Nanoparticle-based therapy for photoreceptor degeneration



 DESCRIPTION (provided by applicant): By encapsulating therapeutic agents within biodegradable nanoparticles, it is possible to provide long-lasting delivery of molecules that are otherwise rapidly cleared or degraded. The purpose of this proposal is to continue evaluation and development of a nanoparticle platform with which to deliver antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) (nano-SOD/CAT) to treat retinal diseases. Oxidative damage mediated via reactive oxygen species (ROS) is an important driving force in photoreceptor degeneration as occurs in human retinal diseases such as retinitis pigmentosa (RP). We have found that "systemic delivery (intraperitoneal injection)" of nano-SOD/CAT significantly slows the rate of photoreceptor cell death in a widely used very aggressive model of human RP - the Pdeb6rd10 (rd10) mouse. To build upon these promising results, we will test the hypothesis that nano-SOD/CAT is effective in slowing the rate of photoreceptor cell death for many genetic forms of RP and can be developed as a chronic therapy to slow down disease progression. In Aim 1, we will define the optimal dose of nano-SOD/CAT, determine which treatment schedule provides the best results, and will also examine whether the beneficial effect of nano-SOD/CAT application is dependent upon the age (disease stage) when treatment begins. In all of these studies, we will evaluate retinal function using electroretinogram (ERG) recordings and retinal structure using light microscopy and by counting the number of cells undergoing apoptosis. In Aim 2, we will inhibit two pathways that play major roles in cellular events initiated by oxidative stress. These studies will use the same outcome measures as Aim 1, and will clarify the mechanism(s) by which nano-SOD/CAT mediated reduction in ROS leads to preservation of photoreceptors. In Aim 3, we will expand this research strategy to three additional mouse models. While human RP is caused by mutations in more than 50 genes, mutations in rhodopsin and peripherin/rds account for a sizeable fraction of affected patients. Therefore, we will determine whether nano-SOD/CAT will slow the degenerative phenotype in three mouse models for autosomal recessive or dominant RP due to Rho or Prhp2 mutations. These mouse models were chosen due to their underlying genetics and their distinct rates of photoreceptor cell loss, all of which are slower than that seen in the rd10 model. Aim 3 will thus provide important information about the general potential for nano-SOD/CAT to slow the rate of photoreceptor degeneration in multiple genetic forms of RP with distinct phenotypes which are also commonly seen in humans. Although nano-SOD/CAT will not correct the underlying genetic defect, significant disease slowing would be meaningful, by allowing affected patients, particularly children to retain useful vision for a substantially longer period of time and potentilly throughout their lifetime.