recombinant TnI. The present invention provides nucleic acids encoding gain of function TnI proteins (e.g., cTnlA164H), vectors containing such nucleic acids, host cells containing such vectors, transgenic animals carrying a gain of function TnI protein (e.g., a cTnlA164H transgene), and therapeutic agents (e.g., comprising recombinant TnI, TnI analogues, synthetic TnI, or the like) or agents for gene therapy of heart failure or disease for research and therapeutic uses.

The present invention relates to a variant of the nicotinic acetylcholine receptor (nAChR) α7 subunit having a substitution within its second transmembrane (TM2) domain. Specifically, the sixth amino acid position within the TM2 domain has the point mutation T→S, such that threonine-244 becomes serine-244. Advantageously, the α7 variant of the present invention retains the essential drug sensitivities of the wild-type α7 receptor, but does not exhibit the response-limiting form of fast desensitization. Therefore, the α7 variant is a “gain of function” mutant that is particularly useful for testing new pharmacological agents. The present invention includes the T6′S variant TM2 domain, T6′S variant α7 subunit, and T6′S variant nACh receptor polypeptides, polynucleotides encoding these polypeptides, recombinant hosts expressing these polynucleotides, and assays utilizing the T6′S variant TM2 domain, T6′S variant α7 subunit, and / or T6′S variant nACh receptor.

The present invention relates to the discovery that mutations in SCN9A are causative of Congenital Indifference to Pain (CIP) in humans. The invention also relates to methods of using compounds small organic compounds to treat pain as well as to predict the effect of analgesic agents in patients, such as those possessing gain of function mutations.

The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.