Provided herein are carboxypeptidase N catalytic subunit (CPN1) variants, comprising at least one modification with respect to a wild type carboxypeptidase N1 of the M14 family, wherein the variants have at least one improved characteristic as compared to the wild type CPN1. Also provided herein are fusion constructs comprising CPN1, or variants thereof. Also provided herein are methods of making and using such variants and constructs. The variant and constructs provided herein may be useful for treating diseases or conditions associated with dysregulation of the complement system.
Provided herein are engineered proteases of the S1A family that are specific for, and capable of, cleaving Factor B. Also provided herein are methods of making and using such engineered proteases. The engineered proteases provided herein may be useful for treating a disease or condition associated with dysregulation of the complement system by reducing complement activation through cleavage and inactivation of Factor B.
Provided herein are Complement Factor I (CFI) variants that exhibit at least one improved characteristic relative to a wild type CFI. CFI variants of the disclosure can exhibit tunable specificity and activity. Also included are CFI-containing fusion constructs comprising at least one domain of CFI, for example, wild type full length CFI fused to human serum albumin. Also included are methods of making and using such CFI variants and fusion constructs. The CFI variants and fusion constructs provided herein may be useful for treating a disease or condition associated with dysregulation of the complement system or a deficiency of CFI.
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY (USA)
Inventor
Blouse, Grant, E.
Pekrun, Katja
Kay, Mark, A.
Abstract
AAV vectors that encode a modified Factor IX (FIX) polypeptide for gene therapy for treatment of hemophilia B are provided. The modified FIX polypeptide has increased potency compared to wild-type FIX polypeptide. The nucleic acid encoding the modified FIX polypeptide includes a portion of an intron. The AAV vectors were generated and selected to infect islet cells, but were found to effectively transduce hepatocytes upon systemic administration, and to express high levels of FIX polypeptide. Relatively low doses of the AAV vectors can be administered to achieve a therapeutic effect. The gene therapy treatment can result in normal or near normal coagulation pharmacokinetics and normal levels of FIX, or mild hemophilia B. Combining an AAV vector with improved properties for transducing hepatocytes, and modified FIX polypeptides with enhanced potency, improves transgene expression and effectively lowers the viral dose needed to achieve therapeutically relevant FIX activity levels.
Provided herein are modified FVII polypetides, and modified FVIIa polypeptides, and methods of treatment of acute and episodic bleeding with modified FactorVIIa polypeptides. To effect treatment and use, in some embodiments, the modified polypeptides are subcutaneously administered to provide on-demand treatment. In some embodiments, the on-demand treatment is provided in a multiple dosing regimen over a twenty-four hour period. The subcutaneous administration of the modified polypeptides of the disclosure exhibit increased coagulant activity, potency, bioavailablilty and prolonged duration.
Provided are u-PA polypeptides and fusion proteins containing the u-PA polypeptides. The u-PA polypeptides are modified to have altered activity and/or specificity so that they cleave a complement protein, such as complement protein C3, to thereby inhibit complement activation. The modified u-PA polypeptides and fusion proteins that inhibit complement activation can be used for treatment of diseases and conditions that are mediated by complement activation, or in which complement activation plays a role. These disorders include ischemic and reperfusion disorders, including myocardial infarction and stroke, sepsis, autoimmune diseases, diabetic retinopathies, age-related macular degeneration, transplanted organ rejection, inflammatory diseases and diseases with an inflammatory component.
The present invention relates to compounds that modulate nicotinic receptors as non-competitive antagonists, methods for use, and their pharmaceutical compositions.
C07C 211/38 - Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
C07C 211/41 - Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
C07D 205/04 - Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
C07D 295/033 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
A61K 31/397 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
A61K 31/40 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
8.
MODIFIED MEMBRANE TYPE SERINE PROTEASE 1 (MTSP-1) POLYPEPTIDES AND METHODS OF USE
Provided are MTSP-1 polypeptides modified to have altered activity and/or specificity so that they cleave a complement protein, such as complement protein C3, to inhibit its activity and thereby inhibit complement activation. The modified MTSP-1 polypeptides that inhibit complement activation can be used for treatment of diseases and conditions in which complement activation plays a role. Such diseases and conditions include inflammatory diseases and diseases with an inflammatory component. Exemplary of these disorders are ischemic and reperfusion disorders, including myocardial infarction and stroke, sepsis, autoimmune diseases, ophthalmic disorders, such as diabetic retinopathies and macular degeneration, including age-related macular degeneration (AMD), and transplanted organ rejection, such as renal delayed graft function (DGF).
