阅读说明：本技术 通过调节氨基酸水平治疗阿尔茨海默病的方法 (Methods of treating alzheimer's disease by modulating amino acid levels ) 是由 耿美玉 孙广强 王薪懿 张靖 冯腾 丁健 于 2020-08-05 设计创作，主要内容包括：提供用于调节氨基酸水平的试剂在制备用于在受试者中治疗阿尔茨海默病的药物中的用途。(There is provided the use of an agent for modulating the level of an amino acid in the manufacture of a medicament for the treatment of alzheimer's disease in a subject.)

Use of an agent for modulating the level of an amino acid in peripheral blood of a mammal in the manufacture of a medicament for treating alzheimer's disease in a subject.

A pharmaceutical composition for treating alzheimer's disease in a subject comprising an effective amount of an agent for modulating the level of amino acids in the peripheral blood of a mammal.

The use according to claim 1 or the pharmaceutical composition according to claim 2, wherein the amino acid is selected from one or more of the following: 4-OH proline, acetylornithine, alanine, alpha-aminoadipic acid, asparagine, aspartic acid, asymmetric dimethylarginine, beta-alanine, carnosine, citrulline, creatinine, GABA, glutamic acid, glutamine, glycine, histidine, taurine, isoleucine, kynurenine, leucine, lysine, methionine sulfoxide, ornithine, phenylalanine, pipecolic acid, proline, putrescine, pyroglutamic acid, serine, serotonin, taurine, threonine, tryptophan, tyrosine and valine; preferably one or more selected from the group consisting of phenylalanine, isoleucine, serotonin, histidine and acetylornithine; more preferably phenylalanine and/or isoleucine; most preferred is phenylalanine.

The use according to claim 1 or the pharmaceutical composition according to claim 2, wherein the agent comprises one or more selected from the group consisting of: an enzyme in an amino acid degradation pathway, an inhibitor of an enzyme in an amino acid synthesis pathway, an amino acid ligand, an agonist or inhibitor of an amino acid transporter, an agent for modulating the relative abundance of an intestinal microorganism, or a combination thereof.

The use or pharmaceutical composition of claim 4, wherein the agent for modulating the relative abundance of gut microbes is selected from a carbohydrate drug, a gut microbial complex, or a combination thereof; wherein the carbohydrate drug is selected from a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a derivative thereof, or a combination thereof and/or a derivative thereof; oligosaccharides and polysaccharides are preferred; more preferably a mannuronic acid oligosaccharide or a composition comprising mannuronic acid oligosaccharide; wherein the gut microbial complex comprises one or more selected from the group consisting of firmicutes, bacteroidetes, proteobacteria, actinomycetes, fusobacteria, cyanobacteria, verrucomicrobia, or combinations thereof.

The use or pharmaceutical composition according to claim 5, wherein the amino acid degrading enzyme is selected from one or more of: phenylalanine-4-hydroxylase; phenylalanine 2-monooxygenase; catalase-peroxidase; phenylacetaldehyde synthase; aromatic-L-amino acid/L-tryptophan decarboxylase; phenylalanine decarboxylase; phenylalanine N-acyltransferase; an aspartate aminotransferase; a tyrosine aminotransferase; an L-amino acid oxidase; phenylalanine dehydrogenase; an aromatic amino acid transaminase; histidinol phosphate aminotransferase; an aromatic amino acid aminotransferase II; a phenylalanine racemase; phenylalanine ammonia lyase; phenylalanine/tyrosine ammonia lyase; a branched chain amino acid aminotransferase; l-amino acid oxidase.

The use or pharmaceutical composition according to claim 5, wherein the amino acid degrading enzyme is selected from one or more of: phenylalanine-4-hydroxylase; aromatic-L-amino-acid/L-tryptophan decarboxylase; an aspartate aminotransferase; tyrosine aminotransferase, TAT; an L-amino acid oxidase.

The use or pharmaceutical composition according to claim 5, wherein the amino acid degrading enzyme is delivered by a vector, preferably the vector is a microorganism, preferably a bacterium, more preferably E.

The use of claim 1 or the pharmaceutical composition of claim 2, wherein the agent modulates the amino acid level by 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 μ Μ or more by detecting a peripheral blood sample from the subject; and/or allowing said amino acid level to approach or reach the corresponding amino acid level of a corresponding normal subject.

