About

Brian Hafler, MD, PhD, is an associate professor of ophthalmology and visual science at Yale School of Medicine. He specializes in the treatment of complex retinal diseases, including age-related macular degeneration (AMD), glaucoma, and stem cell regeneration. His clinical practice is complemented by a research focus on understanding how inflammation and other factors contribute to retinal degeneration, with the aim of developing new treatments to prevent vision loss and improve patient outcomes. Dr. Hafler earned his medical and doctorate degrees from Harvard Medical School, completed his internship at Yale New Haven Hospital, and a fellowship at Massachusetts Eye and Ear Infirmary. His research has led to significant contributions, such as generating the first single-cell human retinal transcriptomic atlas and identifying cell types involved in macular degeneration. He has received numerous awards, including the American Society for Clinical Investigation Young Physician Scientist Award, the Thome Memorial Foundation Award for AMD Research, and the William R. Orthwein, Jr. ’38 Yale Scholar. His work is focused on studying macular degeneration and glaucoma using advanced techniques like single-cell transcriptomics to identify novel therapeutic approaches.

Research topics

• Medicine
• Biology
• Neuroscience
• Ophthalmology
• Endocrinology
• Pathology
• Physiology
• Immunology

Selected publications

• A hierarchical electrical synaptic circuit mechanism for integrative parallel visual processing in the retina

  Neuron · 2026-02-19

  articleOpen access
  PublisherOA PDFDOI

• Intracellular protein GBF1 displays significant associations with amyloid pathology in Alzheimer's disease

  Alzheimer s & Dementia · 2026-04-01

  articleOpen access

  INTRODUCTION: Despite the identification of familial Alzheimer's disease (FAD) genes and neuropathological alterations, AD displays complex genetic heterogeneity and molecular pathogenesis that warrant further investigation. GBF1 (Golgi brefeldin A resistant guanine nucleotide exchange factor 1) regulates protein trafficking, and genetic variants of GBF1 are associated with axonal neuropathy, intelligence, and cognitive function. METHODS: We sought to identify GBF1 neuropathological and molecular alterations using human post mortem brains, 5XFAD mouse brains, and FAD cells, as well as two family-based datasets (total sample size of 2522) to explore candidate GBF1 variants associated with AD. RESULTS: GBF1 revealed neuropathological alterations in association with amyloid plaques. Genetic analysis identified GBF1 suggestive variants associated with AD. Downregulation of GBF1 retarded amyloid beta (Aβ) protein precursor maturation and reduced levels of Aβ proteins. DISCUSSION: Collectively, GBF1 reveals neuropathological alterations in AD, and may lead to AD by a pathogenic mechanism altering Aβ levels and amyloid deposition in the brain.

  PublisherDOI

• The central cholinergic system as a therapeutic target in Parkinson's disease

  Journal of Parkinson s Disease · 2026-03-19

  articleOpen accessSenior author

  The central cholinergic system plays a crucial role in neural communication and physiological regulation, mediated by acetylcholine (ACh) and cholinergic receptors in the central nervous system (CNS). In this review, we explore the extensive distribution and impact of the central cholinergic system and its pivotal involvement in Parkinson's disease (PD). Despite PD being traditionally perceived as primarily a dopaminergic disorder, it exhibits significant cholinergic alterations, contributing to both motor and non-motor symptoms. These PD-specific alterations manifest as neuroanatomical changes, diminished acetylcholinesterase activity, and functional disturbances across various brain regions, impacting cognition, mood, sensory perception, sleep, and motor function. Comprehension of these cholinergic dysfunctions is paramount for the development of targeted therapies aimed at alleviating these PD symptoms. To provide further insight, we explore the therapeutic potential of nicotinic acetylcholine receptors (nAChRs) in PD, highlighting their role in preventing apoptosis, modulating neuroinflammation, and mitigating CNS damage. In summary, this review underscores the critical importance of cholinergic mechanisms in PD pathology and champions cholinergic-based interventions for enhanced patient outcomes and improved quality of life.

