公开(公告)号：WO2019104160A2

公开(公告)日：2019-05-31

申请号：PCT/US2018/062237

申请日：2018-11-21

申请人： MODERNATX, INC.

发明人： RAJENDRAN, Raj ,  FINN, Patrick ,  MARTINI, Paolo G. V. ,  AN, Ding ,  DOUSIS, Athanasios ,  RAVICHANDRAN, Kanchana

CPC分类号： C12N9/0071 ,  A61K48/0066 ,  C12N15/67 ,  C12N2800/22 ,  C12N2830/50 ,  C12Y114/16001

摘要： This disclosure relates to mRNA therapy for the treatment of hyperphenylalaninemias such as phenylketonuria (PKU). mRNAs for use in the invention, when administered in vivo, encode human phenylalanine hydroxylase (PAH), functional fragments thereof (e.g., those comprising the catalytic domain or the catalytic domain and the tetramerization domains), and fusion proteins comprising PAH. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of PAH expression and/or activity in subjects. mRNA therapies of the invention further decrease abnormal accumulation of phenylalanine associated with deficient PAH activity in subjects.

公开(公告)号：WO2015175793A1

公开(公告)日：2015-11-19

申请号：PCT/US2015/030811

申请日：2015-05-14

申请人： UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC. ,  YAN, Yajun ,  LIN, Yuheng

发明人： YAN, Yajun ,  LIN, Yuheng

IPC分类号： C12P13/22

CPC分类号： C12P13/227 ,  A23K20/10 ,  A23L2/52 ,  C12N9/0028 ,  C12N9/0071 ,  C12N9/88 ,  C12Y105/01034 ,  C12Y114/16001 ,  C12Y402/01096

摘要： 5-hydroxytryptophan (5-HTP), a precursor of serotonin, is produced in a microbial host cell. A modified bacterial phenylalanine 4-hydroxylase (P4H) catalyzes the tryptophan 5 -hydroxylation reaction. Optionally the host cell includes a cofactor regeneration mechanism, allowing continuous production of 5-HTP without supplementation of exogenous cofactors.

摘要翻译： 在微生物宿主细胞中产生5-羟色胺（5-HTP），5-羟色胺的前体。 改良的细菌苯丙氨酸4-羟化酶（P4H）催化色氨酸5-羟化反应。 任选地，宿主细胞包括辅因子再生机制，允许在不补充外源辅因子的情况下连续生产5-HTP。

公开(公告)号：WO1991009871A1

公开(公告)日：1991-07-11

申请号：PCT/US1990007619

申请日：1990-12-21

申请人： SERAGEN INCORPORATED

发明人： SERAGEN INCORPORATED ,  MURPHY, John, R.

IPC分类号： C07K13/00

CPC分类号： C07K14/005 ,  C07K14/245 ,  C07K14/25 ,  C07K14/28 ,  C07K14/34 ,  C07K14/415 ,  C07K14/55 ,  C07K14/575 ,  C07K2319/00 ,  C07K2319/55 ,  C07K2319/75 ,  C12N9/0071 ,  C12N9/2408 ,  C12N15/62 ,  C12N2740/16222 ,  C12N2770/24022 ,  C12Y114/16001 ,  G01N33/56966 ,  G01N33/68

摘要： A hybrid molecule including a first part, a second part and a third part connected by covalent bonds, (a) the first part including a portion of the binding domain of a cell-binding ligand, which portion is able to cause the hybrid molecule of the invention to bind to an animal cell; (b) the second part including a portion of a translocation domain of a protein, which portion is capable of translocating the third part across the cytoplasmic membrane of the cell; and (c) the third part including a chemical entity to be introduced into the cell, provided that (i) the hybrid molecule is produced by expression of a recombinant DNA molecule encoding the hybrid molecule, and (ii) the second and third parts are not segments of the same naturally- occurring polypeptide toxin; a recombinant DNA molecule encoding the hybrid molecule; and a method of producing the hybrid molecule.

