Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(3), P. 319 - 319

Published: Feb. 29, 2024

Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer's disease (AD). has been demonstrated as a driver AD pathology cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting progression. However, commonly used aid medications are associated with increased risk AD, highlighting the need for aids novel mechanisms action. The endocannabinoid system holds promise potentially sleep-enhancing target. By using pharmacology genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) therapeutic target improve halt progression transgenic Tau P301S (PS19) model Tauopathy AD. We have recently shown that PS19 mice exhibit form dark phase hyperarousal early symptom precedes robust Acute FAAH inhibition PF3845 resulted immediate improvements behaviors male female mice, supporting suitable sleep-promoting Moreover, sustained drug dosing 5-10 days maintained sleep. To evaluate effect chronic possible strategy, generated FAAH-/- models. Counter our expectations, did not protect from progressive loss, neuroinflammation, Our results provide support therapies but further indicate complete loss activity detrimental.

Language: Английский

Analysis of hepatic lentiviral vector transduction; implications on preclinical studies and clinical gene therapy protocols.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 21, 2024

Lentiviral vector-transduced T-cells were approved by the FDA as gene therapy anti-cancer medications. Little is known about host genetic variation effects on safety and efficacy of lentiviral vector delivery system. To narrow this knowledge-gap, we characterized hepatic vectors across Collaborative Cross (CC) mouse reference population. For 24 weeks, periodically measured luciferase expression from in 41 CC strains. Hepatic splenic copy numbers determined. We report that strains showed highly diverse outcomes following delivery. first time, moderate correlation between strain-specific sleeping patterns transduction efficiency was observed. associated two quantitative trait loci (QTLs) with intra-strain variations phenotypes, which mechanistically relates to phenomenon metastable epialleles. An additional QTL kinetics transgene expression. Genes comprised above QTLs are potential targets personalize protocols. Importantly, identified open new directions characterizing continuous viral silencing HIV latency. Our findings suggest wide-range patient-specific vector-based should be expected. Thus, novel escalating dose-based clinical protocols considered.

Language: Английский