Gene therapy mediated seizure suppression in Genetic Generalised Epilepsy: Neuropeptide Y overexpression in a rat model.

Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures. Three cohorts of GAERS were injected bilaterally into the thalamus (short term n = 14 and long term n = 8) or the somatosensory cortex (n = 26) with rAAV-NPY or rAAV-empty. EEG recordings were acquired weekly post-treatment and seizure expression was quantified. Anxiety levels were tested using elevated plus maze and open field test. NPY and NPY receptor mRNA and protein expression were evaluated using quantitative PCR, immunohistochemistry and immunofluorescence. Viral overexpression of human NPY in the thalamus and somatosensory cortex in GAERS significantly reduced the time spent in seizure activity and number of seizures, whereas seizure duration was only reduced after thalamic NPY overexpression. Human and rat NPY and rat Y2 receptor mRNA expression was significantly increased in the somatosensory cortex. NPY overexpression in the thalamus was observed in rAAV-NPY treated rats compared to controls in the long term cohort. No effect was observed on anxiety behaviour. We conclude that virally-mediated human NPY overexpression in the thalamus or somatosensory cortex produces sustained anti-epileptic effects in GAERS. NPY gene therapy may represent a novel approach for the treatment of patients with genetic generalised epilepsies.

Cardiovascular disease risk assessment in an Aboriginal community-controlled health service: comparing algorithms.

Aboriginal and Torres Strait Islander people have high rates of cardiovascular disease (CVD). The National Vascular Disease Prevention Alliance (NVDPA) CVD risk assessment algorithm is used for all Australians. The Central Australian Rural Practitioners Association (CARPA) algorithm used in the Northern Territory adds five percentage points to all NVDPA risk scores for Indigenous Australians. Information was extracted from an Aboriginal Community-Controlled Health Service for all Aboriginal and Torres Strait Islander regular clients aged 35-74 years without known CVD (n=1057). CVD risk scores were calculated using both algorithms. Prescription of lipid-lowering medications was assessed. Clients with high-risk scores were reviewed and recalled if required. CVD risk scores were calculated for 362 (34.4%) clients. Clients with high CVD risk comprised 17.7% (NVDPA) or 23.8% (CARPA), with most determined clinically. Clients with low CVD risk comprised 73.7% (NVDPA) or 47.2% (CARPA). More than 30% of those with high risk were not on lipid-lowering medications. Significant health and social issues affected treatment uptake. It is unclear which algorithm is most applicable; however, this service has decided to continue to use the NVDPA algorithm. Use of CVD risk assessment and management of high-risk clients could be increased in primary care.