Kenneth S. Shindler

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University of Pennsylvania · Rehabilitation Medicine

Active 1967–2025

h-index55

Citations14.7k

Papers23858 last 5y

Funding$4.6M

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About

Kenneth S. Shindler, M.D., Ph.D., is the F.M. Kirby Professor of Molecular Ophthalmology at the University of Pennsylvania Perelman School of Medicine. He is a faculty member in the Department of Ophthalmology and a Medical Staff Physician at the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center. Dr. Shindler's research focuses on examining potential mechanisms to provide neuroprotection of retinal ganglion cells in optic neuritis, an inflammatory disease of the optic nerve often associated with multiple sclerosis. His studies aim to identify new therapies to prevent nerve damage in this disease, which can lead to permanent vision loss, and these therapies may also benefit other neurodegenerative diseases. In addition to his research, he treats patients with neuro-ophthalmologic conditions, including optic neuropathies, papilledema, and binocular double vision. Dr. Shindler holds degrees from Brown University and Washington University in St. Louis, with a background in biochemistry, medicine, and neuroscience.

Research topics

Geomorphology
Surgery
Orthodontics
Medicine
Biology
Geology
Cell biology

Selected publications

Neuroprotective effects of SIRT1 in human RGCs derived from iPSCs following oxidative stress induction at early and late stages of differentiation
Experimental Eye Research · 2025-07-17 · 1 citations
articleOpen access
BACKGROUND: Neurodegeneration of retinal ganglion cells (RGCs) is the primary cause of irreversible vision loss in optic neuropathies. Preclinical in vivo studies have shown the neuroprotective potential of SIRT1 gene therapy in various optic neuropathy mouse models. This study seeks to build on these findings by utilizing a human cell culture model of induced pluripotent stem cell (iPSC)-derived RGCs to assess the neuroprotective effects of SIRT1 expression. METHODS: RGCs were differentiated from control human iPSCs using a previously defined in vitro methodology with small molecules and peptide modulators. Cell morphology and identity was confirmed by Brn3a and RBPMS immunostaining as well as qPCR analysis of RGC-specific markers. SIRT1 and GFP (control) were expressed using AAV vectors driven by the RGC-selective SNCG promoter. Oxidative stress was induced using tert-butyl hydroperoxide solution (TBHP) or growth factor withdrawal, and neuroprotection was assessed via MTT assay. RESULTS: By day 42 of differentiation, cultures were enriched with Brn3a + cells (>80 %) that demonstrated morphologic features of mature RGCs, and these RGC properties were maintained up to day 90. SIRT1 expression induced significant neuroprotection to human iPSC-derived RGCs following TBHP-induced oxidative stress and with depletion of growth factors. Rescue effects were observed within three weeks of SIRT1 expression, with improved RGC survival compared to controls (∼20 %), at two timepoints: Days 42 and 90. CONCLUSIONS: These findings support the therapeutic success of SIRT1-based gene therapy in an in vitro culture model of human RGCs and confirm those obtained in mouse models of optic neuropathies.
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SIRT1-based therapy targets a gene program involved in mitochondrial turnover in a model of retinal neurodegeneration
Scientific Reports · 2025-04-19 · 6 citations
articleOpen accessSenior author
Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.
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Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis
Biomolecules · 2025-01-28 · 1 citations
articleOpen accessSenior authorCorresponding
Optic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in multiple sclerosis (MS) patients. Sixty percent of patients develop some level of permanent visual loss due to retinal ganglion cell (RGC) damage following optic neuritis, with no known treatment to prevent this loss. Prior studies showed that MP201, a prodrug of 2,4-dinitrophenol (DNP) administered in the experimental autoimmune encephalitis (EAE) mouse model of MS attenuated optic neuritis with preserved vision, increased retinal ganglion cell (RGC) survival, decreased axon loss, and reduced demyelination. Oral administration of MP201, which converts to active form DNP after entry in the portal vein, decreases mitochondrial-derived reactive oxygen species (ROS) and restores calcium homeostasis, which are both implicated in many neurodegenerative diseases. Due to the established therapeutic benefits of prodrug MP201 in EAE mice, we hypothesized that administration of DNP itself may also have significant potential for therapeutic effects. Here, effects of varying doses of DNP treatment in EAE mice were assessed by the extent of spinal cord paralysis, optokinetic response (OKR), RGC survival, and optic nerve demyelination and inflammation. Results show that daily oral doses of 5-10 mg/kg DNP initiated after onset of EAE can significantly reduce spinal cord paralysis, a marker of the EAE MS-like disease, by day 42 after disease induction. DNP treatment significantly reduces RGC loss induced by optic neuritis in EAE mice; however, effects of DNP do not significantly improve visual function, or optic nerve demyelination and inflammation. Current studies show DNP treatment promotes increased RGC survival, but continued inflammation and demyelination likely reduce visual function, suggesting future studies examining combination therapy of DNP with anti-inflammatory agents may be warranted.
