WO2024026509A2 - Sélection de thérapie et traitement de troubles neurodégénératifs - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B25/10—Gene or protein expression profiling; Expression-ratio estimation or normalisation
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
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- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
- G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Definitions
- the present disclosure relates generally to personalized medical treatments and more specifically to genetic methods and kits for individualized monitoring of medical treatments and selection of therapeutic agents.
- Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. Over the last few decades, genomic analysis and profiling have become tools useful to diagnose, treat, and prevent diseases. But there are few reports on how to use genomic profiling to assess the effectiveness of a therapy or selecting a proper therapeutic agent for a specific patient.
- One aspect of the present disclosure encompasses a method of selecting a therapeutic agent for a subject suffering from a disease or a disorder selected from Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, and a disorder related to cardiac muscle contraction.
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject a Sigma receptor agonist for a period of time; obtaining or having obtained a second biological sample of the subject at the end of administration period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify at least one differentially expressed gene and/or overrepresented gene cluster; and selecting the Sigma receptor agonist as the therapeutic agent for the subject, if one of the following conditions is observed: (i) at least one differentially expressed gene is a gene listed in a first gene cluster comprising MS4A4A, COX5B, COX7B, C0X8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA2K2, PSENEN, or NDUFB3; or a gene listed in a second gene
- the therapeutic agent can comprise a Sigma receptor agonist.
- the Sigma receptor agonist can comprise ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA- 4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof, or any combinations thereof.
- the therapeutic agent can comprise a Sigma receptor agonist selected from ANAVEX2-73 (A2-73), A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, or (+) A2-73 enantiomer, or a combination thereof.
- the therapeutic agent can be administered for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks. And the therapeutic agent is administered daily, such as once daily.
- the Sigma receptor agonist can comprise A2-73, A2-73 free base, or any combination thereof.
- the Sigma receptor agonist can comprise A2-73 in crystal form, and is administered in the amount of about 40 mg to about 60 mg once daily for about 6- 11 weeks.
- A2-73 in a crystal form is administered at a dose of about 50 mg daily for up to 11 weeks.
- A2-73 is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6- 11 weeks.
- the Sigma receptor agonist comprises A2-73, A2-73 free base, or a combination thereof.
- A2-73 or A2-73 free base is administered daily in an amount of about 40-60 mg for a period of 6 to 14 weeks.
- the Sigma receptor agonist comprises A2-73 or A2-73 free base in a crystal form, and wherein the A2-73 or A2-73 free base is administered once daily in an amount of about 50 mg for a period of up to 11 weeks.
- the therapeutic agent is a Sigma receptor agonist, and the Sigma receptor agonist comprises A2-73 in a crystal form. The A2-73 crystal is administered once daily for a period of 11 weeks in an escalating amount starting at about 10 mg and ending at about 50 mg.
- Another aspect of the present disclosure encompasses a method of evaluating effectiveness of a neurodegenerative therapy for a subject in need thereof.
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject the neurodegenerative therapy for a period of time; obtaining or having obtained a second biological sample of the subject at the end of therapy period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify differentially expressed genes and overrepresented gene clusters; and identifying the neurodegenerative therapy as effective if one of the following conditions is met: (i) an identified differentially expressed gene is a gene listed in a first gene cluster comprising MS4A4A, COX5B, COX7B, COX8A, NDLIFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA
- a follow-up action can be taken, such as switching to another neurodegenerative therapy, supplementing with another neurodegenerative therapy, adjusting dose if the neurodegenerative therapy being a drug therapy, or switching to a combined neurodegenerative therapy.
- the subject may be a human subject having or suspected of having a neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, or any combination thereof.
- a neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, or any combination thereof.
- the neurodegenerative therapy can be a drug therapy comprising ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA- 4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- the neurodegenerative therapy is a A2-73 drug therapy comprising A2-73 free base, A2- 73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, or (+) A2-73 enantiomer.
- the neurodegenerative therapy can be administered for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the therapeutic agent may be administered daily, such as once or twice daily.
- the neurodegenerative therapy is a drug therapy comprising A2-73, for example in a crystal form, and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks.
- A2-73 is administered in about 50 mg daily for up to 11 weeks.
- the A2-73 is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks.
- Yet another aspect of the present disclosure encompasses a method of identifying a subject responsive to a Sigma-1 receptor agonist therapy.
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject a Sigma receptor agonist for a period of time; obtaining or having obtained a second biological sample of the subject at the end of administration period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample, to identify differentially expressed genes and overrepresented gene clusters; and identifying the subject as responsive to the Sigma-1 receptor agonist therapy, if any one of the following conditions is observed: (i) the identified differentially expressed gene is a gene listed in a first gene cluster comprising MS4A4A, COX5B, COX7B, COX8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CY
- the subject being administered the Sigma-1 receptor agonist therapy is a human subject having or being suspected of having a disorder or disease, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, nonalcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, or a disorder related to cardiac muscle contraction.
- a disorder or disease such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, nonalcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction,
- the Sigma-1 receptor agonist therapy may comprise ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1-41, AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)- pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- the Sigma-1 receptor agonist therapy is a A2- 73 drug therapy comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, or (+) A2-73 enantiomer.
- the Sigma-1 receptor agonist therapy is administered for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the therapeutic agent is administered daily, such as once daily.
- the Sigma-1 receptor agonist therapy can comprise a crystal form of A2-73 or A2-73 free base, and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks.
- a A2-73 crystal or a A2-73 free base crystal is administered in about 50 mg daily for up to 11 weeks.
- A2-73 or A2-73 free base is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks.
- Another aspect of the present disclosure encompasses a method of determining if a subject is having or is suspected of having a disease or disorder, or assessing a risk of a subject for developing such a disease or disorder selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, or a disorder related to cardiac muscle contraction.
- a disease or disorder selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject a composition of ANAVEX 2-73 for a period of time; obtaining or having obtained a second biological sample of the subject at the end of administration period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify differentially expressed genes and overrepresented gene clusters; and identifying the subject as having a disorder or disease as listed above, or as having increased risk of developing such a disorder or disease, if any one of the following conditions is observed: (i) the identified differentially expressed gene is a gene listed in a first gene cluster comprising MS4A4A, COX5B, COX7B, C0X8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA2K2, PSENEN, or
- the disease is Parkinson’s disease, Parkinson’s disease with dementia, or Prion disease.
- the A2-73 composition may comprise A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- the A2- 73 composition may be administered for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the A2-73 composition may be administered daily, such as once daily.
- the A2-73 composition may comprise a crystal of A2-73 or A2-73 free base, and may be is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks.
- A2-73 is administered in about 50 mg daily for up to 11 weeks.
- A2-73 is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks.
- the first and second biological samples can each be selected from a blood serum sample, a blood plasma sample, or any biological sample suitable for transcriptomic analysis as disclosed herein.
- kits for a medical use includes several containers, for example a first container to receive a first biological sample; a second container to receive a second biological sample; a third and any additional containers useful for storing any reagents or components needed for sequencing or measuring gene expression; and a container useful for storing therapeutic compounds or compositions as described herein, such as any Sigma-1 receptor agonist, for example an A2-73 composition.
- the kit may also include instructions in printed or computer readable medium describing the methods disclosed herein and use of the kit to perform the methods.
- a kit as disclosed herein may be used for any of the various disclosed methods, such as selection of a therapeutic agent for a subject, evaluation of the effectiveness of a neurodegenerative therapy, identification of a subject responsive to a Sigma-1 receptor agonist therapy, or determining if a subject is having, is suspected of having, or having an increased risk for developing a disorder or a disease selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, or a disorder related to cardiac muscle contraction.
- the disease or disorder is Parkinson’s disease, Parkinson’s disease with dementia, or Prion disease.
- a composition comprising a Sigma-1 receptor agonist as used in the kit may comprise ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1- 41 , AV1066, ANAVEX3-71 , PRE-084, L-687,384, SA-4503, Dimethyltryptamine, (+)- pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- the composition is a A2-73 oral composition comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- Another aspect of the present disclosure encompasses a method of treating a disorder or a disease in a subject by administering a therapeutically effective amount of a Sigma-1 receptor agonist.
- the disorder or disease comprises Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, a disorder related to cardiac muscle contraction, or any combination thereof.
- the Sigma-1 receptor agonist may comprise ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1-41, AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)- pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- the Sigma-1 receptor agonist comprises A2- 73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- the therapeutically effective amount of A2-73 comprises A2-73 in an amount of 0.5-100 mg per day, such 10-50 mg per day.
- the treatment may be directed to treating Parkinson’s Disease, and comprises administering an effective amount of A2-73 in about 10 mg to 50 mg per day.
- A2-73 may be in a form of free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- the treatment may be directed to treating Prion Disease and comprises administering A2-73 in an amount of 0.5-100 mg per day.
- A2-73 may be in a form of free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- the subject being treated may be a human subject or a non-human mammal.
- Another aspect of the present disclosure encompasses a method of regulating expression of gene MS4A4A in a subject in need thereof, the method comprising administering the subject with a Sigma receptor agonist.
- the subject is having or is suspect of having a microglia dysfunction.
- Such microglia dysfunction may manifest a neurodegenerative disorder, such neurodegenerative disorder comprises Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, and any combination thereof.
