Novel chemogenetics gene therapy regimen for treating Parkinson's disease

By delivering the hM4Di mutant and quetiapine to regulate the neural activity in the STN brain region of Parkinson's disease mice, the problems of insufficient targeting and invasiveness of existing treatments were solved, and a safe, effective and long-term treatment effect was achieved.

CN120699131AActive Publication Date: 2025-09-26LIANGZHU LAB
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Patent Information

Application Number
CN202511220876.1
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2024-12-04
Filing Date
2025-08-29
Publication Date
2025-09-26
Estimated Expiration
2045-08-29

AI Technical Summary

Technical Problem

Existing treatments for Parkinson's disease lack targeting, have significant side effects, and risk of diminished efficacy and dose-dependent toxicity with long-term use. Deep brain stimulation surgery is also highly invasive and difficult to maintain, making it difficult to balance safety and long-term effectiveness.

Method used

The hM4Di mutant is delivered to the STN brain region of the Parkinson's disease mouse model via adeno-associated virus, and combined with quetiapine or its derivatives to achieve targeted regulation of abnormal neural activity, reduce neuronal excitability and reduce abnormal neural activity.

Benefits of technology

It significantly improves the movement disorders, balance ability and motor coordination of Parkinson's disease mice without obvious side effects, has reliable long-term effects, and avoids the risks of electrode implantation and drug resistance.

✦ Generated by Eureka AI based on patent content.

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Abstract

The invention relates to the technical field of medicines, and discloses six adeno-associated virus (AAV) injections carrying novel artificial chemical genetics receptor gene sequences, and a combinatorial chemical genetics scheme formed by the injections and a small molecule agonist quetiapine. Compared with the traditional chemical genetics, the medicine quetiapine with smaller clinical side effect is used as the activating agent for the first time, and a novel chemical genetics system with lower medication risk is developed. The system can effectively reduce the excitatory activity of neurons, avoids the medication risk caused by clozapine or other non-market traditional chemical genetics activators, and improves the feasibility of clinical transformation of the chemical genetics system. In the aspect of application of a novel or traditional chemical genetics system, the combined treatment scheme is applied to intervene in Parkinson's disease (PD) for the first time, abnormal activities of STN and related loops of PD patients can be inhibited, and the dyskinesia symptom can be remarkably improved.
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Claims

1. An hM4Di mutant comprising an amino acid mutation site Y439A relative to wild-type hM4Di.

2. The hM4Di mutant according to claim 1, wherein The wild-type hM4Di amino acid sequence is shown in SEQ ID NO. 9; And / or, relative to wild-type hM4Di, the hM4Di mutant further comprises an amino acid mutation site W435A.

3. The hM4Di mutant according to claim 1 or 2, characterized in that The amino acid sequence of the hM4Di mutant is shown in SEQ ID NO.11 or SEQ ID NO.

14.

4. An isolated polynucleotide, characterized in that It encodes the hM4Di mutant according to any one of claims 1 to 3.

5. An expression vector, characterized in that The expression vector contains the isolated polynucleotide according to claim 4.

6. The expression vector according to claim 5, wherein The expression vector contains a promoter, which includes any one or more of the neuron-specific promoter hSyn or its variants.

7. The expression vector according to claim 6, wherein The promoter is hSyn promoter.

8. The expression vector according to claim 6, wherein The promoter is located upstream of the hM4Di mutant gene.

9. The expression vector according to claim 6, wherein The nucleotide sequence of the promoter hSyn is shown in SEQ ID NO.

1.

10. An adeno-associated virus expression system, characterized in that: The expression system comprises the expression vector according to any one of claims 5 to 9 or the exogenous polynucleotide according to claim 3 integrated into the genome.

11. The adeno-associated virus expression system according to claim 10, wherein The host cells of the expression system are selected from eukaryotic cells or prokaryotic cells.

12. The adeno-associated virus expression system according to claim 10, wherein The host cell of the expression system is HEK293.

13. A recombinant adeno-associated virus, wherein the recombinant adeno-associated virus is obtained by viral packaging using the adeno-associated virus expression system according to any one of claims 10 to 12.