  PublisherDOI

• 415 Designing nanoparticle therapies for age-related macular degeneration

  Journal of Clinical and Translational Science · 2026-04-01

  articleOpen accessSenior author

  Objectives/Goals: Our objective in this study was to develop a nanoparticle-based RNA delivery system that reprograms Müller glia toward neuronal fates in human relevant models, enabling localized and transient regeneration without viral vectors. Methods/Study Population: - Results/Anticipated Results: Fabricated nanoparticles encapsulating RNA cargoes were ~110–150 nm in size with polydispersity indices of ~0.2–0.3 and encapsulation efficiencies >95%. Nanoparticles successfully delivered GFP mRNA in both organoid and retinal explant models, showing significant expression of fluorescent reporters in both live cell imaging and in slides prepared using immunohistochemistry. We anticipate that our delivery system will lead to transcription factor expression after delivery of corresponding RNAs with evidence of proliferation and neuronal marker upregulation. We also hypothesize that this approach will enhance neurogenesis in retinal organoids and explants, potentially establishing a platform for non-viral retinal regeneration. Discussion/Significance of Impact: This work demonstrates a clinically translatable, virus-free strategy for retinal repair through targeted RNA delivery. By enabling transient expression of neurogenic factors, nanoparticle-mediated reprogramming presents a scalable and adaptable approach for restoring vision in degenerative retinal diseases.

  PublisherOA PDFDOI

• Scaling Large Language Models for Next-Generation Single-Cell Analysis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-17 · 27 citations

  preprintOpen access

  Single-cell RNA sequencing has transformed our understanding of cellular diversity, yet current single-cell foundation models (scFMs) remain limited in their scalability, flexibility across diverse tasks, and ability to natively integrate textual information. In this work, we build upon the Cell2Sentence (C2S) framework, which represents scRNA-seq profiles as textual "cell sentences," to train Large Language Models (LLMs) on a corpus comprising over one billion tokens of transcriptomic data, biological text, and metadata. Scaling the model to 27 billion parameters yields consistent improvements in predictive and generative capabilities and supports advanced downstream tasks that require synthesis of information across multi-cellular contexts. Targeted fine-tuning with modern reinforcement learning techniques produces strong performance in perturbation response prediction, natural language interpretation, and complex biological reasoning. This predictive strength enabled a dual-context virtual screen that nominated the kinase inhibitor silmitasertib (CX-4945) as a candidate for context-selective upregulation of antigen presentation. Experimental assessment in human cell models unseen during training supported this prediction, demonstrating that C2S-Scale can effectively guide the discovery of context-conditioned biology. C2S-Scale unifies transcriptomic and textual data at unprecedented scales, surpassing both specialized single-cell models and general-purpose LLMs to provide a platform for next-generation single-cell analysis and the development of "virtual cells."

  PublisherOA PDFDOI

• The amyloid-beta wave hypothesis of Alzheimer’s disease

  Frontiers in Cellular and Infection Microbiology · 2025-11-25

  reviewOpen accessSenior author

  Alzheimer's disease (AD) is a complex and multifactorial disorder that affects all races and genders. Genetic traits influenced by lifestyle and environment lead to a tremendous amount of heterogeneity in Alzheimer's disease onset and severity. Regardless of these unique contributing factors, Alzheimer's disease is traditionally met with amyloid-beta plaque formation in the central nervous system. In this commentary, we shed light on the growing literature surrounding amyloid-beta's ability to act as an antimicrobial peptide in the central nervous system's innate immune response to pathogenic infections. We hypothesize that there are, "amyloid-beta waves" that are created by the responses of neuroglia and neurons to microbial pathogens. The improper clearance and residual buildup of amyloid-beta waves throughout life increases the likelihood of developing Alzheimer's disease. In conclusion, we suggest that anti-amyloid therapies during pathogenic infections or flare-ups may slow the development of Alzheimer's disease by reducing amyloid-beta waves throughout the aging of individuals.

  PublisherOA PDFDOI

• A painless nerve growth factor variant uncouples nociceptive and neurotrophic TrkA signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-18 · 1 citations

  preprintOpen access

  Abstract Nerve growth factor (NGF) binding to the receptor tyrosine kinase, TrkA, drives neurotrophic signaling essential for neuronal development and survival. This interaction simultaneously drives peripheral pain, making this pathway an attractive but complicated therapeutic target for chronic pain. By integrating single-molecule microscopy, structural and electrophysiology analyses, with a human NGF variant, NGF painless , which retains neurotrophic effects but abolishes pain, we delineate the molecular mechanisms that bias TrkA signaling towards neurotrophic functions without triggering nociception. We show that, unlike wild-type NGF, NGF painless fails to sensitize TRPV1 channels to capsaicin, thus disengaging TrkA from the nociceptive pathway. We further show that this selective loss of nociceptive TrkA signaling by NGF painless results from its reduced ability to activate PLCγ1 and trigger calcium release compared to NGF, while still preserving the ERK and AKT signaling essential for neurotrophic functions. This biased signaling arises from reduced electrostatic complementarity at the TrkA:NGF painless complex interface, which shortens the lifetime of this functional complex on native membranes. Mutations in TrkA that restore the electrostatic complementarity at the TrkA:NGF painless interface eliminate biased signaling. This mechanistic understanding of TrkA binding by NGF painless , and how it differs from NGF, will spur the development of two therapeutic classes of molecules - one that selectively suppresses nociceptive signaling while preserving neurotrophic functions in chronic pain, and another that enhances neurotrophic activity without evoking peripheral pain in neurodegenerative conditions.

