The research in my laboratory has focused on developing therapies for inherited and age related diseases of the retina. Retinitis pigmentosa is the most common inherited form of blindness and affects approximately 60,000 people in the United States. It is associated with death of the light detecting photoreceptor cells in the retina. We are studying mutations that cause a dominantly inherited form of this disease. Dominant inheritance may indicate that a mutation confers some new toxic property to a protein or it may mean that the resultant protein can no longer fit in as part of a multi-subunit complex. One of the tools we employ to develop treatments for autosomal dominant retinitis pigmentosa (adRP) is non-coding RNA (described below) delivered by a viral vector derived from Adeno-Associated Virus (AAV). AAV has been particularly useful in delivering genes, including small RNAs, to many parts of the eye and brain. Unlike retroviruses, recombinant AAV does not insert into chromosomes, disrupting genes, but remains stable as an extrachromosomal genetic element.
Age related Macular Degeneration (AMD) is the leading cause of blindness among older adults in the United States and Europe. AMD robs affected individuals of central vision because it affects the macula where light is focused. In neovascular (wet) AMD, blood vessels grow into the center of the retina causing retinal detachment and scarring. In advanced dry AMD, photoreceptors die because of the failure of the retinal pigment epithelium (RPE). This layer of cells normally provides nutrients and oxygen to the photoreceptor cells, recycles the vitamin A derivative (11-cis retinal) needed to detect light, and removes waste products from the retina.
Our approach to therapy for AMD also employs AAV. In this case we delivery genes that block oxidative stress and inflammation that are known to damage the retinal pigment epithelium. We have developed viral vectors that produce secreted and cell penetrating peptides that either stimulate a set of enzymes that mitigate oxidative injury or block the activation of a complex called the inflammasome. Both approaches have shown benefit in acute models of retinal injury.
Gene therapy for retinal degeneration usually employs a sub-retinal injection, leading to transient detachment of the retina. This approach is technically challenging and poses great risk to an already diseased retina. Together with Dr. Qiuhong Li and Dr. Cristhian Ildefonso of the Department of Ophthalmology, we have developed a method to deliver virus to the vitreous humor of the eye, but have the therapeutic protein released and able to penetrate the target cells (photoreceptors and RPE) where treatment is required.
Developing RNA-Based Gene Therapies
Non-coding RNA (ncRNA) molecules do not encode proteins or stable RNAs (rRNA or tRNA) but appear to exert a major influence on the transcription and translation of messenger RNA (mRNA). We have been using several types of non-coding RNA, short interfering RNAs, microRNAs and ribozymes,to regulate gene expression in order to cure dominantly inherited diseases and viral infections. Scientists in my group are designing these small RNAs to block the synthesis of mutant RNAs that lead to disease and to block the spread of human herpes virus.
Postdoctoral Fellow, Biozentrum, University of Basel
Ph.D., University of Chicago
B.A., University of Chicago
Awards, Professional Service:
Junior Faculty Research Award, American Cancer Society
Established Investigator, American Heart Association
UF Research Foundation Professor, 2003
Jules Stein Living Tribute Award, Retinitis Pigmentosa International, 2003
Shaler-Richardson Professorship, 2004-present
Foundation Fighting Blindness, Board of Directors Award, 2011
BrightFocus Foundation, Elizabeth Anderson Macular Degeneration Research Award, 2015
Member, Advisory Panel on Cell Cycle and Growth Control, American Cancer Society, (1997-1998)
Member, NIH Genes, Genomes, and Genetics Study Section, 2004-2012
Member, NIH Diseases and Pathophysiology of the Visual System Study Section, 2012-2016
Editorial boards, Experimental Eye Research, Mitochondrion, Molecular Vision, PLoS One
BCH 7410 Advanced gene Regulation
GMS 5905 RNA interference and microRNAs
GMS 6121 Infectious Diseases
GMS 6905 BMS Laboratory Rotations
GMS 6971 Masters Research
GMS 7191 Research Conference
GMS 7979 Advanced Research
GMS 7980 Doctoral Research