A61K 38/48 - Hydrolases (3) acting on peptide bonds (3.4)
C07K 14/435 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
Modified therapeutic proteins are provided. In particular modified Factor X polypeptides, which includes the Factor X zymogen, Factor Xa and other forms of Factor X, and uses thereof are provided.
Modified therapeutic proteins are provided. In particular modified Factor X polypeptides, which includes the Factor X zymogen, Factor Xa and other forms of Factor X, and uses thereof are provided.
C07K 14/435 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
Modified Factor IX (FIX) polypeptides and uses thereof are provided. Such modified FIX polypeptides include FIXa and other forms of FIX. Among the modified FIX polypeptides provided are those that have altered activities, typically altered procoagulant activity, including increased procoagulant activities. Hence, such modified polypeptides are therapeutics.
The present invention provides N-substituted-2(1H) pyridones or the pharmaceutical acceptable salts thereof, and the pharmaceutical preparations containing the compounds. The compounds of the present invention can be used to treat various fibrotic diseases effectively, e.g., hepatic fibrosis.
A01N 43/40 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
The present invention provides N-substituted-2(1H) pyridones or the pharmaceutical acceptable salts thereof, and the pharmaceutical preparations containing the compounds. The compounds of the present invention can be used to treat various fibrotic diseases effectively, e.g., hepatic fibrosis.
A01N 43/40 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
14.
FACTOR VII POLYPEPTIDES THAT ARE MODIFIED AND USES THEREOF
Modified factor VII polypeptides and uses thereof are provided. Such modified FVII polypeptides include Factor Vila and other forms of Factor VII. Among modified FVII polypeptides provided are those that have altered activities, typically altered procoagulant activity, including increased procoagulant activities. Hence, such modified polypeptides are therapeutics.
Modified factor VII polypeptides and uses thereof are provided. Such modified FVII polypeptides include Factor Vila and other forms of Factor VII. Among modified FVII polypeptides provided are those that have altered activities, typically altered procoagulant activity, including increased procoagulant activities. Hence, such modified polypeptides are therapeutics.
The present invention is directed to a novel use of pyridone derivatives such as pirfenidone for the prevention and treatment of damages to tissues or organs induced by various cytotoxic agents, such as chemotherapeutic agents, biologics, immunosuppressants and radiation. Such prophylactic and/or therapeutic effects of the pyridone derivatives make it possible to increase therapeutic dosages of the cytotoxic agent, thereby enhancing the therapeutic efficacy of the cytotoxic agent and radiation therapy.
A61K 31/4418 - Non-condensed pyridinesHydrogenated derivatives thereof having a carbocyclic ring directly attached to the heterocyclic ring, e.g. cyproheptadine
17.
PROTEASE SCREENING METHODS AND PROTEASES IDENTIFIED THEREBY
TORREY PINES INSTITUTE FOR MOLECULAR STUDIES (USA)
Inventor
Madison, Edwin, L.
Abstract
Methods for identifying modified proteases with modified substrate specificity or other properties are provided. The methods screen candidate and modified proteases by contacting them with a substrate, such as a serpin, an alpha macro globulins or a p35 family protein or modified serpins and modified p35 family members or modified alpha macroglobulins, that, upon cleavage of the substrate, traps the protease by forming a stable complex. Also provided are modified proteases.
Provided are methods for and compounds for modulating the complement system. In particular, compounds are provided that inhibit complement activation and compounds are provided that promote complement activation. The compounds are therapeutics by virtue of their effects on the complement system. Hence, the compounds that inhibit complement activation can be used for treatment of ischemic and reperfusion disorders, including myocardial infarction and stroke, sepsis, autoimmune diseases, inflammatory diseases and diseases with an inflammatory component, including Alzheimer's Disease and other neurodegenerative disorder.
The present invention provides N-substituted-2(1H) pyridones or the pharmaceutical acceptable salts thereof, and the pharmaceutical preparations containing the compounds. The compounds of the present invention can be used to treat various fibrotic diseases effectively, e.g., hepatic fibrosis.
A01N 43/40 - Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
A61K 31/445 - Non-condensed piperidines, e.g. piperocaine
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