公开(公告)号：WO2016109899A1

公开(公告)日：2016-07-14

申请号：PCT/CA2016/050017

申请日：2016-01-08

申请人： MCMASTER UNIVERSITY

发明人： BRITZ-MCKIBBIN, Philip

IPC分类号： A61K31/192 ,  A61K31/519 ,  A61K47/48 ,  A61P3/00 ,  C07C62/04 ,  C07C62/32 ,  C12Q1/00 ,  C12Q1/26

CPC分类号： A61K31/215 ,  A61K31/19 ,  A61K31/191 ,  A61K31/192 ,  A61K31/519 ,  A61K38/51 ,  A61P3/00 ,  A61P43/00 ,  C12Q1/00 ,  C12Q1/26 ,  C12Y114/16001 ,  A61K2300/00

摘要： A method of restoring activity in phenylalanine hydroxylase is provided. The method comprises exposing the phenylalanine hydroxylase to shikimic acid, a functionally equivalent analogue thereof, a pharmaceutically acceptable salt of shikimic acid or analogue thereof, or combinations thereof, A method of screening for allosteric activators for a target enzyme is also provided comprising the steps of: denaturing the target enzyme with a first chaotropic agent to yield denatured enzyme, incubating the denatured enzyme with a candidate compound under denaturing conditions to allow enzyme refolding, and assaying enzyme activity in the presence of enzyme substrate and a candidate compound; and if enzyme activity of the denatured enzyme was restored in step i) by at least about 10% of residual enzyme activity, denaturing the target enzyme with a second chaotropic agent to yield denatured enzyme, incubating the denatured enzyme with the candidate compound under non-denaturing conditions to allow enzyme refolding, and assaying enzyme activity in the presence of enzyme substrate and the candidate compound, wherein an increase in enzyme activity of at least about 10% of residual enzyme activity indicates that the candidate compound is an allosteric activator of the target enzyme.

摘要翻译： 提供了恢复苯丙氨酸羟化酶活性的方法。 该方法包括将苯丙氨酸羟化酶暴露于莽草酸，其功能上等同的类似物，莽草酸或其类似物的药学上可接受的盐或其组合。还提供筛选靶酶的变构激活剂的方法，包括以下步骤： ：用第一离液剂变性目标酶以产生变性酶，在变性条件下将变性酶与候选化合物孵育以允许酶重折叠，并在酶底物和候选化合物存在下测定酶活性; 并且如果在步骤i）中将变性酶的酶活性恢复至少约10％的残留酶活性，则用第二离液剂对目标酶进行变性以产生变性酶，将变性酶与候选化合物在非 - 变性条件以允许酶重折叠，以及在酶底物和候选化合物存在下测定酶活性，其中酶活性的增加至少为残余酶活性的约10％表明候选化合物是靶的变构激活剂 酶。

公开(公告)号：WO2014198788A1

公开(公告)日：2014-12-18

申请号：PCT/EP2014/062156

申请日：2014-06-11

申请人： ERYTECH PHARMA

发明人： GODFRIN, Yann ,  DUFOUR, Emmanuelle ,  CHENG, Seng H. ,  YEW, Nelson S.

IPC分类号： A61K38/00 ,  A61K38/48 ,  C12N9/02 ,  A61K9/50 ,  G01N33/556 ,  A61K9/00

CPC分类号： A61K38/44 ,  A61K9/0019 ,  A61K9/5068 ,  A61K38/443 ,  C12N9/0071 ,  C12Y114/16001

摘要： The present invention relates to Enzyme Replacement Therapy (ERT) based on phenylalanine hydroxylase (PAH) and compositions intended for this use. It concerns an erythrocyte encapsulating PAH, especially in suspension in a pharmaceutically acceptable carrier or vehicle, a pharmaceutical composition comprising erythrocytes encapsulating PAH in a pharmaceutically acceptable carrier or vehicle, and such a pharmaceutical composition for use in the treatment or prevention of phenylketonuria (PKU) and/or other diseases involving a too high level of phenylalanine; the treatment or prevention may be in combination with a Phe-restricted diet. The invention particularly relates to classic PKU, variant PKU and non-PKU hyperphenylalaninemia.

摘要翻译： 本发明涉及基于苯丙氨酸羟化酶（PAH）的酶替代疗法（ERT）和用于此用途的组合物。 它涉及封装PAH的红细胞，特别是在药学上可接受的载体或载体中的悬浮液中，包含在药学上可接受的载体或媒介物中包封PAH的红细胞的药物组合物和用于治疗或预防苯丙酮尿症（PKU）的药物组合物， 和/或涉及太高水平苯丙氨酸的其它疾病; 治疗或预防可以与Phe限制性饮食组合。 本发明特别涉及经典的PKU，变体PKU和非PKU高苯丙氨酸血症。

