Hereditary Ophthalmic Diseases

Hereditary ophthalmic diseases are a diverse group of genetic disorders that primarily affect the structure and function of the eye. These inherited conditions can lead to a wide range of vision impairments, from mild refractive errors to complete blindness. At Protheragen, our team of experienced rare disease and biology experts has been working for many years to improve one-stop genetic eye disease drug and therapy development solutions.

Introduction to Hereditary Ophthalmic Diseases

Hereditary ophthalmic disease drug and therapy development encompasses the preclinical research and translational processes aimed at creating targeted treatments for vision disorders caused by genetic mutations. These disorders are heterogeneous, with pathogenic variants in over 250 genes identified to date, predominantly affecting photoreceptor cells, retinal pigment epithelium (RPE), or other ocular tissues. Preclinical development in this field focuses on unraveling disease mechanisms, validating therapeutic targets, and evaluating candidate interventions using in vitro and in vivo models before advancing to clinical trials.

The core objective of preclinical development for hereditary ophthalmic diseases is to generate robust evidence of safety, efficacy, and delivery feasibility—critical prerequisites for regulatory approval of investigative new drugs (IND). This process integrates genomic analysis, disease modeling, and therapeutic testing to address the unique challenges of ocular genetics, such as variant heterogeneity, tissue-specific drug delivery, and long-term durability of treatment effects. Key areas of focus include correcting or mitigating pathogenic mutations, preserving remaining visual function, and halting disease progression, as most hereditary ophthalmic conditions are progressive and currently untreatable.

Fig.1 Genomics in hereditary eye diseases. (Singh M, et al., 2018)

Genetic Factors of Ophthalmic Diseases

Current Status of Hereditary Ophthalmic Disease Therapy Development

Preclinical development pathways vary by therapeutic modality but share foundational steps: target validation through genomic and functional studies, candidate compound or vector design, efficacy testing in disease-relevant models, and comprehensive safety assessments. For gene-based therapies, this includes optimizing editing precision, vector tropism, and delivery systems to minimize off-target effects and maximize tissue penetration. For small molecules or biologics, it involves characterizing pharmacokinetics/pharmacodynamics (PK/PD) profiles in ocular tissues and evaluating potential toxicity to delicate structures like the retina and optic nerve.

Current Status of Hereditary Ophthalmic Disease Therapy Development

Preclinical research for hereditary ophthalmic diseases has advanced significantly with the advent of gene editing technologies and improved disease modeling. Gene augmentation therapy, which delivers functional copies of mutated genes, has set a precedent with the approval of voretigene neparvovec-rzyl for RPE65-associated Leber Congenital Amaurosis (LCA), but this modality is limited to autosomal recessive or X-linked disorders caused by small, packagable genes. This limitation has driven intense preclinical focus on gene editing tools capable of addressing a broader spectrum of mutations, including large insertions/deletions, autosomal dominant variants, and silenced genes.

CRISPR/Cas systems have emerged as the leading gene editing platform in preclinical studies, outperforming zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) due to their versatility, efficiency, and scalability. Preclinical investigations have demonstrated CRISPR's potential to correct pathogenic variants in models of retinitis pigmentosa (RP), LCA, and X-linked retinitis pigmentosa (XLRP), with ongoing work optimizing delivery systems to enhance retinal targeting. Adeno-associated virus (AAV) vectors remain the most widely studied delivery vehicle, though preclinical efforts are exploring lipid nanoparticles and engineered viral vectors to improve transduction efficiency and reduce immunogenicity.

Disease modeling has undergone transformative advances, with genetically modified animal models and human-induced pluripotent stem cell (iPSC)-derived organoids becoming indispensable preclinical tools. Mouse models such as the rd (retinal degeneration) strain, which mimics autosomal recessive RP, have been foundational for understanding disease mechanisms, while larger animals like pigs—with ocular anatomy, vasculature, and photoreceptor distribution similar to humans—are increasingly used for translational efficacy testing. Zebrafish models, with their cone-dominant vision and conserved retinal architecture, enable high-throughput screening of therapeutic candidates and rapid phenotypic characterization.

