New chemo-genetic gene therapy approach for treatment of parkinson's disease

By delivering the hM4Di mutant and quetiapine to a mouse model of Parkinson's disease, the neural activity in the STN brain region was regulated, overcoming the limitations of existing treatments in terms of targeting and side effects, and achieving safe and effective long-term therapeutic results.

CN120699131BActive Publication Date: 2025-12-09LIANGZHU LAB
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Patent Information

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

AI Technical Summary

Technical Problem

Existing treatments for Parkinson's disease suffer from insufficient targeting, numerous side effects, diminishing efficacy with long-term use, and high risks associated with invasive procedures, making it difficult to achieve safe, effective, and long-term therapeutic results.

Method used

The hM4Di mutant was delivered to the STN brain region of a mouse model of Parkinson's disease via adeno-associated virus. It was then combined with quetiapine or its derivatives to regulate abnormal neural activity and achieve targeted therapy.

Benefits of technology

It significantly improves motor impairment, balance, and motor coordination in Parkinson's disease mice, reduces abnormal neural activity in the target brain region, and has no obvious side effects. The effects can last from several hours to several months.

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Abstract

The application relates to the technical field of medicines, and discloses six adeno-associated virus (AAV) injection solutions carrying novel artificial chemical genetic receptor gene sequences and a combined chemical genetic scheme formed by the AAV injection solutions and a small-molecule agonist quinpirole. Compared with traditional chemical genetics, the application first uses the drug quinpirole with smaller clinical side effects as an activator to develop a novel chemical genetic system with lower drug risk. The system can effectively reduce the excitatory activity of neurons, avoid the drug risk brought by clozapine or other non-marketed traditional chemical genetic activators, and improve the feasibility of clinical transformation of the chemical genetic system. In the application of the novel or traditional chemical genetic system, the application first applies the combined treatment scheme to intervene in Parkinson's disease (PD), can inhibit the abnormal activity of STN and related circuits of PD patients, and significantly improves the symptoms of dyskinesia.
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Claims

1. A hM4Di mutant, wherein the amino acid sequence of the hM4Di mutant is shown as SEQ ID NO. 11 or SEQ ID NO.

14.

2. An isolated polynucleotide, comprising, 2. An isolated polynucleotide encoding the hM4Di mutant of claim 1.

3. An expression vector, characterized by, 3. An expression vector comprising the isolated polynucleotide of claim 2.

4. The expression vector of claim 3, wherein, 4. The expression vector of claim 3, wherein the expression vector comprises a promoter, and the promoter comprises any one or more of a neuronal specific promoter hSyn or a variant thereof.

5. The expression vector of claim 4, wherein, 5. The expression vector of claim 3 or 4, wherein the promoter is a hSyn promoter.

6. The expression vector of claim 4, wherein, 6. The expression vector of claim 3 or 4, wherein the promoter is upstream of the hM4Di mutant gene.

7. The expression vector of claim 4, wherein, 7. The expression vector of claim 3 or 4, wherein the nucleotide sequence of the promoter hSyn is shown as SEQ ID NO.

1.

8. An adeno-associated viral expression system, characterized in that, 8. An expression system comprising the expression vector or genome integrated with the exogenous polynucleotide of claim 2.

9. The adeno-associated virus expression system of claim 8, wherein, 9. The expression system of claim 8, wherein the host cell of the expression system is selected from a eukaryotic cell or a prokaryotic cell.

10. The adeno-associated virus expression system of claim 8, wherein, 10. The expression system of claim 8 or 9, wherein the host cell of the expression system is HEK293.

11. A recombinant adeno-associated virus obtained by the adeno-associated virus expression system of any one of claims 8 to 10.

12. The recombinant adeno-associated virus of claim 11, wherein, 12. The recombinant adeno-associated virus of claim 11, wherein the serotype of the recombinant adeno-associated virus is selected from AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 or AAV13.

13. The recombinant adeno-associated virus of claim 11 or 12, wherein the recombinant adeno-associated virus specifically targets a tissue and / or a cell of the central nervous system, and the cell of the central nervous system is selected from an excitatory neuron and / or an inhibitory neuron, and the tissue of the central nervous system is selected from at least one of the following tissue types: thalamus, cortex, hypothalamus, amygdala, midbrain, spinal cord or cerebellum.

14. A pharmaceutical composition comprising a first drug comprising the recombinant adeno-associated virus of claim 11 or 12 and a pharmaceutically acceptable carrier or excipient.

14. The pharmaceutical composition of claim 13, wherein 15. The pharmaceutical composition of claim 14, wherein the first drug is an injection type drug for administration to a brain region.

15. The pharmaceutical composition of claim 13, wherein 16. The pharmaceutical composition of claim 14 or 15, wherein the first drug is an injection type drug for administration to a pre-supplementary motor area or a subthalamic nucleus.

16. The pharmaceutical composition of claim 13, wherein 17. The pharmaceutical composition of any one of claims 14 to 16, further comprising a second drug, and the second drug is a chemical genetics receptor agonist.

17. The pharmaceutical composition of claim 16, wherein, 18. The pharmaceutical composition of claim 17, wherein the chemical genetics receptor agonist is any one or more of clozapine, clozapine-N-oxide, quetiapine, dechloroclozapine or a derivative thereof.

18. The pharmaceutical composition of claim 16, wherein, 19. The pharmaceutical composition of claim 17 or 18, wherein the administration mode of the second drug is selected from oral, intramuscular, subcutaneous, intravenous or implantation.

19. The pharmaceutical composition of claim 16, wherein 20. Use of the hM4Di mutant of claim 1, the polynucleotide of claim 2, the expression vector of any one of claims 3 to 7, the recombinant adeno-associated virus of claim 11 or 12, or the pharmaceutical composition of any one of claims 13 to 19 in the manufacture of a product having one or more of the following functions: 1) reducing neuronal excitability; 2) preventing and / or treating a nervous system disease; 3) reducing abnormal neural activity in a target brain region.

21. The nervous system disease of claim 20 is selected from Parkinson's disease and Parkinsonism.

21. The use according to claim 20, characterized in that, ​

Citation Information

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