公开(公告)号：WO2003087383A1

公开(公告)日：2003-10-23

申请号：PCT/JP2003/004856

申请日：2003-04-16

申请人： OZAWA, Keiya ,  MIZUKAMI, Hiroaki ,  KUME, Akihiro

发明人： OZAWA, Keiya ,  MIZUKAMI, Hiroaki ,  KUME, Akihiro

IPC分类号： C12N15/86

CPC分类号： C12N15/86 ,  A61K38/44 ,  A61K47/6901 ,  A61K48/0075 ,  C12N2750/14143 ,  C12Y114/16001

摘要： Methods for delivering a heterologous gene to a mammalian subject using recombinant adeno-associated virus (rAAV) virions are described. Recombinant AAV virions containing a heterologous gene encoding a metabolic protein are delivered to a mammalian subject having a metabolic disorder. The rAAV virion-delivered heterologous gene is expressed at a therapeutic level thereby ameliorating a sign or symptom of the metabolic disease. Exemplary examples of metabolic diseases are those caused by defects in aromatic amino acid metabolism. Exemplary examples of heterologous genes include those encoding an aromatic amino acid hydroxylase, aromatic amino acid decarboxylase, and enzymes involved in tetrahydrobiopterin synthesis. Methods for treating phenylketonuria are also described.

摘要翻译： 描述了使用重组腺相关病毒（rAAV）病毒粒子将异源基因递送至哺乳动物受试者的方法。 将含有编码代谢蛋白质的异源基因的重组AAV病毒粒子递送至具有代谢紊乱的哺乳动物受试者。 rAAV病毒粒子传递的异源基因以治疗水平表达，从而改善代谢疾病的征兆或症状。 代谢疾病的典型例子是由芳香族氨基酸代谢缺陷引起的代谢疾病。 异源基因的示例性实例包括编码芳族氨基酸羟化酶，芳香族氨基酸脱羧酶和参与四氢生物喋呤合成的酶的那些。 还描述了治疗苯丙酮尿症的方法。

公开(公告)号：WO2015061491A1

公开(公告)日：2015-04-30

申请号：PCT/US2014/061830

申请日：2014-10-22

申请人： SHIRE HUMAN GENETIC THERAPIES, INC.

发明人： DEROSA, Frank ,  HEARTLEIN, Michael ,  DIAS, Anusha

IPC分类号： A61K48/00

CPC分类号： C12N9/0071 ,  A61K9/1272 ,  A61K38/44 ,  A61K48/00 ,  A61K48/0033 ,  A61K48/005 ,  C12Y114/16001

摘要： The present invention provides, among other things, methods of treating phenylketonuria (PKU), including administering to a subject in need of treatment a composition comprising an mRNA encoding phenylalanine hydroxylase (PAH) at an effective dose and an administration interval such that at least one symptom or feature of PKU is reduced in intensity, severity, or frequency or has delayed in onset. In some embodiments, the mRNA is encapsulated in a liposome comprising one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids

摘要翻译： 本发明尤其提供了治疗苯丙酮尿症（PKU）的方法，其包括向需要治疗的受试者施用包含编码苯丙氨酸羟化酶（PAH）的mRNA的组合物，其有效剂量和给药间隔使得至少一种 PKU的症状或特征在强度，严重程度或频率上降低或发病延迟。 在一些实施方案中，mRNA包封在包含一种或多种阳离子脂质，一种或多种非阳离子脂质，一种或多种基于胆固醇的脂质和一种或多种PEG修饰的脂质的脂质体中

公开(公告)号：WO2014197806A2

公开(公告)日：2014-12-11

申请号：PCT/US2014/041318

申请日：2014-06-06

申请人： ALLENA PHARMACEUTICALS, INC.

发明人： MARGOLIN, Alexey ,  GRUJIC, Danica ,  PIERZYNOWSKI, Stefan

IPC分类号： A61K38/44

CPC分类号： A61M1/287 ,  A01K67/00 ,  A01K2207/20 ,  A01K2227/108 ,  A01K2267/03 ,  A61K38/43 ,  A61K38/44 ,  A61K38/45 ,  A61K38/50 ,  A61K38/51 ,  C12Y101/00 ,  C12Y103/03005 ,  C12Y114/16001 ,  C12Y305/01005 ,  C12Y401/01002 ,  C12Y403/01024

摘要： Compositions of peritoneal dialysis solutions and metabolizing enzymes, and their uses to treat disorders associated with elevated levels of metabolites are disclosed. Animal models of hyperoxalemia are also disclosed.

