Dataset Information

Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.

ABSTRACT: Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.

SUBMITTER: Martier R

PROVIDER: S-EPMC7530328 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.

Martier Raygene R Konstantinova Pavlina P

Frontiers in neuroscience 20200918

Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene ...[more]

PMID: 33071748

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Project description:Purpose: evaluation of the neuroprotective effects of VU846 compound, a positive allosteric modulator highly specific for the M1 muscarinic receptor, using the Next-generation sequencing (NGS) technology in a context of neurodegeneration induced by prion disease. Methods: Tg37 hemizygous mice at 3 to 4 weeks were inoculated with either the Rocky Mountain Laboratory (RML) scrapie prion brain homogenate, causative of the neurodegeneration, or normal brain homogenate for control purposes. Mice were also daily injected with either the M1 specific positive allosteric modulator VU836 or vehicle. The drug treatment started at 7week post brain homogenate inoculations (wpi) and 11wpi. The hippocampi from 3 mice of each group (control + vehicle, control + VU846, prion + vehicle and prion + VU846) were subject to tot RNA extraction. Raw reads were then converted into Fastq format, mapped to the “mouse-mm10” genome using HISAT2 (Galaxy Version 2.1.0) and processed with the StringTie (Galaxy Version 1.3.3.2) for assembling and quantification. Differential gene expression comparisons were performed with DESeq2 statistical tool (Galaxy Version 2.11.40.2) and data further analysed with two online software suites, Gene Ontology Panther (http://www.pantherdb.org/) and Pathway Studio (www.pathwaystudio.com). Results: we use the bioinformatic tool Pathway Studio (www.pathwaystudio.com) to quantitatively assesses the changes in the transcriptome with gene functions reported in the literature to assign an actication score. Strikingly, up and down regulation of genes changed by prion disease promote neuroinflammation and Alzheimer’s disease (AD) (positive activation scores), whereas the M1R specific positive allosteric modulator VU846 treatment modified the expression of genes to inhibit the neuroinflammatory and neurodegenerative processes directly associated with AD (negative activation score). Among these are genes associated with the complement system, microglia and astrocyte activation. Furthermore, consistent with the notion that neuroinflammatory pathways were activated in prion disease and diminished by VU846, the GO Pathway analysis revealed enrichment of genes in pathways such as the complement cascade and chemokine/cytokine signalling. Conversely, a group of genes that were down-regulated in prion disease were transcribed at significantly higher levels in the prion-effect of animals treated with VU846. These genes were strongly associated with synaptic plasticity, learning and memory, cognition and synaptic transmission by the GO Pathway analysis. Conclusions: These data point to the possibility that specific features of neuroinflammation and disease-adaptation may be directly regulated by M1-receptor activity strongly reinforcing the concept that pharmaceutically targeting M1 muscarinic receptor is neuroprotective and it might lead to the development of new treatments of Alzheimer’s like neurodegenerative diseases.

Project description:Understanding the determinants of timely antiretroviral therapy (ART) initiation is useful for HIV programmes intent on developing models of care that reduce delays in treatment initiation while maintaining a high quality of care. We analysed patient- and facility-level determinants of time to ART initiation among patients who initiated ART in Kenya.We collected facility-level information and conducted a retrospective chart review of adults initiating ART between 2007 and 2012 at 51 health facilities in Kenya. We evaluated the association between patient- and facility-level covariates at the time of ART eligibility and time to ART initiation. We also explored the determinants associated with timeliness of ART initiation.The analysis included 11,942 patients. The median age at the time eligibility was first determined was 37 years (interquartile range [IQR] 31-45). Overall, 75% of patients initiated ART within two months of eligibility. The median CD4 cell count at the time eligibility was first determined rose from 132 (IQR 51-217) in 2007 to 195 (IQR 91-286) in 2011 to 2012 (p<0.001). The cumulative probability of ART initiation among treatment-eligible patients increased over time: 87.1% (95% confidence interval [CI] 85.1-89.0%) in 2007; 96.8% (96.0-97.5%) in 2008; 97.1% (96.3-97.7%) in 2009; 98.5% (98.0 -98.9%) in 2010; and 99.7% (95% CI 99.4 -99.8%) in 2011 to 2012 (p<0.0001). In multivariate analyses, attending a health facility with high ART patient volumes within two months of eligibility was considered the key facility-level determinant of ART initiation (adjusted odds ratio 0.57, 95% CI 0.45-0.72, p<0.001). Patient-level determinants included being eligible for ART in the years subsequent to 2007, advanced World Health Organization clinical stage and low CD4 cell count at the time eligibility was first determined.Overall, the time between treatment eligibility and ART initiation decreased substantially in Kenya between 2007 and 2012, with uniform gains across different types of health facilities. Our findings highlight the slow increase in CD4 cell counts at the time of ART eligibility over time, indicating that a large number of patients are still beginning ART with advanced HIV disease. Our findings also support the decentralisation of ART services at all health facilities that have the capacity to initiate treatment. Continued evaluation of programme- and country-level data is needed to monitor timeliness of ART initiation as countries continue to expand treatment access.

Dataset Information

Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.

Publications

Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock.

Similar Datasets

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