- the present disclosure encompasses a method of regulating expression of gene MS4A4A by administering a Sigma receptor agonist, such as ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)- pentazocine, and any crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- a Sigma receptor agonist such as ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)
- the Sigma receptor agonist comprises A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, or (+) A2-73 enantiomer.
- the Sigma receptor agonist is administered daily.
- the Sigma receptor agonist comprises A2-73 free base or A2-73 amorphous form, and wherein the A2-73 is administered daily in an amount of about 10-100 mg for a period of 6 to 14 weeks.
- the Sigma receptor agonist comprises A2-73 in a crystal form or an optical pure form, and wherein the A2-73 is administered once daily in an amount of about 40-60 mg for a period of up to 11 weeks.
- the Sigma receptor agonist comprises A2-73 in a crystal form or an optical pure form, and wherein the A2-73 is administered once daily for a period of 11 weeks in an escalating amount starting at about 10 mg and ending at about 60 mg.
- the present disclosure encompasses a method of evaluating effectiveness of a neurodegenerative therapy in a subject in need thereof.
- the method comprising the steps of (a) obtaining or having obtained a first biological sample of the subject before onset of the neurodegenerative therapy; (b) providing the neurodegenerative therapy to the subject for a period of therapy time; (c) obtaining or having obtained a second biological sample of the subject at the end of the therapy time; (d) determining MS4A4A gene expression level in the first biological sample and that in the second biological sample; and (e) identifying the neurodegenerative therapy as (i) effective for the subject, if the MS4A4A gene expression level in the first biological sample is lower than that in the second biological sample; or (ii) ineffective for the subject, if the MS4A4A gene expression level in the first biological sample is higher than that in the second biological sample.
- the method further comprises one or more of the following: i. switching to another neurodegenerative therapy; ii. supplementing with another neurodegenerative therapy; iii. adjusting dose if the neurodegenerative therapy involves drug therapy; and iv. switching to a combined neurodegenerative therapy.
- the first biological sample or the second biological sample is each independently comprises a blood serum sample, a blood plasma sample, or a sample suitable for transcriptomic analysis.
- the neurodegenerative therapy is for treating a disease selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, and any combination thereof.
- the neurodegenerative therapy comprises a drug therapy selected from ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA- 4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, and any of their crystal forms, enantiomers and pharmaceutically acceptable salts.
- a drug therapy selected from ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA- 4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, and any of their crystal forms, enantiomers and pharmaceutically acceptable salts.
- the neurodegenerative therapy is selected from a drug therapy comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, and (+) A2-73 enantiomer.
- the period of therapy time is up to 14 weeks.
- the period of therapy time is about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the neurodegenerative therapy is administered daily.
- the neurodegenerative therapy comprises a A2-73 drug therapy, and wherein the A2-73 drug therapy comprises daily administering A2-73 or A2-73 free base in an amount of about 10-100 mg, and for a period of 6 to 14 weeks.
- the neurodegenerative therapy comprises a A2-73 drug therapy, and wherein the A2-73 drug therapy comprises administering a crystal form or an optical pure form of A2-73 once daily.
- the neurodegenerative therapy comprises a A2-73 drug therapy, and wherein the A2-73 drug therapy comprises administering a crystal form of A2-73 once daily in an escalating amount starting at about 10 mg and ending about 50 mg, and for a period up to 14 weeks.
- the neurodegenerative therapy comprises a A2-73 drug therapy
- the A2-73 drug therapy comprises administering an optical form of A2-73 once daily in an escalating amount starting at about 10 mg and ending about 60 mg, and for a period up to 14 weeks.
- Another aspect of the present disclosure encompasses a method of identifying a subject responsive to a Sigma-1 receptor agonist therapy, the method comprising the steps of (a) obtaining or having obtained a biological sample of the subject; (b) determining a genetic profile from the biological sample; (c) identifying gene MS4A4A in the genetic profile; (d) detecting coding region of the gene MS4A4A; (e) determining if the coding region possess rs6591561 Wild Type; and (f) identifying the subject being responsive to the Sigma-1 receptor agonist therapy to determine if the subject possesses rs6591561 Wild Type.
- the biological sample comprises a blood serum sample, a blood plasma sample, or a sample suitable for gene analysis.
- the Sigma-1 receptor agonist therapy is a drug therapy selected from ANAVEX2-73 (A2-73), A2-73 free base, ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, L-687,384, SA- 4503, Dimethyltryptamine, (+)-pentazocine, and any of their crystal forms, enantiomers and pharmaceutically acceptable salts.
- the Sigma-1 receptor agonist therapy is a A2-73 drug therapy comprising administration of A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2- 73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- Another aspect of the present disclosure encompasses the foregoing treatment of a human subject having or being suspected of having a disorder selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, a disorder related to cardiac muscle contraction, and any combination thereof.
- the Sigma-1 receptor agonist therapy is provided daily.
- the Sigma-1 receptor agonist therapy comprises a A2-73 drug therapy, and the A2-73 drug therapy comprises daily administering of A2-73 orA2-73 free base in an amount of about 40-60 mg, and for a period of 6 to 14 weeks.
- the Sigma-1 receptor agonist therapy is a A2-73 drug therapy, and wherein the A2-73 drug therapy comprises administering a crystal form of A2-73 or A2-73 freebase once daily in an amount of about 50 mg, and for a period of up to 11 weeks.
- the Sigma-1 receptor agonist therapy comprises a A2-73 drug therapy
- the A2-73 drug therapy comprises administering is a crystal form of A2-73 or A2-73 free base once daily for a period of 11 weeks in an escalating amount starting at about 10 mg and ending at about 50 mg.
- Another aspect of the present disclosure encompasses a method of determining if a subject is having or is suspected of having a microglia dysfunction, the method comprising the steps of (a) obtaining or having obtained a first biological sample of the subject; (b) administering to the subject a composition of A2-73 for a period of time; (c) obtaining or having obtained a second biological sample of the subject at the end of the period of time; (d) determining a gene expression profile for the first biological sample and for the second biological sample; and (e) comparing gene expression level of MS4A4A in the first biological sample with that in the second biological sample. It is to confirm the subject having the microglia dysfunction, if the gene expression level of MS4A4A is increased.
- first biological sample and the second biological sample comprise independently a blood serum sample, a blood plasma sample, or a sample suitable for gene analysis.
- the microglia dysfunction manifests a disease selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, and a disorder related to cardiac muscle contraction.
- the composition of A2-73 comprises A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- the composition of A2-73 comprises an oral composition.
- the period of time is up to 14 weeks.
- the period of time is about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the A2-73 composition is administered daily.
- the A2-73 composition is administered daily in an amount of about 40-60 mg, and for a period of 6 to 14 weeks.
- the A2-73 composition comprises a crystal form of A2-73 or A2-73 free base, and is administered once daily in an amount of about 50 mg, and for a period of up to 11 weeks.
- the A2-73 compositions comprises a crystal form of A2-73 or A2-73 free bases, and is administered once daily in an escalating amount starting at about 10 mg and ending about 50 mg, and for a period of up to 11 weeks.
- Another aspect of the present disclosure encompasses a method of assessing a risk of a subject for developing a disease related to microglia dysfunction, the method comprising the steps of (a) obtaining or having obtained a biological sample from the subject; (b) identifying MS4A4A gene expression in the biological sample; (c) detecting coding region of MS4A4A; (d) determining if the coding region possess rs6591561 Wild Type or rs1582763 Wild Type; and (e) concluding the subject (i) possessing rs6591561 Wild Type has a higher risk of developing the disease related to microglia dysfunction than those without the rs6591561 Wild Type; or (ii) possessing rs1582763 Wild Type has a lower risk of developing the disease related to microglia dysfunction than those with the rs6591561 Wild Type.
- the biological sample comprises a blood serum sample, a blood plasma sample, or a sample suitable for gene analysis.
- the biological sample comprises a blood serum sample
- Another aspect of the present disclosure encompasses A2-73 for use as a medicament in the treatment of a microglia dysfunction wherein the microglia dysfunction is caused by the presence of MS4A4A variant rs6591561 .
- Another aspect of the present disclosure encompasses a method of treating a microglia dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of A2-73, and the therapeutically effective amount is an amount sufficient to transition microglia to an anti-inflammatory (Mic 3) state with efficient lipid metabolism.
- the A2-73 is A2-73 free base, crystal Form I of A2-73, crystal Form II of A2-73, crystal Form III of A2-73, (-) enantiomer of A2-73, (+) enationtiomer of A2-73, or any combination thereof.
- the A2-73 is in an amount of 0.5 -100 mg per day.
- the microglia dysfunction is Parkinson’s Disease and the A2-73 is in an oral amount of 1 -100 mg per day. In yet another aspect, the microglia dysfunction is Parkinson’s Disease with dementia and the A2-73 is in an oral amount of 10-50 mg per day.
- Another aspect of the present disclosure encompasses a method of identifying a disease impactful biomarker through artificial intelligence modeling, the method comprises the steps of (a) designing or having designed an interventional clinical trial to study therapeutic effect of a drug candidate to the disease, wherein the clinical trial specifies a protocol of the drug candidate to be administered, a biomedical information to be collected and time intervals for such administration and collection; (b) enrolling or having enrolled a population of patients having the disease into the interventional clinical trial; (c) gathering or having gathered a set of drug administration information and biomedical information based on the designed clinical trial and at the time intervals specified in the designed clinical trial; (d) generating relationships from the gathered drug administration information and biomedical information; (e) characterizing the generated relationships; (f) identified from the characterized relationships a biomarker with confidence level over 0.5, Lift over 1 , and Fisher’s p value less than ⁇ 0.08; and (g) designating the biomarker as a disease-impactful biomarker.
