Therapies to lower gene expression in brain disease currently require chronic administration into the cerebrospinal fluid (CSF) by intrathecal infusions or direct intracerebral injections. Though well-tolerated in the short-term, this approach is not tenable for a life-time of administration. Nose-to-brain delivery of enriched chitosan-based nanoparticles loaded with anti-HTT siRNA was studied in a transgenic YAC128 mouse model of Huntington's Disease (HD). A series of chitosanbased nanoparticle (NP) formulations encapsulating anti-HTT small interfering RNA (siRNA) were designed to protect the payload from degradation "en route" to the target. Factors to improve production of effective nanocarriers of anti-HTT siRNA were identified and tested in a YAC128 mouse model of Huntington's disease. Four formulations of nanocarriers were identified to be effective in lowering HTT mRNA expression by at least 50%. Intranasal administration of nanoparticles carrying siRNA is a promising therapeutic alternative for safe and effective lowering of mutant HTT expression.

THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery. Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group. An enzyme-linked immunosorbent assay showed that the Aβ1–40 and 1–42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment. Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer’s disease-related cognitive performance.

No abstract

Background: Nanocarriers loaded with siRNA can be administered intranasally to provide a noninvasive, safe alternative to direct intracerebral or intrathecal infusions. Dual-function nanocarriers can also be designed to deliver several payloads that address different components of the pathological process. Aim: To design and test a hybrid nanocarrier with the capacity to lower Huntington's Disease gene ( HTT) expression and prevent or diminish inflammation. Methods: Novel hybrid nanoparticles were fabricated using a chitosan-based matrix core loaded with siRNA and an outer shell consisting of a lipid composition containing cannabidiol. Results: Incubation of hybrid nanoparticles in mesenchymal stem cell cultures obtained from a YAC128 transgenic mouse modeling Huntington's disease resulted in effective lowering of mutant HTT gene expression and reduced levels of expression of the proinflammatory cytokine IL-6. Conclusion: A novel hybrid nanocarrier system with dual actions is effective in lowering HTT gene expression and attenuating inflammatory processes.

No abstract