Despite progress, preclinical development faces significant challenges. Translating efficacy from animal models to humans remains hindered by species-specific differences in disease progression, particularly for age-related retinal disorders that are difficult to recapitulate in short-lived animals. Additionally, preclinical safety assessments must address potential ocular toxicities, including retinal inflammation, photoreceptor loss, and off-target genetic modifications. For XLRP and other severe subtypes, preclinical studies have shown promising results with gene therapy but have yet to yield approved treatments, highlighting the need for improved model validation and translational endpoints.

Table 1. Clinical trials registered on clinicaltrials.gov for different hereditary ophthalmic diseases. (Niu Y., et al., 2024)

Disclaimer: Protheragen focuses on providing preclinical research service. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Protheragen is committed to advancing the field of hereditary ophthalmic disease therapeutic through innovative drug and therapy development services. Our approach is grounded in a deep understanding of the genetic underpinnings of these diseases, allowing us to develop targeted and personalized therapeutic strategies.

Genomic Analysis and Target Validation

Protheragen provides comprehensive genomic services to identify and validate causal variants in hereditary ophthalmic diseases. This includes whole exome and genome sequencing, copy number variant analysis, and variant prioritization using custom bioinformatics pipelines. We offer functional validation studies to confirm the pathogenicity of candidate variants, leveraging in vitro assays to assess gene expression, protein function, and cellular phenotypes in ocular cell lines. Clients can access support for familial segregation analysis and variant classification to meet regulatory standards for target validation.

Custom Disease Model Generation

We deliver tailored in vitro and in vivo disease models to recapitulate key features of hereditary ophthalmic disorders. In vitro models include iPSC-derived retinal organoids and RPE cells, generated from patient samples or CRISPR-edited healthy donor lines to enable direct comparison of wild-type and mutant phenotypes. In vivo models encompass genetically modified mice, zebrafish, and large animal models (such as pigs) engineered to carry disease-specific mutations, including those associated with RP, LCA, choroideremia, and Stargardt disease. All models undergo rigorous phenotypic characterization, including retinal morphology, visual behavior, and photoreceptor function analysis.

Therapeutic Candidate Evaluation

Our preclinical evaluation services assess the efficacy and safety of gene therapies, small molecules, and biologics. For gene-based therapies, we offer vector design optimization, transduction efficiency testing, and gene editing precision analysis. Efficacy studies include phenotypic rescue assays, photoreceptor survival quantification, and functional vision assessments using electroretinography (ERG) and behavioral tests. For small molecules and biologics, we conduct PK/PD profiling in ocular tissues, cell viability assays, and immunofluorescence analysis of key retinal markers to evaluate target engagement and therapeutic effect.

Delivery System Optimization

Protheragen supports the development and optimization of ocular delivery systems to enhance therapeutic bioavailability and tissue targeting. Services include AAV vector engineering to improve retinal tropism, lipid nanoparticle formulation for non-viral delivery, and stability testing under physiological conditions. We evaluate delivery efficiency using in vitro retinal organoid models and in vivo distribution studies, measuring transgene expression or compound accumulation in target tissues (retina, RPE, optic nerve) while assessing off-target tissue exposure.

Types of Hereditary Ophthalmic Diseases

Our Therapeutics Development Solutions

Diagnostics Development

• Karyotype Analysis Service
• Omics Analysis Service
• Biomarker Development Service
• Artificial Intelligence Service

Therapeutic Development

• Small Molecule Drug
• Cell Therapy
• Gene Therapy
• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein

Disease Models

• Cell-based Models Development Service
• Organoid Models Development Service
• Animal Models Development Services

Preclinical Research

• Pharmacodynamics Study Services
• Pharmacokinetics Study Services
• Drug Safety Evaluation Services
• Customized Research Services

At Protheragen, we pride ourselves on our unwavering commitment to delivering cutting-edge drug and therapy development solutions for hereditary ophthalmic diseases. If you are interested in our services, please feel free to contact us for more details and quotation information of related services.

References

• Singh, Mahavir, and Suresh C. Tyagi. "Genes and genetics in eye diseases: a genomic medicine approach for investigating hereditary and inflammatory ocular disorders." International journal of ophthalmology 11.1 (2018): 117.
• Niu, Yifei, et al. "Regenerative treatment of ophthalmic diseases with stem cells: Principles, progress, and challenges." Advances in Ophthalmology Practice and Research (2024).