- the gathered drug administration information and biomedical information comprises at least patients’ clinical diagnosis, co-morbidity, co-medication, age, weight, height, gender, dose received, dosing time points, endpoint assessment, and omics.
- the drug candidate is A2-73.
- the drug candidate comprises A2-73 in a crystal form, in an optical pure form, or as A2-73 freebase.
- the drug candidate comprises A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or a combination thereof.
- the disease is Alzheimer disease, Parkinson’s disease, or Parkinson’s disease with dementia.
- the biomarker identified comprises MS4A4A gene. In yet another aspect, the biomarker identified comprises MS4A4A gene possessing single nucleotide polymorphism rs6591561 or rs1582763. In yet another aspect, the biomarker identified comprises MS4A4A rs6591561 .
- FIG. 1 is an illustrative overview of Phase 2 Proof of Concept (PoC) study design of ANAVEX® 2-73 for treating Parkinson’s Disease with Dementia (PDD), including patient selection, endpoints information and analytical methods.
- PoC Phase 2 Proof of Concept
- FIG. 2A-2B are illustrative overview on multi-disciplinary method to identify genes response pathways of ANAVEX® 2-73 treatment.
- genes clusterization genes were clustered together using WGCNA1 (Weighted correlation network analysis. Correlation networks are being used in biology to analyze large, high-dimensional data sets), starting from their correlation of TPM2 expression (Transcript per million. TPM value represents a relative expression level that should be comparable between samples) values across samples: WGCNA created 17 clusters (size: 13 to 11 ,190 genes). Then, the cluster’s eigengene3 (one of a set of a genes matrix that tabulates the mRNA or gene expression of the genes across the sample) was used as summary of expression level of the cluster.
- cluster filtering the eigengene was used for each cluster as target variable of a linear mixed effect model with 3 covariates: Dose, patient, and timepoint. Clusters without significant (Dunnett’s test) contrasts between treated and placebo across all timepoints were filtered out. The ratio between cluster size and number of pathways was calculated and the top 2 clusters were eventually retained. In clusters biological description, two approaches were studied. FIG. 2A showed characterization and analysis were applied to all the genes of the cluster (whole cluster), and to the genes of the clusters that were known to have biological interactions (reduced cluster).
- FIG. 2B showed each cluster’s functional interactions between the genes of the cluster were assessed using the STRING database (Edge score >0.150; no text mining edges). Genes that have no interaction with any other genes of the cluster were discarded, which led to a reduced cluster. Pathway enrichment analysis was performed on these reduced clusters. False Discovery Rate (FDR, adjustment for multiple testing with the Benjamini-Hochberg procedure) with adjustment for multiple testing (Benjamini-Hochberg procedure) was used to characterize pathway overrepresentation.
- FDR False Discovery Rate
- FIG. 3 is a log P value plot of estimated marginal means of the mixed model, wherein the P value is from Dunnett’s test and linear mixed-effect model has 3 covariates, Actual Dose, Patient, and timepoint.
- FIG. 4A-4B are interaction plots of genes in Cluster 1 with 213 genes, wherein p-values were calculated by Fisher’s test.
- FIG. 4A shows genes involved in the biological pathways of Parkinson’s Disease, Prion Disease and Huntington’s disease. FDR stands for False Discovery Rate, adjustment for multiple testing with the Benjamini-Hochberg procedure. Only edges with score >0.4 were shown.
- FIG. 4B plots genes in KEGG 2022 pathways, and lists genes involved in the biological pathways of Parkinson’s Disease, Alzheimer’s Disease and other neurodegenerative diseases. It showed among 213 genes, 79% of the genes (169) have biological interactions.
- FIG. 5A-5B are interaction plots of genes in Cluster 2 with 962 genes and involved in the biological pathway of degenerative diseases. FDR stands for False Discovery Rate, adjustment for multiple testing with the Benjamini-Hochberg procedure.
- FIG. 5A shows and lists genes with interaction score >0.4.
- FIG. 5B shows among the 962 genes, 70% of the genes (680) have biological interactions correlating to Parkinson’s Disease, Alzheimer’s Disease and other neurodegenerative diseases.
- FIG. 6 depicts the features and progress of Parkinson’s Disease (PD).
- FIG. 7 depicts PD and Parkinson’s Disease with Dementia (PDD) related endpoints incorporated in PDD-001 Phase 2 study, illustrating the potential effects of ANAVEXO2-73 on both PD and PDD.
- PDD Parkinson’s Disease with Dementia
- FIG. 8 depicts the Artificial Intelligence (Al) analysis using Computerized Models to identify new biomarkers.
- FIG. 9 depicts microglia transitions to either a pro-inflammatory (Mic 1 ) or anti-inflammatory (Mic 3) state. Left portion shows interferon-based response with efficient lipid metabolism. Right portion shows a destructive inflammatory response that accumulates lipids.
- Mic 1 pro-inflammatory
- Mic 3 anti-inflammatory
- FIG. 10 depicts the All-Comers Studies for biomarker selection of patient populations in targeted medicine.
- FIG. 11 depicts Biomarker Noise Model, showing biomarker selection of patient populations in targeted medicine for reproducible therapeutic effect.
- the present disclosure is based in part on the discovery that when a subject is for a period of time administered a therapeutic agent such as a Sigma-1 receptor agonist, a set of selected genes are differentially expressed. Further, these genes are involved in distinct biological pathways implicated in certain diseases and disorders.
- the discovered correlation between disease treatment and changes in genetic profiles pre- and post-treatment, such as differentially expressed genes and/or overrepresented gene clusters, can be used to further guide choices concerning the treatment. For instance, the correlation may be used to evaluate therapeutic effectiveness of another therapeutic agent, or to select a therapeutic agent for a subject based on changes induced in genetic profiling, or to assess a subject’s disease state or risk for developing a disease using a therapeutic agent as a probe.
- the present disclosure is focused on Sigma receptor agonist therapy, and it is related diseases and disorders. But the same principle and methods can be similarly applied to other classes of therapeutic agents and diseases.
- Sigma-1 receptors are shown to be involved in higher-ordered brain functions including memory and cognition. Thus, a Sigma-1 receptor agonist therapy is often prescribed to patients having declined memory or cognition functions, such as those with neurodegenerative disorders. It is discovered that after a subject is being treated with a Sigma-1 receptor agonist, his or her gene expression profiles are altered: a set of selected genes are differentially expressed, and their relevant gene clusters are overrepresented. The altered genetic profile can be used as a benchmark to evaluate the therapeutic effect of another therapeutic agent. It can also be used to select a Sigma-1 receptor agonist for a subject. Further, it can also be used to determine if a subject is responsive to a Sigma-1 receptor agonist therapy. Finally, the Sigma-1 receptor agonist can be used a probe to see if a subject is having, or is suspected of having, or at an increased risk of having, a disease linked to the altered gene expression profiles.
- the inventors have discovered that a significant number of genes are differentially expressed after a period of Sigma-1 receptor agonist therapy. These genes are split into two clusters.
- the first gene cluster comprises MS4A4A, COX5B, COX7B, COX8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA2K2, PSENEN, and NDUFB3.
- the second gene cluster comprises COX4I1 , NDUFB11 , PSMA7, COX6A1 , NDUFB2, PSMB1 , COX6B1 , NDUFB7, PSMB4, COX6C, NDUFB8, PSMB5, COX7A2, NDUFB9, PSMB6, COX7C, NDUFC1 , PSMB7, CYC1 , NDUFC2, PSMD8, NDUFA11 , NDUFS3, RPS27A, NDUFA12, NDUFS4, SLC25A6, NDUFA13, NDUFS5, TXN2, NDUFA3, NDUFS6, UQCR10, NDUFA4, NDUFS7, UQCR11 , NDUFA7, NDUFS8, UQCRH, NDUFA8, PARK7, UQCRQ, NDUFB1 , PSMA2, NDUFB10, CDK5, GAPDH, HRAS, HSD17B10, or PSMA6.
- Both clusters present some overrepresented pathways, which are related to various biological processes, dysfunctions and diseases, such as neurodegenerative diseases and metabolic disorders.
- the first gene cluster is found to have correlation with nine (9) diseases or dysfunctions, and five (5) of them are neurodegenerative diseases.
- the nine (9) diseases or dysfunctions are Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, oxidative phosphorylation dysfunction, and proteasome dysfunction.
- the second gene cluster is found to have correlation with fourteen (14) biological functions, diseases or dysfunctions, and five (5) of them are neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, coronavirus disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, oxidative phosphorylation dysfunction, ribosome dysfunction, proteasome function, and thermogenesis function. It is found MS4A4A gene regulates lipid metabolism and immune response in a unique microglia state. For example, in disease conditions, homeostatic microglia can transition to either a pro-inflammatory (Mic 1) or antiinflammatory (Mic 3) state.
- Mic 1 pro-inflammatory
- Mic 3 antiinflammatory
- Mic 3 cells are themselves influenced by protective and risk single nucleotide polymorphisms (SNPs) in the MS4A4A locus, which push these cells into either a helpful, interferon-based response with efficient lipid metabolism, or a destructive inflammatory response that accumulates lipids.
