About

Jean Bennett, MD, PhD, is a Professor of Ophthalmology at the University of Pennsylvania and serves as Vice Chair for Basic Research in the Department of Ophthalmology. Her research focuses on the molecular genetics of inherited retinal degenerations, with the aim of developing rational treatments for these diseases. Her work includes identifying molecular bases of retinal degenerations, generating animal models, evaluating vectors for retinal gene transfer, characterizing immune responses to gene therapy, and developing gene-based approaches to reverse sensory loss and rescue vision in animal models. Dr. Bennett was among the first investigators to use viral vectors for targeted gene delivery in the retina and led the first team to demonstrate proof-of-principle for ocular gene therapy. Her laboratory has developed various strategies for gene therapy-mediated treatments for retinal diseases, including projects targeting other cilia-related disorders in the ear and kidney. Her translational research has led to significant advances, such as reversing blindness in a canine model of a blinding disease affecting infants, which is now being tested in human clinical trials. She is the Scientific Director for a Phase I/II human clinical trial evaluating gene transfer safety and efficacy in Leber congenital amaurosis due to RPE65 mutations, with promising results reported in all subjects.

Research topics

• Biology
• Medicine
• Ophthalmology
• Cell biology
• Genetics

Selected publications

• Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: One-year results of a phase I/II trial

  Molecular Therapy · 2025-07-02 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Central visual pathways affected by degenerative retinal disease before and after gene therapy

  Brain · 2024-03-28 · 4 citations

  articleOpen access

  Genetic diseases affecting the retina can result in partial or complete loss of visual function. Leber's congenital amaurosis (LCA) is a rare blinding disease, usually inherited in an autosomally recessive manner, with no cure. Retinal gene therapy has been shown to improve vision in LCA patients caused by mutations in the RPE65 gene (LCA2). However, little is known about how activity in central visual pathways is affected by the disease or by subsequent gene therapy. Functional MRI (fMRI) was used to assess retinal signal transmission in cortical and subcortical visual structures before and 1 year after retinal intervention. The fMRI paradigm consisted of 15-s blocks of flickering (8 Hz) black and white checkerboards interleaved with 15 s of blank (black) screen. Visual activation in the brain was assessed using the general linear model, with multiple comparisons corrected using the false discovery rate method. Response to visual stimulation through untreated eyes of LCA2 patients showed heightened fMRI responses in the superior colliculus and diminished activities in the lateral geniculate nucleus (LGN) compared to controls, indicating a shift in the patients' visual processing towards the retinotectal pathway. Following gene therapy, stimuli presented to the treated eye elicited significantly stronger fMRI responses in the LGN and primary visual cortex, indicating some re-engagement of the geniculostriate pathway (GS) pathway. Across patients, the post-treatment LGN fMRI responses correlated significantly with performance on a clinical test measuring light sensitivity. Our results demonstrate that the low vision observed in LCA2 patients involves a shift in visual processing toward the retinotectal pathway, and that gene therapy partially reinstates visual transmission through the GS pathway. This selective boosting of retinal output through the GS pathway and its correlation to improved visual performance, following several years of degenerative retinal disease, is striking. However, while retinal gene therapy and other ocular interventions have given hope to RPE65 patients, it may take years before development of therapies tailored to treat the diseases in other low vision patients are available. Our demonstration of a shift toward the retinotectal pathway in these patients may spur the development of new tools and rehabilitation strategies to help maximize the use of residual visual abilities and augment experience-dependent plasticity.

  PublisherOA PDFDOI

• Retinal Disorders

  Cold Spring Harbor Perspectives in Medicine · 2024-04-02 · 2 citations

  editorialOpen access

  Retinal disorders caused by genetic or environmental factors cause severe visual impairment and often result in blindness. The past ten years have seen rapid progress in our understanding of the biological basis of these conditions, as well as significant advances towards gene and cell-based therapies. Regulatory challenges remain, but there is reason to hope that creative approaches will lead to safe and effective breakthrough treatments for these conditions in the near future.

