Yuan Liu

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease caused primarily by pathogenic mitochondrial DNA (mtDNA) variants that impair respiratory chain complex I function. Although bioenergetic failure, oxidative stress, and retinal ganglion cell degeneration are central features of disease pathogenesis, these mechanisms do not fully explain the incomplete penetrance, male predominance, and marked clinical heterogeneity observed in LHON. Emerging evidence suggests that mitochondrial dysfunction can also trigger sterile inflammatory responses through the release of mitochondrial damage-associated molecular patterns (DAMPs), including mtDNA and reactive oxygen species, and through impaired mitophagic clearance. These signals activate innate immune pathways, including cGAS-STING, TLR9, and the NLRP3 inflammasome, potentially contributing to neuroinflammation, glial activation, and secondary neuronal injury. The relevance of immune signaling has gained further attention with the development of AAV-based gene therapies for LHON, where treatment-associated ocular inflammation has emerged as a clinically important challenge. In this review, we examine the evidence linking mitochondrial dysfunction to innate immune activation in LHON, discuss the immunological mechanisms underlying disease progression and gene therapy-associated inflammation, and highlight emerging opportunities for biomarker development, immunomodulatory intervention, and improved therapeutic design. We propose that LHON should be viewed not only as a disorder of mitochondrial bioenergetics but also as a neuroinflammatory disease shaped by the interplay between mitochondrial stress and immune signaling.

The purpose of this study was to establish preclinical safety data to advance mitochondrial targeted AAV-delivered human ND4 (MTSAAV/hND4) for treatment of Leber Hereditary Optic Neuropathy (LHON). MTSAAV/hND4 was bilaterally injected into mouse eyes to evaluate potential adverse effects on visual function using serial pattern electroretinograms (PERGs) and spectral-domain optical coherence tomography (SD-OCT). In rats, MTSAAV/hND4 was administered unilaterally to assess toxicity, biodistribution, and neutralizing antibody levels. Control groups include PBS-injected and untreated naïve mice and rats. No significant adverse effects on visual function were observed in mice treated with MTSAAV/hND4. Retinal thickness remained largely stable, with only a transient, benign increase in RNFL-IPL thickness observed in the low-dose group at 1 month. Postmortem analysis showed no significant differences in RGC density among MTSAAV/hND4-injected mice, PBS-injected controls, and naïve controls (P = 0.214), and axons morphology and distribution were preserved. In rats, viral DNA was primarily detected in the injected eyes with copy number of 4.63 × 10⁴ at day 7 and 4.94 × 103 at day 90 per 100 ng of genomic DNA. Viral DNA levels in non-ocular tissues were low (<500 copies). Histopathological analysis showed no vector-related toxicity. At 6 months post-injection, overall hematological parameters remained within normal limits. All MTSAAV/hND4-injected rats seroconverted by day 90, with neutralizing antibody titers reaching 1:1280. Intravitreal delivery of MTSAAV/hND4 in rodents resulted in favorable biodistribution, with vector DNA largely confined to the injected eye and minimal systemic exposure. No vector-related adverse effects were observed based on functional, anatomic, and histopathological assessments, supporting the ocular safety of this gene therapy strategy. These findings provide preclinical evidence supporting the advancement of MTSAAV-mediated ND4 gene therapy toward clinical trials for LHON.