- SNPs single nucleotide polymorphisms
- Neurodegenerative diseases refer to hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the central or peripheral nervous system structures and may have symptoms in the form of cognition impairment, memory loss, and movement disorders.
- Alzheimer’s disease is a degenerative disease of the brain characterized by the insidious onset of dementia. Early symptoms include impairment of memory, judgment, attention span, and problem-solving skills. In late stage, severe apraxias and a global loss of cognitive abilities may occur. The disease is marked pathologically by severe cortical atrophy and the triad of senile plaques, neurofibrillary tangles, and neuropil threads.
- Parkinson’s Disease is a highly heterogeneous multisystem disorder, it is the second most common neurodegenerative disorder where also cognitive impairment is common. It is considered the second largest CNS disorder with over 10,000 patients worldwide. It is fairly common in older adults, estimated to affect nearly 2 percent of those older than age 65. It is estimated that PD prevalence in US is over 1 ,000,000 patients. PD is a progressive, degenerative neurologic disease characterized by a tremor that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression.
- Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem.
- the brain changes caused by Parkinson’s disease begin in a region that plays a key role in movement. But etiology of cognitive impairment in PD has not yet been fully elucidated. As Parkinson’s brain changes gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task.
- Lewy bodies are present in the substantia nigra and locus coeruleus but may also be found in a related condition characterized by dementia in combination with varying degrees of parkinsonism.
- Parkinson's Disease with Dementia is a decline in thinking and reasoning skills that develops in some people living with Parkinson's disease. Parkinson patients may have movement problems before cognitive symptoms in dementia associated with Parkinson's disease. In dementia with Lewy bodies, cognitive symptoms occur before, or at the same time as, problems with movement.
- Secondary Parkinson’s disease refers to conditions which feature clinical manifestations resembling primary Parkinson’s disease that are caused by a known or suspected condition, such as parkinsonism caused by vascular injury, drugs, trauma, toxin exposure, neoplasms, infections and degenerative or hereditary conditions.
- Clinical features may include bradykinesia, rigidity, parkinsonian gait, and masked facies. In general, tremor is less prominent in secondary parkinsonism than in the primary form.
- Parkinson’s disease expressly incorporates the pathological features, the clinical manifestations, the symptoms and any secondary Parkinson’s disease. Specifically, Parkinson disease used herein expressly incorporates Parkinson’s Disease with Dementia (PDD).
- PDD Parkinson’s Disease with Dementia
- Huntington’s disease is a familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive chorea and dementia in the fourth or fifth decade of life. Common initial manifestations include paranoia, poor impulse control, depression, hallucinations, and delusions. Late symptoms include intellectual impairment, loss of fine motor control, athetosis, and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. Its juvenile variant has a more fulminant course including seizures, ataxia, dementia, and chorea.
- Amyotrophic lateral sclerosis is a degenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord.
- Prion disease is a group of genetic, infectious, or sporadic degenerative human and animal nervous system disorders associated with abnormal prions. These diseases are characterized by conversion of the normal prion protein to an abnormal configuration via a post-translational process. In humans, these conditions generally feature dementia, ataxia, and a fatal outcome.
- Pathologic features include a spongiform encephalopathy without evidence of inflammation. Some older literature may occasionally refer to these as unconventional slow virus diseases.
- Prion disease also called “transmissible spongiform encephalopathies” both humans and animals. They are distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response.
- the causative agents of TSEs are believed to be prions.
- the term “prions’’ refers to abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins called prion proteins that are found most abundantly in the brain. The abnormal folding of the prion proteins leads to brain damage and the characteristic signs and symptoms of the disease. Prion diseases are usually rapidly progressive and always fatal.
- Human Prion disease comprises at least Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler- Scheinker Syndrome, Fatal Familial Insomnia and Kuru.
- Animal Prion disease comprises at least Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), Scrapie, Transmissible mink encephalopathy, Feline spongiform encephalopathy, and Ungulate spongiform encephalopathy.
- BSE Bovine Spongiform Encephalopathy
- CWD Chronic Wasting Disease
- Scrapie Scrapie
- Transmissible mink encephalopathy Feline spongiform encephalopathy
- Ungulate spongiform encephalopathy Ungulate spongiform encephalopathy.
- ALS Amyotrophic lateral sclerosis
- Lou Gehrig's disease (after the baseball player who was diagnosed with it). It is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Its impact often starts in the hands, feet or limbs, and then spreads to other parts of your body. As the disease advances and nerve cells are destroyed, your muscles get weaker. This eventually affects chewing, swallowing, speaking and breathing.
- Symptoms include, but not limited to, difficulty walking or doing normal daily activities, tripping and falling, weakness in your legs, feet or ankles, hand weakness or clumsiness, slurred speech or trouble swallowing, muscle cramps and twitching in your arms, shoulders and tongue, inappropriate crying, laughing or yawning, and cognitive and behavioral changes. There is no cure for this fatal disease.
- Diabetic cardiomyopathy is defined by the existence of abnormal myocardial structure and performance in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes mellitus.
- a change in the metabolic status, impaired calcium homeostasis and energy production, increased inflammation and oxidative stress, as well as an accumulation of advanced glycation end products are among the mechanisms implicated in the pathogenesis of diabetic cardiomyopathy.
- Symptoms of DCM may include, but not limited to, shortness of breath, fatigue, dizziness or fainting, arrhythmia (problem with the rate or rhythm of your heartbeat), swollen feet and ankles, and chest pain.
- the minimal criteria to be diagnosed with DCM include left ventricular diastolic dysfunction and/or reduced left ventricular ejection fraction (EF), pathological left ventricle hypertrophy, and interstitial fibrosis.
- EF left ventricular diastolic dysfunction and/or reduced left ventricular ejection fraction
- Non-alcoholic fatty liver disease is a spectrum of chronic liver disorders, which encompass, among others nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).
- NASH a common cause of chronic liver disease, is defined as having at least 5% hepatic steatosis and inflammation with or without fibrosis. Over time and without treatment, NASH may progress to cirrhosis and even hepatocellular carcinoma (HOC).
- HOC hepatocellular carcinoma
- NAFLD/NASH is strongly associated with obesity and type II diabetes which together affect over 50% of the US population, leading to a heavy economic burden.
- therapeutic options for NASH remain limited, with only slight benefits observed from vitamin E or obeticholic acid treatment. While NASH is the leading cause of chronic liver disease and cirrhosis, there are currently no clinically approved therapies.
- Coronavirus disease is a viral disorder caused by a coronavirus. It is generally characterized by high fever, cough, dyspnea, chills, persistent tremor, muscle pain, headache, and a viral pneumonia. In younger patients, rare inflammatory syndromes may occur, such as atypical kawasaki syndrome, toxic shock syndrome, pediatric multisystem inflammatory disease, and cytokine storm syndrome. COVID-19 and SARS (Severe Acute Respiratory Syndrome) are two severe forms of coronavirus diseases. Diabetic cardiomyopathy is diabetes complications in which ventricular remodeling in the absence of coronary atherosclerosis and hypertension results in cardiac dysfunctions, typically left ventricular dysfunction.
- Non-alcoholic fatty liver disease refers to fatty liver finding without excessive alcohol consumption.
- Fatty liver is a lipid infiltration of the hepatic parenchymal cells resulting in a yellow-colored liver.
- the abnormal lipid accumulation is usually in the form of triglycerides, either as a single large droplet or multiple small droplets, fatty liver is caused by an imbalance in the metabolism of fatty acids.
- Oxidative phosphorylation dysfunction refers to any malfunction or deficiency in the process of electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds.
- Ribosomes have two main functions — decoding the message and the formation of peptide bonds. They are critical for proper protein synthesis. Ribosome dysfunctions compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes.
- Proteasome is a multi-subunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis. Impaired proteasome can cause many diseases, including cancer and a broad array of chronic neurodegenerative diseases.
- Thermogenesis refers to the dissipation of energy through the production of heat and occurs in specialized tissues including brown adipose tissue and skeletal muscle. Some hormones, such as norepinephrine and leptin, may stimulate thermogenesis by activating the sympathetic nervous system. Thermogenesis dysfunction may impact normal lipid metabolism and fat regulations, which in turn cause metabolic syndrome or disorders.
- Other diseases or disorders encompassed by the present disclosure include, but not limited to, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, and a disorder related to cardiac muscle contraction.
- One aspect of the present disclosure encompasses a method of selecting a therapeutic agent for a subject suffering from a disease or a disorder, such as Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, a disorder related to cardiac muscle contraction.
- a disease or a disorder such as Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation,
- One aspect of the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject a Sigma receptor agonist for a period of time; obtaining or having obtained a second biological sample of the subject at the end of administration period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify differentially expressed genes and overrepresented gene clusters; and selecting the Sigma receptor agonist as the therapeutic agent for the subject, if any one of the following conditions is observed: (i) the identified differentially expressed gene is a gene listed in a first gene cluster comprising COX5B, COX7B, COX8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA2K2, PSENEN, or NDLIFB3; or a gene listed in a second gene cluster comprising COX5B
- Another aspect of the present disclosure encompasses a method of evaluating effectiveness of a neurodegenerative therapy for a subject in need thereof.
