Novel chemogenetics gene therapy regimen for treating Parkinson's disease
By using a combination of hM4Di mutant and quetiapine derivatives in a Parkinson's disease model, targeted neuromodulation was achieved in PD mice, overcoming the limitations of existing treatments in terms of targeting and invasiveness, significantly improving motor symptoms and reducing side effects.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-29
- Publication Date
- 2026-03-20
AI Technical Summary
Existing treatments for Parkinson's disease, such as drug therapy, suffer from insufficient targeting, leading to widespread side effects. Long-term use can result in diminishing efficacy and dose-dependent toxicity risks. Deep brain stimulation surgery, on the other hand, involves invasive procedures that may cause brain tissue damage and a long-term management burden.
The hM4Di mutant was delivered to the STN brain region of a PD mouse model via adeno-associated virus and combined with quetiapine or clozapine derivatives to achieve targeted regulation of abnormal neural activity, reduce neuronal excitability and decrease abnormal neural activity.
It significantly improves motor dysfunction, balance, and motor coordination in PD mice without significant brain damage, providing a safe, reversible, and immediate therapeutic effect.
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Figure CN121698989A_ABST
Abstract
Claims
1. An hM4Di mutant, relative to wild-type hM4Di, wherein the hM4Di mutant includes an amino acid mutation site W435G.
2. The hM4Di mutant as described in claim 1, characterized in that, The amino acid sequence of the wild-type hM4Di is shown in SEQ ID NO. 9; And / or, relative to wild-type hM4Di, the hM4Di mutant also includes the amino acid mutation site Y439G.
3. The hM4Di mutant as described in claim 1 or 2, characterized in that, The amino acid sequence of the hM4Di mutant is shown in SEQ ID NO.12 or SEQ ID NO.
15.
4. An isolated polynucleotide, characterized in that, Its encoding is the hM4Di mutant as described in any one of claims 1 to 3.
5. An expression carrier, characterized in that, The expression vector contains the isolated polynucleotide as described in claim 4.
6. The expression vector as described in claim 5, characterized in that, The expression vector contains a promoter, which includes any one or more of the neuron-specific promoter hSyn or its variants. Preferably, the promoter is the hSyn promoter. More preferably, the nucleotide sequence of the hSyn promoter is shown in SEQ ID NO.
1.
7. The expression vector as described in claim 6, characterized in that, The promoter is located upstream of the hM4Di mutant gene.
8. An adeno-associated virus expression system, characterized in that, The expression system contains an expression vector as described in any one of claims 5 to 7 or a genome in which an exogenous polynucleotide as described in claim 4 is integrated.
9. The adeno-associated virus expression system as described in claim 8, characterized in that, The host cell of the expression system is selected from eukaryotic cells or prokaryotic cells, preferably HEK293.
10. A recombinant adeno-associated virus, wherein the recombinant adeno-associated virus is obtained by viral packaging using the adeno-associated virus expression system of claim 8 or 9.
11. The recombinant adeno-associated virus as described in claim 10, characterized in that, 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, wherein 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.
12. A pharmaceutical composition comprising a first drug, the first drug comprising the recombinant adeno-associated virus as described in claim 10 or 11 and a pharmaceutically acceptable carrier or excipient.
13. The pharmaceutical composition according to claim 12, characterized in that, The first drug is an injectable drug that targets brain regions. Preferably, the first drug is an injectable drug that targets the anterior cingulate cortex or the subthalamic nucleus. More preferably, the first drug is injected bilaterally into the anterior cingulate cortex or the subthalamic nucleus, and the coverage of the first drug in the subthalamic nucleus is greater than 30%.
14. The pharmaceutical composition according to claim 12, characterized in that, The pharmaceutical composition further includes a second drug comprising a chemogenetic receptor agonist, preferably one or more of clozapine, clozapine-N-oxide, quetiapine, desclozapine, or derivatives thereof.
15. The pharmaceutical composition according to claim 14, characterized in that, The second drug administration method is selected from any one of oral, intramuscular, subcutaneous, intravenous, or implantation.
16. The pharmaceutical composition of claim 14, characterized in that, The second drug is an oral drug or an injectable drug administered intraperitoneally.
17. Use of the hM4Di mutant as described in any one of claims 1 to 3, the polynucleotide as described in claim 4, the expression vector as described in any one of claims 5 to 7, the recombinant adeno-associated virus as described in claim 10 or 11, the pharmaceutical composition as described in any one of claims 12 to 16, 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 disorders; 3) Reduce abnormal neural activity in the target brain region.
18. The use as described in claim 17, characterized in that, The neurological disorders include Parkinson's disease and Parkinson's syndrome.