About

Jonathan J. Miner, M.D., Ph.D., is an Associate Professor of Medicine (Rheumatology) at the University of Pennsylvania Perelman School of Medicine. He specializes in inherited autoimmune and autoinflammatory diseases resulting from mutations in genes that regulate immune responses to DNA and RNA. Dr. Miner is the Director of the RVCL Research Center at the University of Pennsylvania and chairs the Gene Therapy and Vaccines Ph.D. program at Penn. His research laboratory studies fundamental immunology, mechanisms of genetic disease, and develops custom medicines for patients with rare genetic diseases. Dr. Miner sees patients with rare autoinflammatory diseases and vasculopathies caused by single-gene mutations, including RVCL (also known as RVCL-S), AGS, SAVI, and COPA syndrome. His team has developed animal models featuring human disease-causing mutations in innate immune genes such as STING, TREX1, RELA, STAT1, and IFIH1, which are used to elucidate disease mechanisms and advance personalized therapies. He has received numerous accolades, including membership in the American Society for Clinical Investigation (ASCI) and the Ann Palmenberg Award from the American Society for Virology. Dr. Miner chairs the Gene Therapy and Vaccines Ph.D. program at Penn and has published extensively in top journals, contributing significantly to the understanding of immune regulation and genetic diseases.

Research topics

• Biology
• Medicine
• Immunology
• Virology
• Cell biology

Selected publications

• Drosophila melanogaster model of RVCL-S demonstrates age dependent disease progression

  eLife · 2026-03-06

  articleOpen access

  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a disease that causes deterioration of small vessels, affecting various organs: eyes, brain, liver, and others. The RVCL-S carriers have lower life expectancy. There is no cure available to date. The disease has been linked to mutations in TREX1 gene disrupting its cytoplasmic localization. To facilitate the disease mechanism investigation, we employed model organism D. melanogaster, identified human TREX1 ortholog cg3165, and confirmed its vital significance to flies. Then, we expressed human TREX1 and its mutant form TREX1 V235Gfs in flies and used optical coherence microscopy (OCM) to monitor the dynamics of flies’ vascular system. We detected the relapse of fly dorsal vessel, movement impairment, and reduced longevity in TREX1 V235Gfs-expressing transgenic animals. Vascular deterioration and shorter life span recapitulate the RVCL-S manifestations in humans. We have established a robust quantitative Drosophila RVCL-S phenotypic system that can potentially serve as a screening platform for drug discovery and drug targets identification.

  PublisherDOI

• CD14-deficiency protects against osteoarthritic subchondral bone sclerosis via enhanced osteoclastogenesis following joint injury

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-11

  articleOpen access

  Abstract Aberrant bone remodeling is a hallmark of osteoarthritis, the most common arthritis affecting over 27 million US adults. Subchondral bone sclerosis, one sign of aberrant bone remodeling observable by routine x-rays, occurs as the trabeculae thicken, leading to increased bone volume. Toll-like receptors, pattern-recognition receptors of the innate immune system, have been implicated in OA pathogenesis, with TLR ligands, receptors, and co-receptors shown to mediate the severity and progression of OA. We have previously shown that CD14-deficiency protects mice against post-traumatic OA, and specifically reduces subchondral sclerosis post-injury. We hypothesized that depletion of CD14 protects against TLR4-dependent inhibition of osteoclastogenesis and therefore increases OC density in the SCB after injury, mitigating aberrant bone deposition in a murine model of OA . To determine how cellular changes correlate with bone structure derangements post-DMM, we performed MicroCT, Tartrate-resistant acid phosphatase staining, and alkaline phosphatase staining. To establish mechanistic changes in cellular signaling, we isolated WT and CD14-deficient osteoclast precursors and subjected them to LPS, an osteoarthritis-relevant TLR ligand, during differentiation. CD14-deficient mice, as well as WT mice treated with an anti-CD14 monoclonal antibody, show protection from post-injury increases in both bone volume fraction and bone mineral density. CD14-deficient mice had an increased osteoclast presence in the SCB two weeks post-injury, potentially protecting them from increases in bone volume and density. In vitro , CD14-deficient OCPs differentiated faster than WT OCPs, due to reduced Type I Interferon (IFN-I) signaling. In the presence of an LPS challenge, CD14-deficient OCPs were protected against LPS and TLR4-mediated inhibition, likely due to decreased MyD88-dependent TLR4 signaling. This work opens up new potential pathways to therapeutically target aberrant bone remodeling in the setting of joint injury and PTOA. Lay Summary Osteoarthritis is one of the leading causes of disability worldwide. One of the hallmarks is subchondral sclerosis, or thickening of the bone in and around the joint. In this work, we used a mouse model of osteoarthritis to show that decreasing inflammatory signaling, through removal of CD14, protects against subchondral sclerosis, due to an increased presence of osteoclasts, cells that combat bone thickening. Osteoclasts without CD14 differentiate faster than osteoclasts with CD14, due to decreased Type I Interferon, an inflammatory cytokine. Graphical Abstract