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject the neurodegenerative therapy for a period of time; obtaining or having obtained a second biological sample of the subject at the end of therapy period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify differentially expressed genes and overrepresented gene clusters; and identifying the neurodegenerative therapy as effective if one of the following conditions is observed: (i) the identified differentially expressed gene is a gene listed in a first gene cluster comprising COX5B, COX7B, COX8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA2K2, PSENEN
- Yet another aspect of the present disclosure encompasses a method of identifying a subject responsive to a Sigma-1 receptor agonist therapy.
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject a Sigma receptor agonist for a period of time; obtaining or having obtained a second biological sample of the subject at the end of administration period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify differentially expressed genes and overrepresented gene clusters; identifying the subject as responsive to the Sigma-1 receptor agonist therapy, if any one of the following conditions is observed: (i) the identified differentially expressed gene is a gene listed in a first gene cluster comprising COX5B, COX7B, C0X8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA
- the subject may be a human subject having or suspected of having a disorder or disease selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, or a disorder related to cardiac muscle contraction.
- a disorder or disease selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to
- a follow-up action can be taken, such as switching to another neurodegenerative therapy, supplementing with another neurodegenerative therapy, adjusting dose if the neurodegenerative therapy being a drug therapy, or switching to a combined neurodegenerative therapy.
- the neurodegenerative therapy can be a Sigma-1 receptor agonist therapy, or a NM DA therapy, or a cognition enhancing physical therapy.
- a neurodegenerative therapy can be a drug therapy comprising a Sigma-1 receptor agonist, such as ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- a Sigma-1 receptor agonist such as ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantio
- ANAVEX2-73 (A2-73) has the chemical name of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride.
- A2-73 free base has the chemical name of tetrahydro-N,N-dimethyl-2,2-diphenyl-3- furanmethanamine.
- ANAVEX 19-144 (A19-144) has the chemical name of 1 -(2,2- diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride.
- ANAVEX 1-41 (A1-41) has the chemical name of tetrahydro-N,N-dimethyl-5,5-diphenyl-3- furanmethanamine hydrochloride.
- AV1066 has the chemical name of 1-(3- 4(((1 R,3S,5S)-adamantan-1-yl)(pheny)methyl)propyl)-4-methylpiperazine.
- ANAVEX3-71 (A3-71 , AF-710B) has a chemical name of 1-(2,8-dimethyl-1-thia-3,8- diazaspiro[4.5]decan-3-yl)-3-(1 H-indol-3-yl)propan-1 -one.
- a neurodegenerative therapy is a A2-73 drug therapy comprising administration of A2-73 free base, A2-73 in amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, or (+) A2-73 enantiomer.
- the present disclosure encompasses the polymorphic forms of A2-73.
- the polymorphic forms may be prepared by solvent extraction or by supercritical fluid extraction (SCE).
- SCE supercritical fluid extraction
- the crystal forms prepared from solvent extraction can be found in PCT/US2019/027369 (filed on Apr 12, 2019), published as W02019200345A1.
- A2-73 Crystal Form I is a crystal with XRPD peaks as shown in FIG.1 .
- A2-73 Crystal Form I is further characterized by scanning electron microscope (SEM) micrographs as shown in FIGs. 2-3.
- A2-73 Crystal Form II is a crystal with XRPD peaks as shown in FIG. 4.
- A2-73 Crystal Form II is also characterized by FTIR as shown in FIG. 5.
- the SEM micrographs of A2-73 Crystal Form II is shown in FIG. 7.
- A2-73 Crystal Form III is a crystal with XRPD peaks as shown in FIG.8.
- A2-73 Crystal Form III is characterized by FTIR as shown in FIG. 9.
- A2-73 Crystal Form III is characterized by scanning electron microscope (SEM) micrograph as shown in FIG. 11 .
- SEM scanning electron microscope
- A2-73 free base can be found in PCT/US2019/027369 (filed on Apr 12, 2019), published as WG2019200345A1 .
- a crystal form of A2-73 free base is the crystalline form characterized by XRPD pattern shown in FIG. 16. And such crystalline form possesses particle shapes depicted in FIG. 15.
- the present disclosure encompasses an enantiomer of A2-73 or a mixture of such enantiomer.
- the enantiomer may be an (+) or (-) enantiomer.
- the enantiomer refers to an optical pure or a substantial optical pure entity.
- the substantial optical pure entity refers to the opposite rotation entity may be presented in an amount of no more than 20%, such as at or about 0.1 %, at or about 0.5%, at or about 1 %, at or about 2%, at or about 5%, at or about 8%, at or about 10%, at or about 12%, at or about 15%, at or about 18%, or at or about 20%.
- the present disclosure expressly encompasses the (+) and (-) enantiomer disclosed and characterized in PCT/IB2016/001158 (filed on July 19, 2016), published as US20180169059A1 . The full contents of PCT/IB2016/001158 is expressly incorporated by reference herein.
- the neurodegenerative therapy or the Sigma-1 receptor agonist is administered for a period up to 14 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the therapeutic agent is administered daily, such as once daily.
- the neurodegenerative therapy is a drug therapy comprising A2-73, for example a composition comprising A2-73 in a crystal form, and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks.
- A2-73 is administered in about 50 mg daily for up to 11 weeks.
- A2-73 is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6- 11 weeks.
- One aspect of the present disclosure encompasses a method of determining if a subject is having or is suspected of having a disease or disorder, or assessing a risk of a subject for developing such a disease or disorder.
- the said disease or disorder is for example selected from Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, or a disorder related to cardiac muscle contraction.
- the method comprises obtaining or having obtained a first biological sample from the subject; administering to the subject a composition of ANAVEX 2-73 for a period of time; obtaining or having obtained a second biological sample of the subject at the end of administration period; determining a gene expression profile for the first biological sample and for the second biological sample; comparing the gene expression profile of the first biological sample with that of the second biological sample to identify differentially expressed genes and overrepresented gene clusters; and identifying the subject as having a disorder or disease as listed above, or as having an increased risk of developing such disorder or disease, if any one of the following conditions is observed: (i) the identified differentially expressed gene is a gene listed in a first gene cluster comprising COX5B, COX7B, COX8A, NDUFB6, TXN, PSMA4, CLTB, PSMB3, POLR2F, NDUFA1 , PSMD13, POLR2, NDUFA2, DDIT3, CYBA, AGER, MAPA2K2, PSENEN, or NDUFB3;
- composition of A2-73 may comprise A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2-73 enantiomer, or any combination thereof.
- a composition comprising A2-73 can be administered to the subject for a period of up to 14 weeks, for example 2-3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, or about 14 weeks.
- the therapeutic agent is for example administered daily, such as once daily.
- the composition of A2-73 may comprise a crystal of A2-73 or A2-73 free base, and is administered in the amount of about 40 mg to about 60 mg once daily for about 6-11 weeks.
- the crystal of A2-73 or A2-73 free base is administered in about 50 mg daily for up to 11 weeks.
- A2-73 or A2-73 free base is administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily for 6-11 weeks.
- the method comprises a biological sample.
- a biological sample may comprise a solid, a semisolid, a semi-fluid, a fluid, a tissue, or other material collected from a subject.
- a biological sample may be a fluid biological sample.
- a fluid biological sample may include fluid and some or all of cells, particles, crystals, and other components in the fluid.
- biological samples include but are not limited to, blood, serum, plasma, bone marrow, a nasal swab, a nasopharyngeal wash, saliva, urine, gastric fluid, spinal fluid, tears, stool, mucus, sweat, earwax, oil, a glandular secretion, cerebral spinal fluid, tissue, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, spinal fluid, a throat swab, breath, hair, finger nails, skin, biopsy, placental fluid, amniotic fluid, cord blood, lymphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk and/or other secretions or excretions.
- Biological samples may include nasopharyngeal wash, or other fluid obtained by washing a body cavity or surface of a subject, or by washing a swab following application of the swab to a body cavity or surface of a subject.
- Nasal swabs, throat swabs, stool samples, hair, finger nail, ear wax, breath, and other solid, semi-solid, or gaseous samples may be processed in an extraction buffer, e.g., for a fixed or variable amount of time.
- tissue samples of the subject may include but are not limited to, connective tissue, muscle tissue, nervous tissue, epithelial tissue, cartilage, cancerous sample, or bone.
- the sample may be obtained from a human or animal.
- the sample may be obtained from a vertebrate, e.g., a bird, fish, or mammal, such as a rat, a mouse, a pig, an ape, another primate (including humans), a farm animal, a sport animal, or a pet.
- the sample may be obtained from a living or dead subject.
- the sample may be obtained fresh from a subject or may have undergone some form of pre-processing, storage, or transport.
- blood and “whole blood” refer to blood as it exists within an animal and as directly obtained from a subject in a blood sample. Blood contains red blood cells, white blood cells, proteins such as albumin, globulins, and clotting factors, salts, water, and other constituents.
- a blood sample is a fluid biological sample.
- a biological sample refers to a fluid sample containing suspended cells, cellular material, fungi, antigens, biological factors, immunogens, proteins, and other material of biological origin generally having a size substantially larger than the size of the molecules that comprise the fluid.
- Biological factors refer to compounds made by living organisms or attached to living organisms that have biological or physiological activities. Biological factors include but are not limited to biological markers, antibodies, cytokines, growth factors, and other peptides, proteins, lipids and carbohydrates produced biologically, terms “plasma” and “blood plasma” refer to the liquid portion of blood (e.g., a blood sample) that remains after the removal of blood cells.