14. The recombinant adeno-associated virus according to claim 13, wherein The serotype of the recombinant adeno-associated virus is selected from AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 or AAV13; And / or, the recombinant adeno-associated virus specifically targets tissues and / or cells of the central nervous system, the cells of the central nervous system are selected from excitatory neurons and / or inhibitory neurons, and the tissues of the central nervous system are selected from at least one of the following tissue types: thalamus, cortex, hypothalamus, amygdala, midbrain, spinal cord or cerebellum.

15. A pharmaceutical composition comprising a first drug, wherein the first drug comprises the recombinant adeno-associated virus according to claim 13 or 14 and a pharmaceutically acceptable carrier or excipient.

16. The pharmaceutical composition according to claim 15, wherein The first drug is an injectable drug targeted for administration to the brain region.

17. The pharmaceutical composition according to claim 15, wherein The first drug is an injectable drug targeted at the anterior cingulate cortex or the subthalamic nucleus.

18. The pharmaceutical composition according to claim 17, wherein The injection method is bilateral anterior cingulate cortex brain area or subthalamic nucleus injection, and the coverage rate of the first drug in the subthalamic nucleus is greater than 30%.

19. The pharmaceutical composition according to claim 15, wherein The pharmaceutical composition also includes a second drug comprising a chemogenetic receptor agonist.

20. The pharmaceutical composition according to claim 19, wherein The chemogenetic receptor agonist includes any one or more of clozapine, clozapine-N-oxide, quetiapine, desclozapine or their derivatives.

21. The pharmaceutical composition according to claim 19, wherein The second drug administration method is selected from any one of oral, intramuscular, subcutaneous, intravenous or implantation.

22. The pharmaceutical composition according to claim 19, wherein The second drug is an oral drug or an intraperitoneal injection drug.

23. Use of the hM4Di mutant according to any one of claims 1 to 3, the polynucleotide according to claim 4, the expression vector according to any one of claims 5 to 9, the recombinant adeno-associated virus according to any one of claims 10 to 12, the pharmaceutical composition according to any one of claims 15 to 22, or quetiapine in the preparation of a product having one or more of the following functions: 1) Reduce neuronal excitability; 2) Prevention and / or treatment of neurological diseases; 3) Reduce abnormal neural activity in the target brain area.

24. The use according to claim 23, characterized in that The nervous system diseases include Parkinson's disease and Parkinson's syndrome.

25. A method for treating Parkinson's disease, comprising administering to an individual with Parkinson's disease a therapeutically effective amount of the hM4Di mutant according to any one of claims 1 to 3, the polynucleotide according to claim 4, the expression vector according to any one of claims 5 to 9, the recombinant adeno-associated virus according to any one of claims 10 to 12, the pharmaceutical composition according to any one of claims 15 to 22, or the product for use according to claim 23 or 24.

26. The method of claim 25, wherein: The method administers a first drug of the pharmaceutical composition to an individual with Parkinson's disease; And / or, the method causes the hM4Di mutant to be expressed in the brain region of the Parkinson's disease individual; And / or, the method is to inject the second drug in the pharmaceutical composition 2 to 4 weeks after injecting the first drug in the pharmaceutical composition.

27. The method of claim 25, wherein: The method administers a first drug of the pharmaceutical composition to an individual with Parkinson's disease using an intracranial injection device; And / or, the method allows the hM4Di mutant to be expressed in the anterior cingulate cortex or subthalamic nucleus of the Parkinson's disease individual.

28. The method of claim 25, wherein: The method uses a microsyringe to administer the first drug in the pharmaceutical composition to an individual with Parkinson's disease.

Citation Information

Patent Citations

  • Quetiapine fumarate tablet drug composition and preparation method thereof

    CN109001353A

  • Analysis method for determining releasing rate of quetiapine fumarate sustained release tablet

    CN110133134A

  • Gene therapy methods to control organ function

    CN113301956A

  • Preparation for treating Parkinson's disease and application thereof

    CN113398244A

  • Combined use of a vector encoding a modified receptor and its exogenous agonist in the treatment of seizures

    US20160375097A1

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