The retina and optic nerve, as direct extensions of the central nervous system (CNS), provide a unique window into neurological health (1). Neuro-ophthalmology leverages this relationship to diagnose and manage systemic and neurological disorders that manifest in the visual pathway. Neuro-ophthalmic diseases, with their complex pathophysiology and diverse clinical presentations, demand advanced diagnostic tools (2)(3)(4). Recent advancements in multimodal imaging have revolutionized this field, enabling precise visualization of structural and functional changes (5,6). This editorial highlights two research objectives: (1) pioneering novel imaging technologies to redefine clinical paradigms, and (2) uncovering innovative applications of established techniques to enhance diagnostic and therapeutic precision.Elevated Intracranial Pressure: Unveiling Biomarkers with Advanced Imaging Michaela et al. harnessed cutting-edge imaging modalities-including en-face OCT, Bscans, adaptive optics scanning light ophthalmoscopy (AOSLO), and fundus photography-to identify peripapillary hyperreflective ovoid mass-like structures (PHOMS), peripapillary wrinkles (PPW), and retinal folds (RF) as biomarkers for elevated intracranial pressure (ICP). Elevated ICP, a life-threatening condition often linked to idiopathic intracranial hypertension or space-occupying lesions, lacks reliable non-invasive diagnostic tools. PHOMS, appearing as hyperreflective ovoid lesions adjacent to the optic disc on OCT, were previously misclassified as variants of optic disc drusen. However, Michaela et al. demonstrated their distinct association with axoplasmic stasis secondary to optic nerve head compression. This work positions PHOMS as critical biomarkers for early ICP detection, offering clinicians a non-invasive diagnostic avenue.Functional Imaging in Visual Field Defects: Bridging Structure and Function Cheng et al. (2024) reviewed the role of functional imaging techniques-magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and optical coherence tomography (OCT)-in diagnosing visual field defects (VFDs). Traditional perimetry identifies functional deficits but provides limited insight into underlying structural pathology. Cheng et al. emphasized how MRI localizes retrochiasmal lesions (e.g., occipital infarcts), DTI quantifies white matter integrity in the optic radiations, and OCT detects retinal ganglion cell layer thinning. This multimodal approach bridges the gap between functional loss and structural damage, enabling targeted interventions for conditions like glaucoma, optic neuritis, and stroke.The COVID-19 pandemic has unveiled rare but significant neuro-ophthalmic complications. Zhao et al. (2024) conducted the first comparative analysis of COVID-19associated optic neuritis (ON) against classical subtypes, such as neuromyelitis optica (NMO-ON) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-ON). Orbital MRI emerged as pivotal, revealing bilateral, long-segment optic nerve enhancement without intracranial lesions-a hallmark of COVID-19 ON. Additionally, universal optic disc edema on fundus imaging and rapid glucocorticoid response suggested an immune-mediated mechanism, likely triggered by molecular mimicry postinfection. This study underscores the role of multimodal imaging in characterizing emerging diseases and guiding therapy.Qing Xiao et al. demonstrated the utility of optical coherence tomography angiography (OCTA) in distinguishing non-arteritic anterior ischemic optic neuropathy (NAION) from demyelinating optic neuritis (DON). By analyzing peripapillary vessel density changes over time, they found that NAION exhibited early, persistent capillary dropout, while DON showed transient reductions with recovery. This differentiation is critical, as NAION requires vascular risk factor management, whereas DON necessitates immunomodulation. OCTA thus serves as a biomarker for early, accurate diagnosis, improving patient outcomes.In a separate study, Xiao et al. leveraged OCT, OCT angiography (OCTA), and fundus imaging to delineate the characteristics of peripapillary hyperreflective ovoid mass-like structures (PHOMS) across diverse conditions, including tilted disc syndrome, papilledema, and even healthy individuals. Their work emphasized OCT's ability to differentiate PHOMS from optic disc drusen through features like smooth margins and homogeneous hyperreflectivity. OCTA further revealed microvascular changes within PHOMS, suggesting their role as biomarkers of mechanical or inflammatory stress on the optic nerve. This study redefines PHOMS as indicators of axoplasmic stasis rather than drusen variants, highlighting OCT's value in refining neuro-ophthalmic diagnoses.High Myopia and Optic Nerve Head Abnormalities: Multimodal Surveillance Ruihan Hu et al. emphasized the role of multimodal imaging-including OCT, OCTA, fundus photography, and indocyanine green angiography (ICGA)-in diagnosing and monitoring optic nerve head (ONH) abnormalities in high myopia. OCT and OCTA provide highresolution insights into peripapillary atrophy, choroidal thinning, and microvascular dropout, while AI-driven analysis enhances early detection of myopic optic neuropathy. These tools enable personalized interventions to mitigate irreversible vision loss in this growing population.Devahuti Chaliha et al. explored the application of OCT and OCTA in migraine, linking retinal thickness and perfusion deficits to aura severity. Focal capillary constriction and ganglion cell layer thinning suggest neurovascular dysregulation, positioning OCTA as a non-invasive biomarker for migraine subtyping and therapeutic monitoring.The collective advancements highlighted in this Research Topic underscore the transformative role of multimodal imaging in neuro-ophthalmology. From identifying peripapillary hyperreflective ovoid mass-like structures (PHOMS) as biomarkers of elevated intracranial pressure to...