- Red blood cells and white blood cells may be removed by centrifugation of a blood sample, leaving plasma above the pelleted cells in the bottom of the centrifuge tube.
- Plasma retains blood clotting factors, and is obtained from anticoagulated blood samples.
- a sample of plasma is a fluid biological sample.
- the terms “serum” and “blood serum” refer to the liquid portion of blood that remains after blood is allowed to clot, and the clot is removed. Serum differs from plasma in that serum lacks clotting factors: since clotting requires fibrin, thrombin, and other proteins, which form and remain part of a blood clot, serum lacks these proteins while plasma contains them.
- a sample of blood serum is a fluid biological sample.
- the present disclosure comprises a first biological sample and/or a second biological sample.
- the first and the second biological sample can be the same type of biological sample, but taken at different time.
- the first and the second biological sample may be a different type of biological sample taken from the same subject.
- the first and the second biological sample may be different type of biological sample taken at different time from the same subject.
- the first and the second biological sample may be the same type of biological sample taken at the same time, but from different subjects.
- the first and the second biological sample each is independently any biological sample recited above.
- the first and the second biological sample each independently, comprises a blood serum sample, a plasma sample, or a biological sample suitable for transcriptomic analysis.
- Transcriptome analysis is the study of the transcriptome, of the complete set of RNA transcripts that are produced by the genome, under specific circumstances or in a specific cell, often using high-throughput methods.
- the transcriptomic analysis is useful in identifying the functions of genes, and/or identification of pathways that respond to or ameliorate environmental stresses.
- RNA-Seq can also identify disease-associated gene fusions, single nucleotide polymorphisms and even allele-specific expression.
- the present disclosure expressly incorporate any biological sample that are suitable and/or capable of being used for transcriptomic analysis.
- kits for a medical use includes one or more containers for receiving and holding biological samples that may be taken at different points in time, and reagents for carrying out gene expression analysis.
- the kit may have a first container for receiving a first biological sample as used in the disclosed methods; a second container for receiving a second biological sample as used in the disclosed methods; and additional one or more containers for receiving and/or storing reagent(s) useful for sequencing or measuring a gene expression. Additional containers may be included to receive and store composition(s) in a safe, stable and durable way.
- the composition may comprise a Sigma-1 receptor agonist, such as a composition comprising A2-73 or A2-73 free base.
- the kit can include an instruction in hard copy printed from or in a computer readable form, which explains the use of the kit components to perform any of the methods described herein. The instruction may be written with the medical practitioner and/or the patient as the intended reader. [0076] In one aspect of the present disclosure, the kit may be used for various purposes, such as selection of a therapeutic agent for a subject, evaluation effectiveness of a neurodegenerative therapy, identification of a subject responsive to a Sigma-1 receptor agonist therapy, or determining if a subject is having, is suspected of having, or having an increased risk for developing a disorder or a disease.
- Such disorder or disease may include Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, or a disorder related to cardiac muscle contraction.
- One aspect of the present disclosure encompasses a method of treating a disorder or a disease in a subject by administering a therapeutically effective amount of a Sigma-1 receptor agonist.
- the disorder or disease comprises Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, a disorder related to cardiac muscle contraction, or any combination thereof.
- the Sigma-1 receptor agonist may comprise ANAVEX2-73 (A2-73) in any form, ANAVEX 19-144, ANAVEX1-41, AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)- pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
- the treatment is for Parkinson’s Disease, Parkinson’s disease with dementia, or for treating Prion Disease.
- the Sigma-1 receptor agonist may be A2-73 in the forms of A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, (+) A2- 73 enantiomer, or any combination thereof.
- the therapeutically effective amount of A2-73 comprises A2-73 in an amount of 0.5-100 mg per day, such 10-50 mg per day.
- the therapeutically effective amount of A2-73 can range from about 0.5 mg to about 20 mg, about 1 mg to about 60 mg, about 30 mg to about 50 mg, or about 3 mg to about 5 mg.
- the therapeutically effective amount of A2-73 can range from about 0.5 mg/day to about 100 mg/day, from about 1 to about 60 mg/day, from about 20 to about 50 mg/day, from about 20 to about 30 mg/day, or from about 15 to about 25 mg/day.
- Administering the anti-neurodegenerative effective amount of A2- 73 can provide blood levels of about 10 ng/ml, about 12 ng/ml of A2-73.
- A2-73 can be administered to the subject daily or more than once daily. Further, A2-73 can be administered every 2, 3, 4, 5, 6, 7, 14, or every 30 days. A2- 73 can be administered over a period ranging from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months. A2-73 can also be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some aspects, A2-73 is administered over a period of about 6 weeks, 8 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 57 weeks, about 148 weeks, about 208 weeks, indefinitely, or until resolution of the condition being treated.
- any biological samples suitable for transcriptome or gene analysis can be used in the present disclosure.
- suitable biological samples include fluid samples, biopsy samples, skin samples, and hair samples. Fluid samples may include blood, serum, plasma, saliva, tears, and lymph.
- the biological sample is a blood sample, a serum sample, a plasma sample or any transcroptomic sample. Methods of collecting a biological sample from a subject are well known in the art.
- Gene expression measurement includes both DNA and RNA measurements. They may be accomplished by a variety of methods including northern blotting, quantitative real-time PCR (qRT-PCR), nucleic acid microarrays, Luminex microspheres, and nuclease protection assay. Methods of determining a substantially different level of RNA expression are known in the art, and include distribution analysis. In some aspects, a substantially different level of RNA expression is determined by normalizing RNA expression values as Transcripts Per Kilobase Million (TPM).
- TPM Transcripts Per Kilobase Million
- the Al Modeling not only considers omics data, but also a broad range of other subjects’ data.
- data include, but not limited to, subject’s clinical diagnosis, co-morbidity, co-medication, age, weight, height, and gender.
- the Al Modeling used in the present disclosure also include trial data, such as doses received, dosing time points, endpoint assessment, and behavior impacts, such as sleep or cognition impacts. Thorough data collection and advanced algorithm, the Al Modeling in the present disclosure is able to generate and analyze over 24 million relationships and concludes with biomarkers with convincing confidence and p values.
- One aspect of the disclosure encompasses a pharmaceutical composition comprising a neurodegenerative agent and/or a Sigma-1 receptor agonist.
- a pharmaceutical composition comprises a therapeutically effective amount of an active pharmaceutical ingredient, and any pharmaceutically acceptable salt thereof.
- Pharmaceutically acceptable salts include, without limitation, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.
- a composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1g to about 5 g, or from about 0.5 g to about 3 g of A2-73.
- Formulations comprising A2-73 can be found in, e.g., U.S. Patent No. 9750746, U.S. Patent Publication No. 20170360798, U.S. Patent Publication No. 20190022052, U.S. Patent Publication No. 20180360796, U.S. Patent Publication No.
- the active pharmaceutical ingredient can be formulated and administered to a subject by several different means.
- a composition can generally be administered parenteraly, intraperitoneally, intravascularly, transdermally, subcutaneously, or intrapulmonarily in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection, or infusion techniques.
- Formulation of pharmaceutical compositions is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).
- a pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients.
- excipients include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof.
- excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.
- the active pharmaceutical ingredient can in general be formulated for improving patient compliance, preventing a subject from removing the drug-delivery device.
- Sigma-1 receptor agonists could be formulated for improved patient compliance and preventing removal of a drug-delivery device by providing formulations for extended delivery.
- Extended delivery can range for periods ranging from more than one day, to months. This may be especially relevant for patients with compromised cognitive and/or motor-control abilities. Extended delivery for periods can range from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months.
- Extended release formulations could be used for substantially continuous delivery of drug at a preselected rate.
- the drug can be delivered at a rate of from about 1 mg to about 100 mg/day, from about 40 to about 60 mg/day, or from about 10 to about 30 mg/day.
- Appropriate amounts of crystalline A2-73 can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the drug by the extended release formulation, the delivery mechanism, the particular formulation, and the relative potency of the drug among other factors.
- Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
- the polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.
- the binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art.
- the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.
- Non-limiting examples of diluents include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpyrrolidone (PVP).
- Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.
- Disintegrents can be effervescent or non-effervescent.
- non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
- Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
- Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, o-aminobenzoic acid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylened
- Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like.
- Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof.
- Other non-limiting examples of flavors include cinnamon oils, oil of Wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.
- Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low- substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and polyethylene glycol
- Non-limiting examples of sweeteners include glucose (com syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.
- glucose com syrup
- dextrose invert sugar
- fructose fructose
- mixtures thereof when not used as a carrier
- saccharin and its various salts such as
- the lubricant compositions may be utilized to lubricate ingredients that form a pharmaceutical composition.
- the lubricant facilitates removal of solid dosage forms during the manufacturing process.
- Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
- the pharmaceutical composition will generally comprise from about 0.01 % to about 10% by weight of a lubricant. In some aspects, the pharmaceutical composition will comprise from about 0.1 % to about 5% by weight of a lubricant. In a further aspect, the pharmaceutical composition will comprise from about 0.5% to about 2% by weight of a lubricant.
- Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants.
- HLB hydrophilic-lipophilic balance
- Suitable color additives include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. pH modifiers
- Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.
- a chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to metal ions, in order to inhibit the oxidative degradation of the morphinan by these oxidative groups.
- oxidative groups including but not limited to metal ions
- Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).
