Kathy Steece-Collier, Margaret E Caulfield, Molly J Vander Werp, Scott J Muller, Jennifer A Stancati, Yaping Chu, Ivette M Sandoval, Timothy J Collier, Jeffrey H Kordower, Fredric P Manfredsson
{"title":"老年帕金森雄性和雌性猕猴壳膜CaV1.3-shRNA基因治疗的疾病改善和多维疗效","authors":"Kathy Steece-Collier, Margaret E Caulfield, Molly J Vander Werp, Scott J Muller, Jennifer A Stancati, Yaping Chu, Ivette M Sandoval, Timothy J Collier, Jeffrey H Kordower, Fredric P Manfredsson","doi":"10.1016/j.ymthe.2025.05.027","DOIUrl":null,"url":null,"abstract":"<p><p>There remain several unmet clinical needs in Parkinson's disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. Ca<sub>V</sub>1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against Ca<sub>V</sub>1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum. We report here unprecedented evidence that magnetic resonance imaging-guided intraputaminal AAV-Ca<sub>V</sub>1.3-shRNA in aged (25-29 years) male and female nonhuman primates with long-standing (8 months) advanced parkinsonian motor deficits results in a significant progressive reversal of functional deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-Ca<sub>V</sub>1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Last, AAV-Ca<sub>V</sub>1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 months), twice-daily, dose-escalation levodopa. The realization of these first-in-class multimodal gene therapy attributes in the clinic would represent a major therapeutic advancement for PD.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Disease-modifying, multidimensional efficacy of putaminal Ca<sub>V</sub>1.3-shRNA gene therapy in aged parkinsonism male and female macaques.\",\"authors\":\"Kathy Steece-Collier, Margaret E Caulfield, Molly J Vander Werp, Scott J Muller, Jennifer A Stancati, Yaping Chu, Ivette M Sandoval, Timothy J Collier, Jeffrey H Kordower, Fredric P Manfredsson\",\"doi\":\"10.1016/j.ymthe.2025.05.027\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>There remain several unmet clinical needs in Parkinson's disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. Ca<sub>V</sub>1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against Ca<sub>V</sub>1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum. We report here unprecedented evidence that magnetic resonance imaging-guided intraputaminal AAV-Ca<sub>V</sub>1.3-shRNA in aged (25-29 years) male and female nonhuman primates with long-standing (8 months) advanced parkinsonian motor deficits results in a significant progressive reversal of functional deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-Ca<sub>V</sub>1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Last, AAV-Ca<sub>V</sub>1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 months), twice-daily, dose-escalation levodopa. The realization of these first-in-class multimodal gene therapy attributes in the clinic would represent a major therapeutic advancement for PD.</p>\",\"PeriodicalId\":19020,\"journal\":{\"name\":\"Molecular Therapy\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":12.0000,\"publicationDate\":\"2025-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ymthe.2025.05.027\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.05.027","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Disease-modifying, multidimensional efficacy of putaminal CaV1.3-shRNA gene therapy in aged parkinsonism male and female macaques.
There remain several unmet clinical needs in Parkinson's disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. CaV1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against CaV1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum. We report here unprecedented evidence that magnetic resonance imaging-guided intraputaminal AAV-CaV1.3-shRNA in aged (25-29 years) male and female nonhuman primates with long-standing (8 months) advanced parkinsonian motor deficits results in a significant progressive reversal of functional deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-CaV1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Last, AAV-CaV1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 months), twice-daily, dose-escalation levodopa. The realization of these first-in-class multimodal gene therapy attributes in the clinic would represent a major therapeutic advancement for PD.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.