Accelerating Breakthrough Discoveries into Medicines

2015 Gund-Harrington Scholars

Konstantin Petrukhin, PhD

Konstantin Petrukhin, PhD

Dr. Petrukin’s current research focuses on characterizing new pharmacological treatments for Stargardt disease and age-related macular degeneration.

Konstantin Petrukhin, Ph.D. serves as an Associate Professor of Ophthalmic Sciences (in Ophthalmology) at the Columbia University Medical Center.

Stargardt disease (STGD) is the most common form of inherited juvenile-onset macular dystrophy with an estimated prevalence of 1:10,000 in the general population. There is no proven therapy for Stargardt disease. Experimental and clinical data indicate that dramatic accumulation of cytotoxic lipofuscin aggregates in the retina is responsible for the photoreceptor death and severe vision loss in patients with Stargardt disease.

Inhibition of bisretinoid synthesis in the retina is a valid strategy for the STGD treatment. Biosynthesis of lipofuscin bisretinoids is fueled by the influx of serum retinol (vitamin A) from circulation to the retina. Partial pharmacological reduction of vitamin A delivery to the retina represents a target area in the STGD treatment. Serum vitamin A is transported to the retina by the delivery protein called Retinol-Binding Protein 4, RBP4.

In previous studies, Dr. Petrukhin and his team identified a new class of RBP4 antagonists that can reduce the uptake of serum retinol to the retina and inhibit the formation of cytotoxic bisretinoids in the mouse model of Stargardt disease. As a result of this research, they identified a lead compound that can serve as a starting point in developing a treatment for Stargardt disease.

Dr. Petrukhin received his Ph.D. in Bioorganic Chemistry from the Institute of Bioorganic Chemistry in Moscow, Dr. Petrukhin became a postdoctoral research scientist in the Department of Psychiatry, Columbia University and Assistant Professor of Clinical Neuroscience, studying human genetics and neuropsychiatry. His work led to the discovery of the Wilson disease gene. In 1996, Dr. Petrukhin was recruited by Merck Research Laboratories to lead the genetic research in the field of ophthalmic disorders. Dr. Petrukhin held positions of increasing importance at Merck and served as a head of the Department of Ophthalmics Research while chairing several research and licensing committees. In 2006 he rejoined the faculty of the Columbia University Medical Center, bringing his extensive experience and expertise to bear on the problem of Stargardt disease.

Albert La Spada, MD, PhD

Albert La Spada, MD, PhD

Dr. La Spada’s translational research in pursuit of therapeutic agents for spinocerebellar ataxia type 7 (SCA7) could lead to a therapy for all retinal disease resulting from toxic protein production.

Albert La Spada, MD, PhD is Professor and Division Head of Genetics in Pediatrics and Cellular & Molecular Medicine at the University of California, San Diego (UCSD), and is a founding faculty member of the UCSD Institute for Genomic Medicine.

Since the expression of toxic ataxin-7 protein drives all subsequent disease pathology in SCA7, the most attractive therapeutic paradigm for these diseases is to terminate the expression of the mutant gene product. Dr. La Spada and his team are implementing ataxin-7 “gene silencing” using a strategy that has already been successfully applied to reduce the expression of a toxic protein: oligonucleotide knock-down, based upon two related, but distinct experimental strategies.

To achieve the goals of this translational research program, they have created an academic-industrial-clinical partnership. In collaboration with ISIS Pharmaceuticals, Dr. La Spada’s team will pursue a two-pronged strategy to develop reagents for ataxin-7 gene “knock-down”, whereby the expression of the toxic disease protein in the eye will be reduced. In parallel with ataxin-7 knock-down drug production and evaluation in rodents, they are initiating a clinical natural history study of SCA7 retinal degeneration in collaboration with Dr. Brian Brooks, Chief of the Ophthalmic Genetics & Visual Function Branch of the National Eye Institute (NEI), with the goal of tracking the progression of SCA7 cone-rod dystrophy retinal degeneration in at least 20 patients over the course of 5 years.

If successful, this study will define the best outcome measures for tracking SCA7 retinal disease progression and will lead to a clinical trial. 

Dr. La Spada graduated Summa Cum Laude from the University of Pennsylvania with a degree in Biology in 1986. As a recipient of a Medical Scientist Training Program award, he pursued combined M.D. - Ph.D. training at the University of Pennsylvania School of Medicine. Dr. La Spada is the recipient of numerous grants and awards from the National Institutes of Health, Howard Hughes Medical Institute, Muscular Dystrophy Association, Hereditary Disease Foundation, CHDI, Coulter Foundation, and American Federation for Aging Research. Among his funding awards is the prestigious Paul Beeson Physician Faculty Scholar Aging Research Award. In 2006, Dr. La Spada was inducted into the American Society for Clinical Investigation. In 2007, he was bestowed with the Lieberman Award by the Hereditary Disease Foundation for excellence in Huntington’s Disease research, and in 2011, he received the Molecular Mechanisms of Neurodegeneration Distinguished Research Award in Milan, Italy. In 2013, Dr. La Spada was inducted into the Association of American Physicians.

Donald J. Zack, MD, PhD

Donald J. Zack, MD, PhD

Dr. Zack’s lab is developing approaches to use gene therapy-based gene targeting (CRISPR/Cas9) approaches for the treatment of retinitis pigmentosa and related retinal degenerations.

Donald J. Zack, M.D., Ph.D., is the Guerrieri Professor of Genetic Engineering and Molecular Ophthalmology at the Wilmer Eye Institute, Johns Hopkins University and a professor in the Departments of Molecular Biology and Genetics, Neuroscience, and the Institute of Genetic Medicine.

Dr. Zack’s team is developing a novel strategy for ADRP treatment, one that utilizes a recently developed and revolutionary technology that allows precise and targeted editing of a living organisms genomic information, i.e. it allows therapeutic modulation of one’s genes. They will use this new technology, called CRISPR/Cas9 gene editing, to specifically alter the mutated copy of the disease-causing gene so that it does not express its toxic gene product, while not affecting expression of the WT gene.

If successful, these studies will validate a new approach for gene therapy based on custom genetic engineering of retinal cells for the treatment of ADRP. The approach being developed may also be applicable to other forms of retinal degeneration, and Dr. Zack is hopeful that the proposed work will lay the groundwork for development of new gene therapy-based treatments for retinal disease.

Dr. Zack graduated from the Albert Einstein College of Medicine in 1984, where he received a medical degree and a Ph.D. in molecular immunology, under the mentorship of Dr. Matthew Scharff. Dr. Zack was appointed Assistant Professor at Johns Hopkins in 1991, Associate Professor in 1997, and Professor in 2001. Dr. Zack has published over 200 peer-reviewed journal articles and has won a number of awards, including the Alcon Research Award. He is a former chairperson of the National Eye Institute (NEI) study section that is responsible for determining funding priorities for a large number of retinal research grants, and is currently the Co-Chair of the Board of Scientific Counselors at the NEI. Dr. Zack is co-director of the new Wilmer Stem Cell Ocular Regenerative Medicine (STORM) Center at Johns Hopkins University.