  PublisherOA PDFDOI

• Report From the Second Global Scientific Conference on Clinical Trial Design and Outcome Measures for <i>RDH12</i>-Associated Inherited Retinal Degeneration

  Translational Vision Science & Technology · 2024-08-09 · 1 citations

  articleOpen access

  Following the success of the first multi-stakeholder workshop to accelerate the development of treatments for patients with RDH12-associated inherited retinal dystrophies in 2019, the patient organizations Eyes on the Future and the RDH12 Fund for Sight convened a second one day, multi-stakeholder workshop in November 2022, focusing on the challenges in clinical trial design and outcome measure selection for studies involving patients with RDH12-associated inherited retinal disease (IRD). Face to face and virtual participants included representatives from patient organizations, academic and industry clinicians, and scientists, as well as representatives from multiple regulatory agencies. Key areas of discussion focused on RDH12 phenotypic heterogeneity, retinal structural-functional relationships, and the targeting of areas most likely to respond to gene therapies, the need for comprehensive natural history data to inform appropriate outcome measures, and the outcome measures most valued by the patient community including the lack of validated patient reported outcome measures. Learnings from recent IRD gene therapy trials and their relevance for RDH12-associated IRDs were discussed. Innovative trial designs with outcome measures selected relevant for the RDH12 patient population, adaptive strategies, collaboration among scientists and clinicians, alignment among regulators, and close engagement with the patient community can enhance the future feasibility and success of clinical studies for RDH12 retinal dystrophy. Translational Relevance: A multi-stakeholder, patient centric approach will be critical to the design of future successful clinical trials with outcome measures relevant to the RDH12-IRD population.

  PublisherOA PDFDOI

• AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes

  Gene Therapy · 2024-01-10 · 9 citations

  article
  PublisherDOI

• CRISPR-Cas9 correction of a nonsense mutation in LCA5 rescues lebercilin expression and localization in human retinal organoids

  Molecular Therapy — Methods & Clinical Development · 2023-05-17 · 26 citations

  articleOpen access

  Mutations in the lebercilin-encoding gene LCA5 cause one of the most severe forms of Leber congenital amaurosis, an early-onset retinal disease that results in severe visual impairment. Here, we report on the generation of a patient-specific cellular model to study LCA5-associated retinal disease. CRISPR-Cas9 technology was used to correct a homozygous nonsense variant in LCA5 (c.835C>T; p.Q279∗) in patient-derived induced pluripotent stem cells (iPSCs). The absence of off-target editing in gene-corrected (isogenic) control iPSCs was demonstrated by whole-genome sequencing. We differentiated the patient, gene-corrected, and unrelated control iPSCs into three-dimensional retina-like cells, so-called retinal organoids. We observed opsin and rhodopsin mislocalization to the outer nuclear layer in patient-derived but not in the gene-corrected or unrelated control organoids. We also confirmed the rescue of lebercilin expression and localization along the ciliary axoneme within the gene-corrected organoids. Here, we show the potential of combining precise single-nucleotide gene editing with the iPSC-derived retinal organoid system for the generation of a cellular model of early-onset retinal disease.

  PublisherOA PDFDOI

• Motion-selective areas V5/MT and MST appear resistant to deterioration in choroideremia

  NeuroImage Clinical · 2023-01-01 · 4 citations

  articleOpen access

  Choroideremia (CHM) is an X-linked recessive form of hereditary retinal degeneration, which preserves only small islands of central retinal tissue. Previously, we demonstrated the relationship between central vision and structure and population receptive fields (pRF) using functional magnetic resonance imaging (fMRI) in untreated CHM subjects. Here, we replicate and extend this work, providing a more in-depth analysis of the visual responses in a cohort of CHM subjects who participated in a retinal gene therapy clinical trial. fMRI was conducted in six CHM subjects and six age-matched healthy controls (HC's) while they viewed drifting contrast pattern stimuli monocularly. A single ∼3-minute fMRI run was collected for each eye. Participants also underwent ophthalmic evaluations of visual acuity and static automatic perimetry (SAP). Consistent with our previous report, a single ∼ 3 min fMRI run accurately characterized ophthalmic evaluations of visual function in most CHM subjects. In-depth analyses of the cortical distribution of pRF responses revealed that the motion-selective regions V5/MT and MST appear resistant to progressive retinal degenerations in CHM subjects. This effect was restricted to V5/MT and MST and was not present in either primary visual cortex (V1), motion-selective V3A or regions within the ventral visual pathway. Motion-selective areas V5/MT and MST appear to be resistant to the continuous detrimental impact of CHM. Such resilience appears selective to these areas and may be mediated by independent retina-V5/MT anatomical connections that bypass V1. We did not observe any significant impact of gene therapy.

