mRNA Therapy for Retinal Neurodegenerative Diseases: Preclinical Promise and Challenges
Potential of mRNA therapy for retinal neurodegeneration
A review has examined the potential use of messenger RNA (mRNA) therapy to protect neurons and suppress pathological angiogenesis in retinal neurodegenerative diseases. However, the evidence for therapeutic effects summarized in the review remains preclinical. According to the abstract, no candidate has yet entered a clinical trial for a retinal indication.
Retinal neurodegeneration is a major cause of irreversible vision loss, and current treatments have limitations. Adeno-associated virus (AAV)-based gene delivery has shown clinical potential, but safety, efficacy, and the size of the genetic payload it can carry are cited as constraints. mRNA is being studied as an alternative: it can rapidly drive protein expression without integrating into the genome.
Lipid nanoparticle delivery and preclinical findings
The review, published in Neural Regeneration Research, summarizes advances in mRNA design, delivery vehicles, and administration routes for retinal applications. Delivery vehicles including lipid nanoparticles (LNPs) have been used in intraocular administration to improve mRNA stability and cellular uptake, and to deliver it to retinal neurons, Müller glia, and the retinal pigment epithelium.
Preclinical studies have used mRNA to express gene-editing tools, transcription factors, and proteins intended to supplement cellular function. The review describes neuroprotective effects and suppression of pathological angiogenesis in models such as optic nerve crush and laser-induced choroidal neovascularization. Favorable ocular safety has also been reported in these models, but these findings do not demonstrate restored vision or prevention of blindness in people.
Repeat-dosing strategies and the gap to clinical use
The review explains that transient expression from mRNA and its relatively low immunogenicity support strategies involving repeat dosing. This does not mean that the clinical safety or long-term efficacy of repeated administration has been established. The abstract does not provide dosing intervals, effect sizes, or cell-specific delivery rates for the individual studies.
The researchers propose repeated, multitarget interventions tailored to disease stage. These strategies are intended to support neuroprotection, axonal regeneration, and neurovascular regulation, but specific approaches suited to complex retinal diseases remain insufficiently explored. Further validation is needed to determine whether preclinical promise can translate into treatment.
The research is described in the review abstract and bibliographic record indexed by Europe PMC.
Retinal neurodegeneration remains a major cause of irreversible vision loss, yet current therapeutic options are limited in effectiveness. Although gene therapies have shown clinical potential, the overexpression platforms they rely on, such as adeno-associated virus DNA, are constrained by safety concerns, limited efficacy, and cargo size restrictions. In contrast, mRNA therapy has gained recognition as a compelling alternative, enabling rapid and efficient protein expression without the risk of genomic integration. This review synthesizes recent advances in mRNA engineering, delivery systems, and administration routes for retinal applications, and highlights strategies to enhance targeting, penetration, and controlled release through interdisciplinary collaboration between ophthalmology and bioengineering. In recent years, engineered mRNA formats, including chemically modified linear, circular, and self-amplifying RNA, can achieve higher translation efficiency within a tunable expression window. The transient nature and relatively low immunogenicity of in vitro transcribed mRNA support repeat dosing without insertional mutagenesis. Advances in nanocarriers, particularly lipid nanoparticles, have enabled preferential delivery to retinal neurons, Müller glia, and pigment epithelium via intraocular administration, while improving mRNA stability and transfection efficiency. In preclinical studies, mRNA has been widely used to deliver gene-editing tools, transcription factors, and supplementary functional proteins. In disease models such as optic nerve crush and laser-induced choroidal neovascularization, mRNA-based therapies enhance neuroprotection and suppress pathological angiogenesis in the injured retina, with favorable ocular safety profiles. However, it remains largely unexplored how the intrinsic advantages of mRNA therapy can be leveraged to develop tailored strategies for complex retinal disorders. Consistent with this gap, mRNA platforms have not yet been widely
Transient protein expression from mRNA can be considered as a research strategy for adjusting therapeutic targets and dosing times to the stage of retinal disease. For example, expressing proteins needed for neuroprotection or axonal regeneration requires evaluating both the delivery vehicle’s ability to reach the relevant cells and the appropriate duration of expression. The review’s value lies in organizing examples and approaches that can inform delivery-vehicle selection and experimental design. It does not establish a treatment for patients. According to the review abstract, no candidate has entered a clinical trial for a retinal indication, and the safety of repeat dosing and sustained therapeutic effects remain to be evaluated separately.