- An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi.
- microbial agents including but not limited to bacteria and fungi.
- Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.
- Release-controlling polymers may be included in the various aspects of the solid dosage pharmaceutical compositions incorporating compounds according to this disclosure.
- the release-controlling polymers may be used as a tablet coating.
- a releasecontrolling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold.
- Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.
- Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum,
- a solid dosage comprising a compound according to this disclosure may comprise a coating, wherein such a coating may control release of the compound, act as a moisture barrier, or buffer or modify pH.
- a “control releasing coat” or “controlled release coat” as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof.
- the coating when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of a compound according to this disclosure when applied to an uncoated dosage form.
- the control releasing coat can be designed such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the compound according to this disclosure, such as a “modified-release”, “controlled-release”, “sustained-release”, “extended-release”, “delayed-release”, “prolonged-release,” or combinations thereof.
- the “control releasing coat” may optionally comprise additional materials that may alter the functionality of the control releasing coat.
- moisture barrier is one which impedes or retards the absorption of moisture.
- Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition over time under highly humid conditions.
- the proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat.
- the moisture barrier may comprise an enteric and/or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer.
- the permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating.
- the moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation.
- Coating and matrix materials which may be used in accordance with the present disclosure are those known in the art for use in controlled-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols (i.e., acids and alcohols containing alkyl chains of at least 10 carbon atoms), for example aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, 12-hydroxystearl alcohol, glyceryl mono- or dipalmitate; glyceryl mono-, di- or tri stea rate; my
- the pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used in antacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; composite aluminum/magnesium compounds, for example AI2O3-6MgO CO2- 12H2O, (Mg6AI2(OH)16CO3-4H2O), MgO AI2O3-2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH- buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.
- a group of compounds usually used in antacid formulations for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate
- composite aluminum/magnesium compounds for example AI2O3-6Mg
- a pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (Gl) tract, e.g., the stomach or small intestine.
- Gl gastrointestinal
- the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the Gl tract.
- the coating is often called an “enteric coating”.
- a pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., EudragitTM); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate crotonic acid cop
- the term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like.
- the terms “comprising” and “including” as used herein are inclusive and/or open-ended and do not exclude additional, unrecited elements or method processes.
- the term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or items and those that do not materially affect the essential characteristics of the present disclosure.
- the term “gene” means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.
- expression includes but is not limited to one or more of the following: transcription of the gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce mature mRNA; mRNA stability; translation of the mature mRNA into protein (including codon usage and tRNA availability); and glycosylation and/or other modifications of the translation product, if required for proper expression and function.
- the term “differentially expressed gene” means expression levels of a gene in two experimental conditions or in two samples possess statistically significant difference or change.
- the terms “overrepresented” genes or gene clusters means genes from a predefined set are present more than expected.
- transcriptome analysis means to characterize transcriptional activity (coding and non-coding), focus on a subset of relevant target genes and transcripts, or profile thousands of genes at once to create a genetic profile.
- mutant means any heritable variation from the wild-type that is the result of a mutation, e.g., single nucleotide polymorphisms (“SNP”) and insertions/deletions.
- SNP single nucleotide polymorphisms
- mutant is used interchangeably with the terms “marker”, “biomarker”, and “target” throughout the specification.
- polynucleotide means any RNA or DNA, which may be unmodified or modified RNA or DNA.
- Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, RNA that is mixture of single- and double-stranded regions, and hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions.
- polynucleotide refers to triplestranded regions comprising RNA or DNA or both RNA and DNA.
- the term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons.
- polypeptide means any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
- Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
- Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
- Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well-known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
- the terms “disease”, “disorder” or “dysfunction” are used interchangeably in the present disclosure. They refer to any condition, disorder or disease manifested as one or more physiological, physical and/or psychological symptoms or dysfunctions for which treatment is desirable, and includes previously and newly identified diseases, disorders or dysfunctions on any organs, tissues or biological activities.
- the term “medical use” is any use or means related to restore, remedy, or preserve health orwell being of a subject.
- the term “subject” means that preferably the subject is a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like).
- domestic animals e.g., dogs, cats and the like
- farm animals e.g., cows, sheep, pigs, horses and the like
- laboratory animals e.g., cynomolgus monkey, rats, mice, guinea pigs and the like.
- the administration of an agent or drug to a subject or patient includes self-administration and the administration by another. It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean “substantial”, which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
- ANAVEX®2-73 (blarcamesine), an agonist of Sigma-1 receptor (SIGMAR1), has been shown mechanistically focusing on a new target relevant to Alzheimer’s disease, Parkinson’s disease, Parkinson’s disease with dementia, and other neurological diseases. SIGMAR1 activation is a compensatory mechanism to chronic CNS diseases.
- the direct occupancy of ANAVEX®2-73 at SIGMAR1 has been established using quantitative PET scan.
- ANAVEX®2-73 bladecamesine oral capsules in treating cognitive impairment in patients with Parkinson’s Disease with Dementia (PDD)
- PDD Parkinson’s Disease with Dementia
- FIG. 1 A phase 2 study, coded “ANAVEX®2-73- PDD-001 study” (FIG. 1), was conducted.
- the study was multi-center, randomized, double blind, placebo-controlled, parallel group with 3-arm.
- the study included a 2- week Screening/Baseline Observation Period and a 14-week Treatment Period (including a 2 week Titration Period), and a 2-week Safety Follow-Up Period.
- a total of 132 patients were enrolled in the study and were randomly assigned to three testing arms (FIG.1).
- ANAVEX2-73 High Dose arm 44 patients were given oral capsules of ANAVEX2-73 once daily in an escalating dose of 10 mg, 20 mg, 30 mg and 50 mg.
- ANAVEX2-73 Mid Dose arm 44 patients were given oral capsules of ANAVEX2-73 once daily in an escalating dose of 10 mg, 20 mg, and 30 mg.
- placebo group 44 patients were given placebo capsules.
- CDR Cognitive Drug Research
- CDR Cognitive Drug Research
- CDR Computerized Assessment System on Continuity of Attention
- Change from Baseline to End of Treatment in Continuity of Attention as measured by Cognitive Drug Research (CDR) Computerized Assessment System Continuity of Attention
- MDS-UPDRS Part III Total Score Motor Scores
- SDS- CL-25 [ Time Frame: 14 weeks ]
- Incidence of sleep disorders symptoms SDS-CL- 25
- DNA/RNA Sequencing included Cognitive Drug Research (CDR) Computerized Assessment System on Continuity of Attention; Change from Baseline to End of Treatment in Continuity of Attention as measured by Cognitive Drug Research (CDR) Computerized Assessment System Continuity of Attention; Number of participants
- the trial can also identify the effects of ANAVEX®2-73 on PD patients.
- the PDD-001 Phase 2 trial provided an opportunity to identify potential effects of ANAVEXO2-73 on both PD and PDD related endpoints.
- the trial enrolled 132 adults, ages 50-85, with PDD, and was successfully concluded in Sep 2020. Participants, recruited at multiple sites in Spain and Australia, were randomly assigned to one of two doses groups (with an escalating ANAVEX 2-73 dose up to 30 or 50 mg oral capsules) or to a placebo, once daily for 14 weeks (see FIG. 1 for details).
- the trial’s main goals were to assess the therapy’s safety and changes in patients’ cognitive function, measured using the cognitive drug research computerized assessment system — a test that looks at multiple cognitive skills, such as choice reaction time (choosing between similar objects), vigilance, and episodic memory (remembering new personal experiences or shared information).
- ANAVEX 2-73 use by patients also resulted in a significant increase in SIGMAR1 levels, a rise that was significantly associated with improvements in attention measures, and reductions in both MDS-UPDRS total and MDS-UPDRS Part III (motor scores). Overall, these data confirmed the therapy’s mechanism of action and supported SIGMAR1 as a biomarker of clinical response to ANAVEX 2-73.
- RNA sequencing was done to the collected 130 samples and the expression of 14,150 genes was measured.
- the genes were clustered together using WGCNA, starting from their correlation of TPM expression values across samples. Seventeen clusters with size ranging from 13 to 11 ,190 genes were obtained through this gene clusterisation.
- the TPM expression values of genes in clusters were then aggregated in a single “eigengene” for each cluster. This eigengene served as a representant of the overall dysregulation of the cluster.
- a cluster filtering was performed, wherein patients’ arm and dose information were taken into account based on mixed effect models.
- the eigengene was used as target variable of a linear mixed effect model with 3 covariates: ActualDose, Patient, and timepoint.
- the contrast ActualDose i.e. treated vs placebo were evaluated across all timepoints. P-values were obtained with Dunnett’s test.
- pathways with less than 4 genes in a cluster were removed, to compensate for the large variability of cluster size and corresponding variability of number of pathways identified in each clusters. The ratio between cluster size and number of pathways was calculated, and top 2 clusters were retained for further Analysis.
- Alzheimer disease 15/369 0.001
- Amyotrophic lateral sclerosis 14/364 0.001
- Huntington disease 13/306 0.001
- Prion disease 13/273 0.001
- Parkinson disease 12/249 0.001
- Diabetic cardiomyopathy 9/203 0.007
- Non-alcoholic fatty liver disease 8/155 0.006
- Oxidative phosphorylation 8/133 0.003
- Pathways database KEGG 2021 ;
- Pathways database KEGG 2021 ;
- RNAseq Whole Blood T ranscriptomics Analysis (RNAseq) of patients with Parkinson’s disease with dementia (PDD) was performed for the ANAVEXO2-73- PDD-001 study (FIG. 1) at two timepoints: Baseline and Week 14 (end of trial). All available RNA samples with RIN>41 (RNA integrity number, using 130 samples) were analyzed. The expression of 14,150 genes at these two timepoints were analyzed from both placebo and ANAVEXO2-73 treated patients.