  PublisherDOI

• Gene therapy helps combat some forms of blindness – and ongoing clinical trials are looking to extend these treatments to other diseases

  2023-05-12

  preprint1st authorCorresponding
  PublisherDOI

• Optimization and Validation of a Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations

  Translational Vision Science & Technology · 2023-01-30 · 9 citations

  articleOpen access1st author

  Purpose: To optimize a virtual reality (VR) orientation and mobility (O&M) test of functional vision in patients with inherited retinal degenerations (IRDs). Methods: We developed an O&M test using commercially available VR hardware and custom-generated software. Normally sighted subjects (n = 20, ages = 14-67 years) and patients with IRDs (n = 29, ages = 15-63 years) participated. Individuals followed a dim red arrow path to a "course exit," while trying to identify nine obstacles adjacent to, or directly in their path. Dark-adapted subjects completed 35 randomly selected VR courses at increasing luminances, twice per luminance step, binocularly, and uni-ocularly. Performance was graded automatically by the software. Patients with IRD completed a modified Visual Function Questionnaire (VFQ). Results: Normally sighted subjects identified approximately 50% of the obstacles at the dimmest course luminance. Except for two patients with IRD with poor vision, all patients were able to complete the test, although they required brighter (by >2 log units) luminances to identify 50% of the obstacles. In a single-luminance screening test in which normal subjects detected at least eight of nine objects, most patients with IRD underperformed; their performance related to disease severity, as measured by visual acuity, kinetic visual field extent, and VFQ scores. Test-retest differences in object detection were similar to the differences between the two eyes (±2 SD = ±2 objects). Conclusions: This VR-O&M test was able to distinguish subjects with IRDs from normal subjects reliably and reproducibly. Translational Relevance: This easily implemented, flexible, and objectively scored VR-O&M test promises to become a useful tool to assess the impact that IRDs and their treatments have on functional vision.

  PublisherOA PDFDOI

• Dynamic structural remodeling of the human visual system prompted by bilateral retinal gene therapy

  Current Research in Neurobiology · 2023-01-01 · 1 citations

  articleOpen access

  The impact of changes in visual input on neuronal circuitry is complex and much of our knowledge on human brain plasticity of the visual systems comes from animal studies. Reinstating vision in a group of patients with low vision through retinal gene therapy creates a unique opportunity to dynamically study the underlying process responsible for brain plasticity. Historically, increases in the axonal myelination of the visual pathway has been the biomarker for brain plasticity. Here, we demonstrate that to reach the long-term effects of myelination increase, the human brain may undergo demyelination as part of a plasticity process. The maximum change in dendritic arborization of the primary visual cortex and the neurite density along the geniculostriate tracks occurred at three months (3MO) post intervention, in line with timing for the peak changes in postnatal synaptogenesis within the visual cortex reported in animal studies. The maximum change at 3MO for both the gray and white matter significantly correlated with patients' clinical responses to light stimulations called full field sensitivity threshold (FST). Our results shed a new light on the underlying process of brain plasticity by challenging the concept of increase myelination being the hallmark of brain plasticity and instead reinforcing the idea of signal speed optimization as a dynamic process for brain plasticity.

  PublisherDOI

Recent grants

• NIH Grant DP1OD008267

  NIH · $800k · 2012

• NIH Grant R01EY010820

  NIH · $4.9M · 2009

• NIH Grant DP1EY023177

  NIH · $3.2M · 2017

• NIH Grant R21EB018064

  NIH · $430k · 2017

• Research on normal and abnormal mechanisms of vision

  NIH · $6.4M · 1976–2030

Frequent coauthors

• Albert M. Maguire

  Children's Hospital of Philadelphia

  512 shared

• Tomas S. Alemán

  University of Pennsylvania

  252 shared

• Daniel C. Chung

  162 shared

• Samuel G. Jacobson

  Penn Presbyterian Medical Center

  100 shared

• Katherine A. High

  Rockefeller University

  88 shared

• Jeannette Bennicelli

  Penn Presbyterian Medical Center

  87 shared

• Artur V. Cideciyan

  University of Pennsylvania

  85 shared

• Alberto Auricchio

  Scuola Superiore Meridionale

  72 shared

Labs

• Bennett LabPI

Education

• MD

  Harvard Medical School

  1986

• PhD, Zoology

  University of California Berkeley

  1980