Identification and Therapeutic Targeting of Pathogenic Nucleic Acids in AMD

  • Kleinman, Mark (PI)

Grants and Contracts Details


Age-related macular degeneration (AMD) is an epidemic in the developed world and the leading cause of irreversible vision loss in people over 55 years old. The hallmark of the disease is the formation of subretinal deposits called drusen that induce inflammation, spur leaky choroidal vascular in-growth, and result in atrophy of overlying specialized retinal cell types. While the etiology of this disorder is likely multifactorial, the downstream signaling pathways by which critical photoreceptor and other trophic cellular architecture are destroyed may be convergent. Current therapies arrest the growth of choroidal neovascularization and fluid extravasation into the subretinal space, but there are inadequate pharmacologic approaches to address the irreversible loss of retinal pigment epithelium (RPE) in the atrophic form of the disease. In both human specimens and experimental models of atrophic AMD, we have identified specific molecular triggers including a toxic nucleic acid which uniformly induce RPE cell death. The work currently underway with the support of the Foundation Fighting Blindness is allowing me to gain expertise in next generation biomedical technologies in order to advance and translate scientific investigations into recently discovered molecular pathways in dry AMD and loss of the critical RPE cell layer which is required for optimal vision. In the past year, I have been able to successfully analyze several samples through advanced bioinformatics pipelines developed to detect and localize toxic non-coding RNA transcripts in a cell culture model of RPE apoptosis using massively parallel sequencing. The development of this pipeline is rigorous and critical to the correct and appropriate analyses of extremely high-quality RNA that has been prepared from normal and affected human eyes. We are correlating our next-generation sequencing results with Nanostring™ based transcriptomics and targeted arrays. Further work in proteomic signatures of non-coding RNA induced RPE cell death has also been performed resulting in a new map of this blinding disease that we are exploring in a targeted fashion with culture and animal models.
Effective start/end date7/1/11 → 6/30/15


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