  PublisherOA PDFDOI

• Drosophila melanogaster model of RVCL-S demonstrates age dependent disease progression

  eLife · 2026-03-06

  articleOpen access

  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a disease that causes deterioration of small vessels, affecting various organs: eyes, brain, liver, and others. The RVCL-S carriers have lower life expectancy. There is no cure available to date. The disease has been linked to mutations in TREX1 gene disrupting its cytoplasmic localization. To facilitate the disease mechanism investigation, we employed model organism D. melanogaster, identified human TREX1 ortholog cg3165, and confirmed its vital significance to flies. Then, we expressed human TREX1 and its mutant form TREX1 V235Gfs in flies and used optical coherence microscopy (OCM) to monitor the dynamics of flies’ vascular system. We detected the relapse of fly dorsal vessel, movement impairment, and reduced longevity in TREX1 V235Gfs-expressing transgenic animals. Vascular deterioration and shorter life span recapitulate the RVCL-S manifestations in humans. We have established a robust quantitative Drosophila RVCL-S phenotypic system that can potentially serve as a screening platform for drug discovery and drug targets identification.

  PublisherDOI

• Neuroimaging Biomarkers of Disease Progression and Cognitive Change in Patients With Retinal Vasculopathy With Cerebral Leukoencephalopathy

  Neurology · 2026-02-20

  article

  BACKGROUND AND OBJECTIVES: A monogenic, age-related cerebral small vessel disease (cSVD), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), causes accelerated vascular dementia, vision loss, and premature death. Given knowledge is limited regarding its pathophysiology, we examined the natural history of progression in imaging and cognitive endpoints to define the rate and variability of progression in a prospective RVCL-S cohort. We hypothesized that cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as metrics of cerebral hypoxia-ischemia, would be associated with neurologic disease progression. METHODS: We performed sequential brain MRI and a cognitive battery in a prospective RVCL-S cohort. Arterial spin labeling and asymmetric spin echo quantified CBF and OEF in normal-appearing white matter (WM), respectively. Three neuroimaging endpoints of cSVD included the following: log-transformed, normalized fluid-attenuated inversion recovery WM hyperintensity (WMH) volume; WM microstructure using mean diffusivity; and normalized WM volume. Five cognitive and motor endpoints included Digit Symbol Substitution Test (DSST), category fluency, free recall, Montreal Cognitive Assessment (MoCA), and gait speed. Linear mixed-effects models examined age, CBF, and OEF in association with neuroimaging and cognitive progression. RESULTS: = 0.029). Neither OEF nor CBF was independently associated with cognitive decline. DISCUSSION: Elevated OEF in at-risk WM was associated with progression in WMH and impairment in WM microstructure, suggesting a role for tissue hypoxia-ischemia in underlying RVCL-S pathophysiology. Cerebral OEF holds promise as a predictive biomarker to risk-stratify patients with RVCL-S and other forms of cSVD.

  PublisherDOI

• Adult-onset STING-associated vasculopathy

  Journal of Human Immunity · 2026-04-10

  articleOpen accessSenior author

  Genetic contributions to systemic autoimmunity are often considered more significant in children than in adults. As such, genetic evaluation may be more frequently pursued in pediatric rheumatology patients. Motivated by the discovery of a STING-associated vasculopathy with onset in infancy (SAVI) mutation in a patient with adult-onset relapsing polychondritis and systemic lupus erythematosus, we hypothesized that STING gain-of-function mutations might underlie a broader spectrum of autoimmune disease in adults. We systematically screened 43,731 exomes from the Penn Medicine Biobank, revealing five additional unrelated adults with SAVI-associated STING gain-of-function mutations, including several patients with clinical features of SAVI, as well as asymptomatic individuals with type I IFN signatures. We propose the term adult-onset STING-associated vasculopathy (AO-SAVI) to describe these patients. Our findings challenge the conventional symptom-driven diagnostic paradigm, revealing that parallel molecular classification can uncover shared mechanisms and genetic etiologies across seemingly distinct diseases.

