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University of Pennsylvania Health System

Department of Ophthalmology

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Ophthalmology Education

Penn Vision Clinical Scientist Program

Mentors

Mentors include:

Laura Balcer, MD, MSCE
Jean Bennett, MD, PhD
Artur Cideciyan, PhD
Samuel Jacobson, MD, PhD
Maureen Maguire, PhD
Eric Pierce, MD, PhD


Laura Balcer, MD, MSCE

Dr. Balcer's primary research area is the identification and development of clinical visual outcome measures for trials and other research in neurological diseases. Ongoing projects in Dr. Balcer's group, funded jointly by the National Eye Institute (R01 EY 13273) and the National Multiple Sclerosis (MS) Society (RG 3208-A-1), focus on determining which clinical tests best identify visual dysfunction in MS patients, and systematically defining the visual profile of MS in a large cohort (400 patients). These cross-sectional studies also examine the relation of visual function to neurological impairment, demyelinating lesion burden and neuronal loss by MRI/proton MR spectroscopy, and health-related quality of life (HRQOL). Data from these and other investigations at Penn have led to the inclusion of contrast letter acuity as a secondary outcome measure in two international MS treatment trials. In addition, Dr. Balcer has received funding to perform longitudinal assessments of visual function, neurological impairment, and HRQOL for patients enrolled in the cross-sectional studies described above Pilot work and grant applications are in development for extending the methodology used to study MS to Parkinson's disease, myasthenia gravis, and Friedreich ataxia.

Dr. Balcer's research programs will provide numerous opportunities for training of K12 candidates. The above-described projects that focus on the relation of visual function to neurological impairment, MR imaging parameters, and health-related quality of life (HRQOL) in MS involve the use of novel design paradigms, and have generated significant cross-sectional and longitudinal data for sub-hypotheses and investigation by K12-level trainees. Such projects will be based upon the following research questions:

  1. Which visual function tests are the most significant predictors of brain MRI lesion burden in MS?
  2. How well do visual function scores in MS patients predict scores on vision-specific, disease-specific, and generic HRQOL measures?
  3. What content areas will increase the sensitivity and applicability of standard vision-specific HRQOL questionnaires (VFQ-25) in patients with MS and other neuro-ophthalmologic disorders?
  4. Does the incorporation of a visual function test increase the capacity for the MS Functional Composite measure to distinguish MS patients from disease-free controls?

These research questions and the above outlined research paradigms for investigation of visual function will also be applicable to other neuro-ophthalmologic disorders, particularly Parkinson's disease, myasthenia gravis, and Friedreich ataxia.

Jean Bennett, MD, PhD

Dr. Bennett is leading several major research efforts in retinal disease and has effectively incorporated medical students, graduate students, residents, clinical fellows, and post-doctoral fellows in both short-term (3-6 month) and long-term research projects. Her efforts continue to develop, characterize and improve viral vectors that could be used for evaluating biological mechanisms that normally occur in the retina and for gene therapy applications. Work has continued on adeno-associated virus (AAV) vectors generated with capsids of different AAV serotypes.

Dr. Bennett's laboratory has evaluated six genes for prospects for gene therapy for haploinsufficiency, PDEb, RHO (AR-RP), RPE65 (Leber Congenital Amaurosis), REP-1 (choroideremia) and MPSVI (mucopolysaccharidosis VI) and MPSVII and developed methods for delivering the viral vectors at early postnatal/fetal time points in the diseases that have a rapid onset of degeneration (AR-RP). Gene therapy studies for RPE65 mutations causing Leber Congenital Amaurosis (LCA) continue to be successful, leading to the funding of a multi-investigator, multi-center research/clinical plan to develop viral vector-based gene therapy for RPE65 Leber congenital amaurosis (LCA) and to begin phase I/II clinical testing. Dr. Bennett leads module 3, Identification of the ideal vector for human studies using the RPE65-/- mouse.