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The fusion peptide of the spike protein S2 domain may be a mimetic analog of β-coronaviruses and serve as a novel virus-host membrane fusion inhibitor
Antiviral Research · 2025-03-16 · 1 citations
article
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Neuroprotective Effects of Sirt1 in Human Rgcs Derived from Ipscs Following Oxidative Stress Induction at Early and Late Stages of Differentiation
SSRN Electronic Journal · 2025-01-01
preprintOpen access
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Response to comment on “Neuroprotective effects of SIRT1 in human RGCs derived from iPSCs following oxidative stress induction at early and late stages of differentiation”
Experimental Eye Research · 2025-08-21
letter
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APOSTEL-R Recommendations for Reporting Retinal Optical Coherence Tomography Studies in Rodents
Neurology Neuroimmunology & Neuroinflammation · 2025-10-08
articleOpen access
BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) in rodent models has been used to longitudinally image retinal changes, to define end points for more costly or time-consuming experiments, and to better understand the pathophysiology underlying OCT findings in human diseases. No standardization of rodent OCT reporting currently exists. Here, we aim to establish consensus recommendation for reporting results from retinal OCT studies in rodents. METHODS: Initial recommendations were developed based on the APOSTEL criteria for quantitative OCT reporting in humans by a core team. Using a modified Delphi process, an expert panel of rodent OCT researchers (N = 31) and the wider scientific community discussed, refined, and voted on these initial recommendations. The list of recommendations was then revised and approved by the expert panel. RESULTS: The final 7-point checklist includes reporting recommendations regarding the study protocol, OCT device, acquisition settings and modifications, scanning protocol, funduscopic imaging, postacquisition data selection and image data analyses, and qualitative and quantitative results. With a median agreement score of 3 or 4 out of 4, the scientific community agreed with these recommendations. After revisions, the expert panel accepted the final recommendations. DISCUSSION: The Advised Protocol for OCT Study Terminology and Elements for reporting OCT studies in rodents (APOSTEL-R) originates from an expert consensus. They will provide guidance throughout the experimental process and will contribute to the standardization and quality improvement of preclinical OCT studies.
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AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes
Gene Therapy · 2024-01-10 · 9 citations
article
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Pharmacological Activation and Transgenic Overexpression of SIRT1 Attenuate Traumatic Optic Neuropathy Induced by Blunt Head Impact
Translational Vision Science & Technology · 2024-09-27 · 1 citations
articleOpen accessSenior authorCorresponding
Purpose: Resveratrol (RSV) is a nutraceutical compound known for its therapeutic potential in neurodegenerative and metabolic diseases. RSV promotes survival signals in retinal ganglion cells (RGCs) through activation of SIRT1, an NAD+-dependent deacetylase. RSV and SIRT1 reduce RGC loss induced by direct optic nerve injury, but effects in indirect models of traumatic optic neuropathy remain unknown and are examined in this study. Methods: An electromagnetic stereotaxic impactor device was used to impart five traumatic skull impacts with an inter-concussion interval of 48 hours to wild type (WT) and SIRT1 knock in (KI) C57BL/6J mice overexpressing the SIRT1 gene. A cohort of WT mice also received intranasal administration of RSV (16 mg/kg) throughout the experimental period. Loss of righting reflex (RR), optokinetic response (OKR) scores, and immunolabeled RGC count are determined to assess optic neuropathy in this model of traumatic brain injury (TBI). Results: TBI significantly decreases RGC survival and decreases OKR scores compared with control uninjured mice. Either RSV administration in WT mice, or SIRT1 overexpression in SIRT1 KI mice, significantly increases RGC survival and improves OKR scores. RR time increases after the first few impacts in all groups of mice subjected to TBI, demonstrating that RSV and SIRT1 overexpression are able to attenuate optic neuropathy following similar degrees of TBI. Conclusions: Intranasal RSV is effective in preserving visual function in WT mice following TBI. Constitutive overexpression of SIRT1 recapitulates the neuroprotective effect of RSV. Translational Relevance: Results support future exploration of RSV as a potential therapy for indirect traumatic optic neuropathy.
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Intranasal Resveratrol Nanoparticles Enhance Neuroprotection in a Model of Multiple Sclerosis
International Journal of Molecular Sciences · 2024-04-05 · 16 citations
articleOpen accessSenior authorCorresponding
PURPOSE: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. METHODS: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. RESULTS: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. CONCLUSIONS: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.
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