- genes clusterization genes were clustered together using WGCNA1 (Weighted correlation network analysis. Correlation networks are being used in biology to analyze large, high-dimensional data sets), starting from their correlation of TPM2 expression (Transcript per million. TPM value represents a relative expression level that should be comparable between samples) values across samples: WGCNA created 17 clusters (size: 13 to 11 ,190 genes). Then, the cluster’s eigengene3 (one of a set of a genes matrix that tabulates the mRNA or gene expression of the genes across the sample) was used as summary of expression level of the cluster.
- WGCNA1 Weighted correlation network analysis. Correlation networks are being used in biology to analyze large, high-dimensional data sets
- cluster filtering the eigengene was used for each cluster as target variable of a linear mixed effect model with 3 covariates: Dose, patient, and timepoint. Clusters without significant (Dunnett’s test) contrasts between treated and placebo across all timepoints were filtered out. The ratio between cluster size and number of pathways was calculated and the top 2 clusters were eventually retained. In clusters biological description, each cluster’s functional interactions between the genes of the cluster were assessed using the STRING database (Edge score >0.150; no text mining edges). Genes that have no interaction with any other genes of the cluster were discarded, which led to a reduced cluster. Pathway enrichment analysis was performed on these reduced clusters. False Discovery Rate (FDR, adjustment for multiple testing with the Benjamini-Hochberg procedure) with adjustment for multiple testing (Benjamini-Hochberg procedure) was used to characterize pathway overrepresentation.
- FDR False Discovery Rate
- RNAseq ANAVEXO2-73 transcriptomics analysis
- PDD Parkinson’s disease with dementia
- Biological relevance of this gene network was assessed through pathway analysis and confirmed the impact of ANAVEX®2-73 treatment on pathways involved in neurodegenerative diseases, especially Alzheimer’s disease and Parkinson’s disease.
- ANAVEX® 2-73 over 70% of the genes are known to have biological interactions.
- Pathway enrichment analysis revealed that multiple neurodegenerative pathways, including Alzheimer’s disease and Parkinson’s disease were significantly (adjusted p-value ⁇ 0.005) enriched for these genes, as shown in FIG. 4B and FIG.
- the study identified a unique set of genes impacted by ANAVEX2-73 (blarcamesine) treatment.
- the genes were differentially expressed, and their respective expression was correlated to a range of neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phosphorylation, a disorder related to proteasome dysfunction, a disorder related to ribosome dysfunction, a disorder related to retrograde endocannabinoid signaling, a disorder related to cardiac muscle contraction.
- neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, diabetic cardiomyopathy, non-alcoholic fatty liver disease, a coronavirus disease, a disorder related to thermogenesis, a disorder related to oxidative phospho
- Results showed while genes were down-regulated in Alzheimer’s disease and Parkinson’s disease, ANAVEXO2-73 singularly impacted expression levels of these genes in multiple pathways by countering the pathological downregulation of genes in both Alzheimer’s (p ⁇ 0.005) and Parkinson’s disease (p ⁇ 0.005) and other degenerative diseases (p ⁇ 0.005) and these may represent additional potential biomarkers of disease pathology and response.
- Parkinson’s Disease is a highly heterogeneous multisystem disorder, some patients would progress to PDD.
- PD is the second most common neurodegenerative disorder where also cognitive impairment, such as characterized PDD, is common.
- the PDD-001 Phase 2 study incorporated endpoints related to both PD and PDD (FIG. 7), thus is capable of illustrating the potential effects of ANAVEXO2-73 on both PD and PDD.
- patients’ data, including sequence profiles and others, obtained from PDD-001 trial (FIG. 1) were further analyzed by Artificial Intelligence (Al) aided Computer Modeling (Al Modeling) to identify key new biomarkers.
- the Al Modeling considered a wide range of factors and/or variables, include clinical factors, Omics (genomics, proteomics, and phenomics), Actigraphy-sleep data, and interacted them variables such as time-points, doses and end-points.
- Clinical factors included clinical assessments, patient’s co-medications, age, gender, and weight.
- Omics refers to data on genomics, proteomics, and phenomics.
- Actigraphy data are sleep parameters and average motor activity over a period of days to weeks using a noninvasive accelerometer, such as one housed in a wristwatch. Time points used were baseline time, Week 8 and Week 14 postadministration. Doses included placebo dose, low, medium, and high doses.
- End points were clinical assessments based on MDS-UPDRS, genetic variant analysis and COMT as defined in the clinical trial. Through Al Modeling, 24,848,764 relationships were generated. Al Modeling identified three (3) biomarkers for patient selection. [0140] The three biomarkers identified are MS4A4A gene, and its single nucleotide polymorphism variants rs6591561 and rs1582763. These biomarkers displayed confidence* > 0.75, Lift* > 1.5, Fisher’s p ⁇ 0.05. Their concordant evolutions were observed with dose and with the subgroup levels improved outcome at respective dose, and effect, at least 2 treatment doses, 2 subgroup levels and 2 different evolutions for the endpoint.
- MS4A4A gene mutation functioned as a switch for microglia metabolism which correlated with disease progression in AD, PD and PDD.
- homeostatic microglia can transition to either a pro-inflammatory (Mic 1 ) or antiinflammatory (Mic 3) state.
- Mic 3 cells are themselves influenced by protective (green) and risk (red) SNPs in the MS4A4A locus, which push these cells into either a helpful, interferon-based response with efficient lipid metabolism (left), or a destructive inflammatory response that accumulates lipids (right).
- SNP rs6591561 a variant in the MS4A4A coding region that raises AD risk and was also present in nearly one-third of the cohort.
- This risk variant altered expression of 1 ,597 microglial genes, powering proinflammatory proteins such as cytokines, while suppressing interferon signaling and lipid metabolism genes. It lowered expression of MS4A4A itself. Therefore, rs6591561 was identified as a risk variant in MS4A4A.
- rs1582763 was found to be a protective variant in the MS4A4A locus, by promoting anti-inflammatory microglia. These microglia express interferons and metabolize lipids well. Different ANAVEXO2-73 response depending patients’ MS4A4A (rs6591561 ) carrier status in PDD-001 study was observed.
- a PD pivotal trial phase 3 was designed, reflecting sub-scores MDS- UPRDS grouped as Part I, II, III and IV.
- sample size analysis was conducted to detect the signal of both efficacy MDS-UPDRS Total score and efficacy MDS-UPDRS individual scores at Week 14.
- Sample sizes were computed with pwr package on R and are based on observed Cohen’s d effects sizes. Sample sizes were adjusted with the variant prevalence in the general population. This sample size may be used to detect the signal for MS4A4A rs6591561 Wild Type (excluding rs6591561 homozygous) cohort assuming the prevalence is similar to the prevalence in the general population (i.e. , 70%) as shown in TABLE 4.
- MDS- UPDRS score [Part II] demonstrated strongest response with MS4A4A Wild Type rs6591561 cohort (excluding rs6591561 homozygous mutation carriers). Detailed analysis and correlation of MDS-UPDRS score versus MS4A4A Wild Type rs6591561 cohort are to be conduct. It is likely that this selection gene [MS4A4A rs6591561 Wild Type (excluding rs6591561 homozygous)] might be also beneficial in other CNS indications using ANAVEX2-73.
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Abstract
La présente invention concerne des procédés de sélection individualisée, et de surveillance d'un traitement à l'aide d'un agent thérapeutique neurodégénératif tel qu'une thérapie par agoniste du récepteur Sigma-1 pour un sujet, sur la base de changements de l'expression de gènes pré-traitement et post-traitement. La présente invention concerne également des procédés pour évaluer l'état actuel ou le risque actuel d'un sujet dans le développement de troubles neurodégénératifs. L'invention concerne également des kits pour mettre en oeuvre les procédés.
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US202363523281P | 2023-06-26 | 2023-06-26 | |
US63/523,281 | 2023-06-26 |
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US20040137566A1 (en) * | 2001-12-10 | 2004-07-15 | Tedder Thomas F. | Identification of novel ms4a gene family members expressed by hematopoietic cells |
EP3746476A1 (fr) * | 2018-01-31 | 2020-12-09 | Alector LLC | Anticorps anti-ms4a4a et leurs procédés d'utilisation |
WO2019222754A1 (fr) * | 2018-05-18 | 2019-11-21 | Anavex Life Sciences Corp. | Méthode associée à l'agoniste sigma-1 optimisé de sélection et de traitement de répondeur |
WO2020018461A1 (fr) * | 2018-07-16 | 2020-01-23 | The University Of Virginia Patent Foundation | Compositions et méthodes pour le diagnostic et le traitement de maladies neurologiques |
EP3914071A4 (fr) * | 2019-01-23 | 2022-10-19 | The Regents of the University of California | Cellules rapporteurs de construction génomique humaine et modèles de souris pour cribler des agents thérapeutiques contre des gènes associés à une maladie exprimée par la microglie |
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