Other recent accomplishments that continue to be explored in the laboratory include:

  • Developing methods for in utero retinal gene therapy in the mouse allowing testing of gene therapy for early onset severe blinding diseases
  • Development of methods to correct single base pair mutations in somatic cells
  • Successful use of gene therapy techniques to inhibit retinal neovascularization in animal models of retinopathy of prematurity and of choroidal neovascularization.

With such an extensive research laboratory, Dr Bennett will be able to provide training/support to candidates interested in a variety of bench research projects. In the past, she has trained individuals at different levels of training on a variety of topics including: cloning, analysis of promoter function, generation of recombinant viruses, use of recombinant viruses in evaluating immune response/retinal cell differentiation, use of viral vectors for retinal gene therapy, approaches for blocking retinal neovascularization, generation of animal models for retinal disease, identification of mutations which cause retinal disease, methods with which to measure visual behavior in small and large animals, pathogenetic basis of retinal disease. Dr. Bennett would tailor a bench science-training program to accommodate the needs/desires of a trainee interested in retinal disease. In addition to the hands-on bench research training, she would advise the candidate on how to present the research findings in both manuscript format and lecture format. Dr. Bennett encourages trainees to attend local and international research meetings to share research results. On a local level, trainees attend the weekly Bennett lab meeting, the weekly research meeting at the F.M. Kirby Center for Molecular Ophthalmology, the University of Pennsylvania gene therapy trainee presentation seminar series, and numerous lectures and retreats offered by a number of institutes/ centers at Penn (including the Cell and Molecular Biology and the Neuroscience graduate groups, and the Institute of Neuroscience).

Artur Cideciyan, PhD

The Phototransduction and Visual Cycle Laboratory aims to understand the in vivo function of specific molecules expressed in the human retina. Aims are achieved through non-invasive measurement and quantitative analysis of visual function and structure in patients with hereditary retinopathies caused by known molecular defects. Knowledge obtained from such retinopathies is used to glean molecular foundations of normal human vision. Studies performed in parallel with similar experimental methods in animal models are used to determine the correspondence between the models and the patients, and potential therapeutic strategies are tested as appropriate. Research methods include state-of-the-art commercial equipment, custom developed equipment, mathematical modeling and software development. Dr. Cideciyan is available to mentor candidates in quantitative non-invasive methods as applied to patient-oriented research. His projects on specific irregularities of the visual system of patients and animals with specific mutations lend themselves well to having a K12 trainee take responsibility for a well-defined project for which the trainee would have prime responsibility while working in a laboratory environment with a number of ongoing projects in various states of development.

Samuel Jacobson, MD, PhD

The Center for Hereditary Retinal Degenerations, directed by Dr. Jacobson, has both clinical and research activities aimed at understanding the underlying mechanisms of human genetic human retinal degenerative diseases. Patients are evaluated clinically and evaluations are complemented by psychophysical, electrophysiological and retinal imaging studies. Extensive scientific interaction with other laboratories throughout the world has led to discoveries of the molecular bases and disease expression in a host of retinal degenerations. Clarity of mechanism has occurred, for example, in Leber congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, maculopathy, the enhanced S-cone syndrome, Usher syndrome and the Bardet-Biedl syndrome. A major collaboration among three academic institutions recently led to the first human trial of gene replacement therapy for one molecular subtype of Leber congenital amaurosis and Dr. Jacobson is the clinical principal investigator of this research. At the Center, there are ongoing pilot studies of nutritional and medical intervention in certain inherited retinal degenerations. Preclinical experiments are also performed in genetically engineered and naturally occurring rodent and large animal models of the human retinal degenerative diseases with the goal of translating these results from the laboratory to the clinical population served by the Center. There are many opportunities for K12 trainees to identify and extend research projects associated with the main goals of the Center.

