Research Advances in PRA: From Gene Discovery to Vision Restoration

When I began my career in veterinary ophthalmology, we could diagnose PRA but knew little about its genetic basis. We could not distinguish one form from another except through clinical progression patterns. We certainly could not offer treatment. The transformation over subsequent decades represents one of the great success stories of veterinary genetic research.

Today, we have identified over 20 distinct genes causing PRA in different breeds. DNA tests allow precise diagnosis and prevention. Gene therapy has moved from laboratory curiosity to FDA-approved human treatment, with canine applications expanding. The pace of discovery continues to accelerate, bringing hope for breeds and variants still lacking solutions.

The Gene Discovery Era

The first PRA-causing gene, PDE6B in Irish Setters, was identified in 1993. This breakthrough established that PRA could be characterized at the molecular level and that dogs could serve as models for human inherited retinal disease. The discovery opened floodgates of research that continue today.

Each gene discovery enables development of specific DNA tests, allowing precise identification of affected, carrier, and clear dogs. The cumulative effect has been transformation of PRA from mysterious blindness to predictable and preventable genetic condition in many breeds.

The Gene Therapy Revolution

Perhaps no development has generated more excitement than gene therapy. The concept is elegantly simple: if a mutation prevents production of a functional protein, deliver a working copy of the gene to restore that function. The execution required decades of refinement, but the results have validated the approach.

The Briard work proved that large animal blindness could be treated with gene replacement. Dogs went from non-functional vision to confidently navigating obstacle courses. This proof of principle enabled the human trials that culminated in Luxturna approval, the first FDA-approved gene therapy for inherited disease.

Current Research Priorities

Active research programs address several PRA-related challenges:

New Variant Identification

Several breeds still harbor PRA forms without identified causative mutations. Border Collies, Tibetan Spaniels, and certain Mastiff lines show clinical PRA that does not map to known variants. Genome-wide association studies and whole genome sequencing approaches continue to identify candidate genes.

Recent technological advances have dramatically reduced sequencing costs, enabling larger studies with more affected dogs. What once required years of linkage analysis can now be accomplished in months with next-generation sequencing approaches.

Expanded Gene Therapy Targets

Research groups are developing gene therapy approaches for additional mutations beyond RPE65. Current programs include:

• CNGB1 (PRA1 in Papillons) - Clinical trials in dogs showing promising results
• RPGR (X-linked retinal dystrophy) - Human trials ongoing, informed by canine research
• PRCD - Early research given the large affected population across breeds
• PDE6B - Research addressing the Irish Setter and Collie variants

Alternative Therapeutic Approaches

Beyond gene replacement, researchers explore additional strategies:

Gene editing: CRISPR-based approaches could potentially correct mutations rather than adding replacement genes. Early research shows promise, though significant challenges remain regarding delivery and efficiency.

Optogenetics: For advanced cases where photoreceptors have died, introducing light-sensitive proteins into surviving retinal cells might restore rudimentary vision. This approach could help dogs with late-stage PRA who would not benefit from gene therapy targeting photoreceptors.

Neuroprotection: Compounds that slow photoreceptor death could extend the therapeutic window for gene therapy or preserve useful vision longer. Several candidate molecules are under investigation.

The Human-Canine Research Partnership

PRA research exemplifies the one-medicine concept, recognizing that discoveries in one species illuminate biology across species. The partnership between veterinary and human ophthalmology has been remarkably productive.

Dogs provide advantages as research models: they develop spontaneous inherited retinal diseases analogous to human conditions, their eyes are similar in size to human eyes, and they live long enough to assess treatment durability. Discoveries in dogs enable human clinical trials, while human research informs refinements in canine protocols.

The child who can now see stars because of Luxturna owes that vision partly to Lancelot the Briard and the dogs who followed. Understanding how dogs adapt to vision loss also informs human research. The Papillon whose vision might be preserved by future CNGB1 therapy will benefit from lessons learned in human RPE65 trials. This bidirectional flow accelerates progress for both species.

Impact on Breed Health Programs

Research advances have practical implications for breeding programs. Each new gene identified enables a new DNA test. Each new test allows more precise carrier management. The cumulative effect has been dramatic reduction in PRA frequency in breeds that embrace testing.

Irish Setters provide the clearest example. After rcd1 identification in 1993 and subsequent test development, systematic testing and breeding reduced carrier frequency from over 30% to near zero over two decades. The breed demonstrates what becomes possible when research, testing, and breeding practice align.

Similar progress is underway in other breeds, though at different stages. The challenge lies in maintaining momentum, encouraging universal testing, and ensuring that newly identified variants are incorporated into breeding protocols promptly.

Challenges and Limitations

Despite remarkable progress, significant challenges remain:

• Treatment accessibility: Gene therapy remains expensive and available only at specialized centers. Cost barriers limit access for many affected dogs and their owners.
• Timing constraints: Gene therapy works best before significant photoreceptor loss. Early diagnosis is essential for treatment eligibility.
• Variant coverage: Approved treatments target specific mutations. Dogs with other variants cannot benefit until research addresses their particular genes.
• Testing gaps: Some breeds lack tests for all their PRA variants. Incompletely characterized breeds face ongoing risk despite testing available variants.

Future Directions

Looking ahead, I anticipate continued acceleration of progress. Sequencing costs will continue declining, enabling identification of remaining uncharacterized variants. Gene therapy platforms will expand to address additional mutations. Alternative approaches may provide options for late-stage disease.

Most importantly, I hope for cultural change in breeding communities. The tools for prevention exist. Research has provided the knowledge and the tests. What remains is universal adoption of testing protocols and breeding practices that eliminate affected offspring.

Every affected dog born today represents not just individual suffering but missed opportunity to apply available knowledge. Research has done its part. The responsibility now lies with breed communities to use what research has provided. When they do, PRA will become a historical footnote rather than ongoing tragedy. The Herding Gene resource tracks research developments affecting herding and working breeds specifically.

Dr. Amanda Foster, Veterinary Ophthalmologist