  PublisherDOI

• Misdirected yet intact TREX1 exonuclease activity causes human cerebral and systemic small vessel disease

  Brain · 2025-06-06 · 8 citations

  articleOpen access

  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an incurable microvascular disease caused by C-terminus truncation of the TREX1 exonuclease. There is a pressing need to understand disease mechanisms and identify therapeutic targets. We evaluated TREX1 sequencing data from 469 229 UK Biobank participants together with RVCL-S-related microvascular clinical and imaging outcomes. We show that mono-allelic truncating mutations in TREX1 require intact nuclease activity in order to cause endothelial disease. Differential proteomics identifies loss of interaction with endoplasmic reticulum insertion proteins such as Guided Entry of Tail-Anchored Proteins Factor 3 as a major consequence of pathogenic TREX1 truncation, and this altered trafficking results in the unregulated presence of enzymatically active TREX1 in the nucleus. In endothelial cells with a patient mutation, mislocalized yet enzymatically active TREX1 causes accumulation of a spectrum of DNA damage. These pathological changes can be rescued by inhibiting exonuclease activity. In summary, our data implicate exonuclease-dependent DNA damage in endothelial cells as a key therapeutic target in the pathogenesis of RVCL-S.

  PublisherOA PDFDOI

• Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

  Nature Nanotechnology · 2025-08-11 · 42 citations

  articleOpen access
  PublisherOA PDFDOI

• The intersection of TREX1, cGAS, STING and the DNA damage theory of aging

  Frontiers in Aging · 2025-12-04

  articleOpen accessSenior authorCorresponding

  Genetic syndromes of immune dysregulation have opened a door toward understanding mechanisms linking inflammation, premature aging, and normal aging. Here, we discuss new insights into the relationship between DNA damage, premature senescence, and nucleic acid-sensing pathways that detect or regulate DNA damage. First, we review mechanisms by which the DNA exonuclease TREX1 negatively regulates the cytosolic DNA sensor cGAS and its downstream effector STING, and we propose a model of TREX1-mediated DNA damage and cellular senescence that implicates age-related, inducible TREX1 expression in the context of genetic disease and inflamm-aging. Our central thesis is that two TREX1-associated diseases-Aicardi-Goutières syndrome (AGS) and retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S), historically regarded as inflammatory conditions-can serve as models for research into mechanisms of premature aging.

  PublisherOA PDFDOI

• Distinct components of mRNA vaccines cooperate to instruct efficient germinal center responses

  Cell · 2025-12-01 · 16 citations

  articleOpen access
  PublisherOA PDFDOI

• <i>Drosophila melanogaster</i> model of RVCL-S demonstrates age dependent disease progression

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-10

  preprintOpen access

  Abstract Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a disease that causes deterioration of small vessels, affecting various organs: eyes, brain, liver, and others. The RVCL-S carriers have lower life expectancy. There is no cure available to date. The disease has been linked to mutations in TREX1 gene disrupting its cytoplasmic localization. To facilitate the disease mechanism investigation, we employed model organism D. melanogaster, identified human TREX1 ortholog cg3165 , and confirmed its vital significance to flies. Then, we expressed human TREX1 and its mutant form TREX1 V235Gfs in flies and used optical coherence microscopy (OCM) to monitor the dynamics of flies’ vascular system. We detected the relapse of fly dorsal vessel, movement impairment, and reduced longevity in TREX1 V235Gfs-expressing transgenic animals. Vascular deterioration and shorter life span recapitulate the RVCL-S manifestations in humans. We have established a robust quantitative Drosophila RVCL-S phenotypic system that can potentially serve as a screening platform for drug discovery and drug targets identification.

  PublisherOA PDFDOI

Recent grants

• Organoids and Gene Editing Core

  NIH · $36.1M · 2000–2030

• Contributions of IRF5 to Chikungunya Viral Arthritis

  NIH · $612k · 2017–2022

• Mechanisms of STING-associated autoinflammation

  NIH · $4.6M · 2019–2029

• PATHOGENESIS OF OCULAR ZIKA VIRUS INFECTION

  NIH · $419k · 2017–2019

Frequent coauthors

• Rodger P. McEver

  University of Oklahoma Health Sciences Center

  19 shared

• Andria L. Ford

  Washington University in St. Louis

  19 shared

• M. Kathryn Liszewski

  18 shared

• John Atkinson

  18 shared

• Madonna Bogacki

  Center for Rheumatology

  17 shared

• Michael M. Binkley

  Washington University in St. Louis

  17 shared

• Peter Kang

  Saint Peter's University

  17 shared

• Jin‐Moo Lee

  Mallinckrodt (United States)

  17 shared

Labs

• Miner LabPI

Awards & honors

• Ann Palmenberg Award from the American Society for Virology
• Member of the American Society for Clinical Investigation (A…