The use according to claim 1 or the pharmaceutical composition according to claim 2, wherein the agent modulates the amino acid level by 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000 μmol/g or more by detecting a stool sample from the subject; and/or allowing said amino acid level to approach or reach the corresponding amino acid level of a corresponding normal subject.

The use according to claim 1 or the pharmaceutical composition according to claim 2, wherein said modulating the level of amino acids in the peripheral blood of a mammal is increasing the level of one or more amino acids in the peripheral blood of a mammal and/or decreasing the level of one or more amino acids in the peripheral blood of a mammal; preferably the level of one or more amino acids selected from the group consisting of: 4-OH proline, acetylornithine, alanine, alpha-aminoadipic acid, asparagine, aspartic acid, asymmetric dimethylarginine, beta-alanine, carnosine, citrulline, creatinine, GABA, glutamic acid, glutamine, glycine, histidine, taurine, isoleucine, kynurenine, leucine, lysine, methionine sulfoxide, ornithine, phenylalanine, pipecolic acid, proline, putrescine, pyroglutamic acid, serine, serotonin, taurine, threonine, tryptophan, tyrosine and valine; more preferably, the level of one or more amino acids selected from the group consisting of phenylalanine, isoleucine, serotonin, histidine and acetylornithine in the peripheral blood of a mammal; still more preferably, the level of phenylalanine and/or isoleucine in the peripheral blood of the mammal is reduced; most preferably, the level of phenylalanine in the peripheral blood of the mammal is reduced.

A method for screening a candidate drug useful for treating alzheimer's disease comprising:

a) administering a test agent to a mammalian model having a level of amino acids in peripheral blood, and

b) selecting a test agent that modulates the amino acid level as a candidate drug useful for treating alzheimer's disease.

The method of claim 12, further comprising administering GV-971 as a positive control to a mammalian model having a level of amino acids in peripheral blood, preferably selecting a test agent that modulates the amino acid level substantially in line with the GV-971.

The method of claim 12 or 13, further comprising administering a selected test agent to a mammalian model having a level of amino acids in peripheral blood for validation, wherein the selected test agent modulates the level of amino acids by 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 μ Μ or more by detecting a peripheral blood sample from the mammalian model; and/or allowing said amino acid level to approach or reach the corresponding amino acid level of a corresponding normal mammalian model.

The method of claim 12 or 13, further comprising administering to a mammalian model having a level of amino acids in peripheral blood selected test agents for validation, wherein the selected test agents modulate the amino acid level by 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000 μmol/g or more by detecting a fecal sample from the mammalian model; and/or allowing said amino acid level to approach or reach the corresponding amino acid level of a corresponding normal mammalian model.

The method according to any one of claims 12 to 15, wherein the amino acid is selected from one or more of: 4-OH proline, acetylornithine, alanine, alpha-aminoadipic acid, asparagine, aspartic acid, asymmetric dimethylarginine, beta-alanine, carnosine, citrulline, creatinine, GABA, glutamic acid, glutamine, glycine, histidine, taurine, isoleucine, kynurenine, leucine, lysine, methionine sulfoxide, ornithine, phenylalanine, pipecolic acid, proline, putrescine, pyroglutamic acid, serine, serotonin, taurine, threonine, tryptophan, tyrosine and valine; preferably one or more selected from the group consisting of phenylalanine, isoleucine, serotonin, histidine and acetylornithine; more preferably phenylalanine and/or isoleucine; most preferred is phenylalanine.

The method of any one of claims 12 to 16, wherein the modulating amino acid levels is increasing the levels of one or more amino acids and/or decreasing the levels of one or more amino acids; preferably reducing the level of one or more amino acids selected from the group consisting of phenylalanine, isoleucine, serotonin, histidine and acetylornithine in the peripheral blood of a mammal; more preferably, the level of phenylalanine and/or isoleucine in the peripheral blood of the mammal is reduced; most preferably, the level of phenylalanine in the peripheral blood of the mammal is reduced.

A method of treating a patient with alzheimer's disease comprising:

(a) detecting the amino acid level of the patient and comparing it with the corresponding amino acid level of a corresponding normal population to select amino acids whose levels differ from the corresponding amino acid level of the corresponding normal population;

(b) administering to the patient an agent for modulating the level of an amino acid in the peripheral blood of a mammal to modulate the level of the selected amino acid to approach or reach the corresponding amino acid level of the corresponding normal population.