Gene therapy holds great promise for new treatments for many diseases. Despite great pre-clinical successes, few gene therapy treatments have been effective in patients. In this grant application, is proposed a new type of gene therapy system, namely morpholino-nanoparticles. Morpholinos are highly effective for suppressing gene expression and, notably, for suppressing microRNA function. The nanoparticles used will possess the following features: morpholinos attached using a dithiol bond that will be cleaved in endosomes;a polymer coating that can disrupt endosomes for morpholino release into the cytoplasm;PEG chains to allow a long circulation half-life;galactose targeting to hepatocytes;an iron core for MRI and TEM detection;and a fluorophore for fluorescence techniques. The iron oxide and fluorophore components of the nanoparticle allow for a theranostic Heart disease is the number one killer in the USA, and also leads to poor quality of life for those who suffer from it. High cholesterol levels lead to a higher likelihood a heart attack. While the class of drugs known as statins has been successful for lowering the cholesterol levels of many patients, there are still large populations for whom cholesterol levels are too high. In this application are proposed new methods for reducing cholesterol levels where nanoparticles deliver drugs called morpholinos that will shut down cholesterol production. We will focus on developing these morpholino-nanoparticle systems and evaluating their potential to reduce cholesterol levels.Public Health Relevance
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