摘要翻译： 公开了腹膜透析溶液和代谢酶的组合物及其用于治疗与代谢物水平升高相关的疾病的用途。 还公开了高氧血症的动物模型。

公开(公告)号：WO2009104174A3

公开(公告)日：2009-11-12

申请号：PCT/IL2009000169

申请日：2009-02-12

申请人： TECHNION RES & DEV FOUNDATION ,  KUHN JONATHAN CHARLES ,  ZUSSMAN EYAL ,  GREEN MICHAL

发明人： KUHN JONATHAN CHARLES ,  ZUSSMAN EYAL ,  GREEN MICHAL

IPC分类号： D01D5/00 ,  B01D69/08 ,  C02F1/58 ,  C02F3/00 ,  D01D5/24 ,  D01F1/10 ,  D01F8/14 ,  G01N33/53

CPC分类号： C12N11/04 ,  A61K9/0092 ,  A61K38/44 ,  B82Y30/00 ,  C02F3/102 ,  C02F3/34 ,  C02F3/342 ,  C02F2101/18 ,  C02F2101/20 ,  C02F2101/306 ,  C02F2101/36 ,  C02F2305/08 ,  C09D167/04 ,  C09D171/02 ,  C12M21/18 ,  C12M23/06 ,  C12M23/16 ,  C12Q1/66 ,  C12Y113/12007 ,  C12Y114/16001 ,  D01D5/003 ,  D01D5/247 ,  D01F1/10 ,  D01F8/14 ,  G01N33/54393 ,  G01N2333/90241 ,  Y02W10/15 ,  Y10T428/1393

摘要： A method of attaching a cell or a membrane-coated particle-of-interest to a microtube is provided. The method comprising: co-electrospinning two polymeric solutions through co-axial capillaries, wherein a first polymeric solution of the two polymeric solutions is for forming a shell of the microtube and a second polymeric solution of the two polymeric solutions is for forming a coat over an internal surface of the shell, the first polymeric solution is selected solidifying faster than the second polymeric solution and a solvent of the second polymeric solution is selected incapable of dissolving the first polymeric solution and wherein the second polymeric solution comprises the cell or the membrane-coated particle-of-interest, thereby attaching the cell or the membrane-coated particle-of-interest to the microtube. Also provided are microtubes with attached, entrapped or encapsulated cells or membrane-coated particles and methods of using same.

摘要翻译： 提供将细胞或膜包被的感兴趣颗粒附着到微管的方法。 该方法包括：通过同轴毛细管共同静电纺两种聚合物溶液，其中两种聚合物溶液的第一聚合溶液用于形成微管的壳，并且两种聚合物溶液的第二聚合溶液用于形成涂层 所述壳的内表面选择所述第一聚合物溶液比所述第二聚合物溶液凝固得更快，并且所述第二聚合物溶液的溶剂被选择为不能溶解所述第一聚合物溶液，并且其中所述第二聚合物溶液包含所述电池或所述膜 - 涂覆的感兴趣的颗粒，由此将细胞或膜包被的感兴趣的颗粒附着到微管。 还提供了具有附着，包埋或包封的细胞或膜包衣颗粒的微管及其使用方法。

公开(公告)号：WO2016070166A3

公开(公告)日：2016-08-18

申请号：PCT/US2015058534

申请日：2015-11-01

申请人： ARCTURUS THERAPEUTICS INC

发明人： CHIVUKULA PADMANABH ,  WARREN LUIGI ,  TACHIKAWA KIYOSHI ,  PAYNE JOSEPH E

IPC分类号： C12N15/11 ,  A61K48/00 ,  C12N15/85

CPC分类号： C12N9/1018 ,  A61K39/00 ,  A61K48/00 ,  C07K14/445 ,  C07K14/463 ,  C07K14/47 ,  C07K14/4712 ,  C07K14/4717 ,  C07K14/505 ,  C07K14/524 ,  C07K14/575 ,  C07K14/705 ,  C07K14/745 ,  C07K14/805 ,  C07K14/8125 ,  C12N9/0071 ,  C12N9/1051 ,  C12N9/1205 ,  C12N9/2451 ,  C12N9/644 ,  C12N9/88 ,  C12N2740/16222 ,  C12N2840/105 ,  C12N2840/60 ,  C12Y114/16001 ,  C12Y201/03003 ,  C12Y204/01025 ,  C12Y207/0104 ,  C12Y302/01033 ,  C12Y304/21022 ,  C12Y403/02001

摘要： This invention provides a range of translatable messenger UNA (mUNA) molecules. The mUNA molecules can be translated in vitro and in vivo to provide an active polypeptide or protein, or to provide an immunization agent or vaccine component. The mUNA molecules can be used as an active agent to express an active polypeptide or protein in cells or subjects. Among other things, the mUNA molecules are useful in methods for treating rare diseases.

摘要翻译： 本发明提供了一系列可转译信使UNA（mUNA）分子。 可以在体外和体内翻译mUNA分子以提供活性多肽或蛋白质，或提供免疫剂或疫苗组分。 mUNA分子可以用作活性剂以在细胞或受试者中表达活性多肽或蛋白质。 除此之外，mUNA分子可用于治疗罕见疾病的方法。