Maureen Maguire, PhD

The Center for Preventive Ophthalmology and Biostatistics (CPOB), directed by Dr. Maguire, leads and collaborates in clinical research through study design, protocol development, comprehensive data management, cutting-edge interpretation of fundus images, statistical analysis, and interpretation of data. The Center is actively involved in clinical research projects ranging from small, single investigator studies to large, multi-center, multi-disciplinary clinical research studies. The Complications of Age-related Macular Degeneration Prevention Trial (CAPT) is an NEI-sponsored, randomized, clinical trial involving 23 clinical centers nationwide, and 1000 patients. The trial is evaluating laser treatment among patients at high risk of developing severe loss of vision from age-related macular degeneration. Both Coordinating Center and the Fundus Photograph Reading Center are part of the CPOB. The Vision in Preschoolers Study (VIP) is an NEI-sponsored multi-center study to evaluate the accuracy of traditional and newly developed screening tests for detecting amblyopia, strabismus, and significant refractive error in preschool children. Through a series of evaluation cycles, nearly 10,000 children will be tested through five clinical centers nationwide over a period of 5 to 6 years. The Coordinating Center for VIP is part of CPOB. Through the Biostatistics Module of the Penn Core Grant for Vision Research, CPOB methodologists (statisticians and epidemiologists) and data management staff consult with clinical and basic scientists within the Department of Ophthalmology and in other Penn departments (Neurology, Neuroscience, Physiology) on study design and data analysis and interpretation.

Multicenter clinical investigations often engender ancillary research studies that would provide research topics for K12 trainees. The growing archive of color stereoscopic and fluorescein angiographic images of clinically well-characterized patients with various stages of age-related macular degeneration offer opportunities in the areas of natural history, correlations of physiologic changes with visual function, and computer-assisted analysis of images. In addition, as new instrumentation and approaches to vision screening are developed, studies of accuracy, reliability, and responsiveness to change will be needed. Dr. Maguire is currently working with investigators within the Department of Ophthalmology as well as with investigators from other institutions (Johns Hopkins University, Jefferson Medical College, Beth Israel Hospital) on plans for large scale clinical research studies in low vision rehabilitation, the interplay of loss of vision from AMD and depression, the treatment of patients with ocular myasthenia gravis, and the predictive value of features of the retinal vasculature in the progression of renal disease and development of cardiovascular events in patients with chronic renal insufficiency. Depending on the time to maturation of these plans, K12 trainees may take major roles in working with collaborators in designing the execution, analysis, and interpretation of these studies. Finally, trainees will be able to observe and participate in the data monitoring activities and administrative structures of multi-center, interdisciplinary studies.

Eric Pierce, MD, PhD

The long-term objective of Dr. Pierce's research is to improve the understanding of how inherited and age-related retinal degenerations cause blindness, so that therapies to prevent vision loss can be developed. Currently, the laboratory is actively investigating how mutations of one of the genes (RP1) identified as causing retinitis pigmentosa lead to blindness. In order to study how mutations in pre-RNA processing factors lead to blindness, the Pierce laboratory is creating mouse models of RP18, RP13 and RP11 by using gene-targeting techniques to produce mice with mutations in Prpf3, Prpf8 and Prpf31. The next step will be to investigate the effects of the mutant proteins on RNA splicing in the retina and other tissues in order to determine the causes of photoreceptor cell death in these forms of RP. Another project is directed toward developing an improved method for producing animals with specific single-base mutations to use as models of inherited diseases. Work is now proceeding toward using oligonucleotide-directed gene targeting to modify endogenous genes in embryonic stem cells. Mice generated from the targeted embryonic stem cells could be used to study the pathogenesis of inherited retinal degenerations, or other inherited diseases. The final major area of investigation is biochemical basis of retinal neovascularization. The laboratory is using two molecular biologic techniques to identify the proteins responsible for abnormal retinal blood vessel growth. To date, over 70 candidate proteins that may play an important role in retinal neovascularization have been identified. Some of these candidate proteins are known blood vessel growth factors, but their role in the retina has not yet been defined. Other candidate proteins have not been previously investigated.

Dr. Pierce would work with K12 trainees to identify important questions requiring investigation and to develop a research plan. In addition, trainees would attend lab meetings, the weekly research meeting at the F.M. Kirby Center for Molecular Ophthalmology, the University of Pennsylvania gene therapy trainee presentation seminar series, and numerous lectures and retreats offered by a number of institutes/centers at Penn (including the Cell and Molecular Biology and the Neuroscience graduate groups, and the Institute of Neuroscience).

 

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