Key Features in the Design and Function of Nanocarriers for Intranasal Administration of Gene Therapy in Huntington Disease.

A major obstacle to fulfilling the therapeutic promise of gene therapies for hereditary brain diseases, such as Huntington' Disease (HD), is the requirement for viral vectors and/or an invasive delivery system (stereotaxic injection into brain or infusion into the intrathecal space). HD is an autosomal dominant neurodegenerative disease for which several clinical trials have demonstrated gene-lowering effects following intrathecal administration. These technical limitations have given impetus to the development of alternative non-invasive delivery systems for gene therapy of brain diseases.

Multi-Targeting Intranasal Nanoformulation as a Therapeutic for Alzheimer's Disease.

Melatonin, insulin, and Δ9-tetrahydrocannabinol (THC) have been shown to reverse cognitive deficits and attenuate neuropathologies in transgenic mouse models of Alzheimer's disease (AD) when used individually. Here, we evaluated the therapeutic properties of long-term intranasal treatment with a novel nanoformulation containing melatonin, insulin, and THC in aged APPswe/PS1ΔE9 (APP/PS1) mice, a transgenic model of AD. Transgenic mice at the age of 12 months were intranasally administered with a new nanoformulation containing melatonin, insulin, and THC at doses of 0.

Measurement of ΔTHC and metabolites in the brain and peripheral tissues after intranasal instillation of a nanoformulation.

Background: Comparative bioavailability of cannabinoids following their administration by dosing routes has been studied previously, but there are no quantitative reports of distribution of ΔTHC, nor its metabolites, across various brain regions following intranasal (i.n.) administration.

The Memory Benefit to Aged APP/PS1 Mice from Long-Term Intranasal Treatment of Low-Dose THC.

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.

Dual-function hybrid nanoparticles with gene silencing and anti-inflammatory effects.

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. To design and test a hybrid nanocarrier with the capacity to lower Huntington's Disease gene () expression and prevent or diminish inflammation.

Data on enrichment of chitosan nanoparticles for intranasal delivery of oligonucleotides to the brain.

Data on preparation and characterization of chitosan-based nanoparticles (NP) carrying small interfering RNA (siRNA) for non-invasive gene therapy is presented. Polyelectrolyte complexation method was carried out in diluted concentrations to obtain relatively small (less than 200 nm) NP. To provide substantial dose of siRNA within tolerable volume of intranasal administration the NP were subjected to enrichment process.

Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington's disease gene expression following intranasal administration.

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).

Optimizing Nanoparticle Design for Gene Therapy: Protection of Oligonucleotides from Degradation Without Impeding Release of Cargo.

Gene therapy delivery systems that rely on synthetic nanocarriers can be optimized by assays of nucleic acid protection and kinetic studies of nucleic acid release. These empirical measurements ensure nanoparticle stability and predict potential efficacy. Quantitative methods for assessment of the capacity of nanoparticles to protect oligonucleotide cargo and to measure the rate of release of the cargo were developed and tested based on six commercial cationic matrices.