  PublisherOA PDFDOI

• SARS-CoV-2 induces Alzheimer’s disease–related amyloid-β pathology in ex vivo human retinal explants and retinal organoids

  Science Advances · 2025-07-04 · 8 citations

  articleOpen accessSenior authorCorresponding

  While the etiology of Alzheimer's disease remains unknown, there is growing support for the amyloid-β antimicrobial hypothesis. Amyloid-β, the main component of amyloid plaques in Alzheimer's disease, has been shown to be generated in the presence of microbes. Entrapment of microbes by aggregated amyloid-β may serve as an innate immune response to pathogenic infections. To understand the association of amyloid-β plaques and pathogenic infections in the central nervous system, we obtained viable short-interval postmortem human retinal tissue and generated human retinal organoids that contain electrophysiologically active neurons. Here, we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces amyloid-β extracellular protein aggregates in human retinal explants and retinal organoids. Last, pharmacological inhibition of neuropilin-1 resulted in reduced amyloid-β deposition in human retinal explants treated with SARS-CoV-2 Spike 1 protein. These results suggest that Spike 1 protein, during infection with SARS-CoV-2, can induce amyloid-β aggregation, which may be associated with the neurological symptoms experienced in COVID-19.

  PublisherDOI

• R-Spondin 1 Suppresses Inflammatory Cytokine Production in Human Cortical Astrocytes

  Neuroglia · 2024-11-11 · 1 citations

  articleOpen access

  Background/Objectives: Wnt signaling pathways are essential in various biological processes, including embryonic development and tissue homeostasis, and are implicated in many diseases. The R-Spondin (RSpo) family, particularly RSpo1, plays a significant role in modulating Wnt signaling. This study aims to explore how RSpo1 binding to astrocytic LGR6 receptors influences central nervous system (CNS) homeostasis, particularly in the context of inflammation. Methods: Human-induced pluripotent stem cell-derived astrocytes were treated with RSpo1 to assess its impact on inflammatory cytokine release. A proteomic analysis was conducted using a Human Cytokine Array Kit to measure differential protein expression. Pathway enrichment analysis was performed to identify affected signaling pathways. Results: RSpo1 treatment led to a suppression of inflammatory cytokines such as IL-10, IFN-γ, and IL-23 in astrocytes, while TNF-α and CXCL12 levels were increased. Pathway analysis revealed significant alterations in key signaling pathways, including cytokine–cytokine receptor interaction, chemokine signaling, and TNF signaling pathways, suggesting RSpo1’s role in modulating immune responses within the CNS. Conclusions: RSpo1 significantly influences inflammatory responses in astrocytes by modulating cytokine release and altering key signaling pathways. These findings enhance our understanding of the interaction between cell-specific Wnt signaling and CNS inflammation, suggesting potential therapeutic applications of RSpo1 in neuroinflammatory and neurodegenerative diseases.

  PublisherOA PDFDOI

• Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in <i>Mertk</i> -associated retinitis pigmentosa

  Science Advances · 2023-01-20 · 29 citations

  articleOpen access

  Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation are determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3 . Here, we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk −/− mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration–associated with Mertk loss of function.

  PublisherDOI

Recent grants

• Identification of the genetic pathways that give rise to the chicken rod-free zone and human fovea using epigenomic profiling

  NIH · $1.4M · 2019–2021

• Targeting the inflammatory response in age-related macular degeneration

  NIH · $1.6M · 2022–2027

Frequent coauthors

• Sarah Wassmer

  Health Canada

  16 shared

• Lívia S. Carvalho

  University of Western Australia

  16 shared

• Luk H. Vandenberghe

  Smith-Kettlewell Eye Research Institute

  16 shared

• Leo A. Kim

  Harvard University

  16 shared

• Aliete Langsdorf

  Innovative Genomics Institute

  14 shared

• David M. Wu

  Harvard University

  14 shared

• Lawrence Lim

  Smith-Kettlewell Eye Research Institute

  12 shared

• Dean Eliott

  Harvard University

  12 shared

Labs

• Ophthalmology Interest Group (OIG)PI

Education

• B.A.

  Princeton University

• Other

  Harvard Medical School

Awards & honors

• American Society for Clinical Investigation Young Physician…
• Thome Memorial Foundation Award for AMD Research
• William R. Orthwein, Jr. ’38 Yale Scholar
• Cushing Foundation Award for excellence and creativity in sc…