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Breakthroughs in the field of gene therapy for Leber's hereditary optic neuropathy (LHON) are profoundly changing our understanding of this rare and debilitating disease, which mainly affects young adults, causing sudden vision loss in one or both eyes usually around the age of 20.

News from genetic research

Prof. Alfredo Sadun, a neuro-ophthalmologist who heads the Department of Ophthalmology at the University of California's Doheny Eye Institute, led an studio innovative on the effects of gene therapy in LHON. The work of his research team reported a surprising result: the injection of AAV2 viral vectors improved vision in LHON patients in both eyes, even though the injection was administered in only one eye.

Gene therapy in LHON

Gene therapy for LHON is based on the use of viral vectors to introduce corrective genes into cells affected by the disease.

I viral vectors are genetically modified viruses capable of transmitting and expressing specific genes within host cells. These viruses exploit their natural ability to infect cells and release their genetic material, allowing external genes, known as 'transgenes', to be inserted into the genome of the host cell.

In the case of LHON, theAdeno-Associated Virus type 2 (AAV2), injected intravitreally as a vehicle to transport the correct genetic material into the target cells.

Unexpected Effects of Gene Therapy

At 96 weeks of rAAV2/2-ND4 injection, LHON patients carrying the m.11778G>A mutation and treated within 6 months of vision loss had visual improvements in both the eye that had received the injection and in the contralateral eye.

The presence of the corrective gene in both eyes suggests a diffusion mechanism that, according to scientists' hypotheses, could involve the central nervous system or other as yet unidentified pathways, such as the lymphatic system or other body fluids.

Implications for Other Eye Diseases

The discoveries made in the treatment of LHON could be applied to other inherited retinal diseases, such as Leber's congenital amaurosis and retinitis pigmentosa, for which there are currently no effective treatments.

Challenges and Limits of Therapy

Despite promising results, gene therapy still has some critical aspects, such as:

• Immune reactionspatients could develop immune responses against viral vectors.
• Long-term effectivenessThe duration of the positive effects of therapy is not yet defined.
• Costs and accessibilityProduction and application of gene therapy involve high costs.

Addressing these obstacles will be essential for the future success of gene therapies.

Clinical Trial Results

The Doheny Eye Institute study enrolled two patients with LHON who were treated with gene therapy. Both patients received an injection of the AAV2 vector in one eye, while the other eye was used as a control.

• Patient 1showed a distribution of the corrective gene in both eyes, with a higher concentration in the treated eye.
• Patient 2gene distribution was similar, but with less post-treatment inflammation.

Post-Mortem Observations

Both patients treated with intravitreal AAV2 unfortunately died, which provided the opportunity to perform post-mortem analyses of their ocular tissues to assess the presence and distribution of the corrective gene.

The analysis confirmed the bilateral presence of the gene in retinal tissues, supporting clinical observations. These data proved crucial to better understand how gene therapy interacts with ocular cells.

Differences between Patients

The differences in the results observed in the two patients underline the complexity of the effects of gene therapy.

• Immune response: Varies according to individual factors.
• Gene distributionMay differ depending on the specific biology of the individual.

These variations indicate the need to customise treatments to optimise results.

Long-Term Impacts

Gene therapy has been shown to improve vision in patients with LHON, but the duration of the positive response and the possibility of long-term side effects require prolonged monitoring of treated patients.

In addition, it appears that the age of patients can significantly influence the effectiveness of gene therapy.

Studies suggest that:

• Young adultsThey may respond better to treatment, due to increased biological plasticity.
• Older adultsThey may have a potentially reduced response.

These results are crucial for optimising treatment protocols.

Prospects for Future Treatments

Current discoveries open the way to new possibilities for the treatment of other genetic eye diseases, through:

• Expansion of therapeutic indications
• Development of new carriers
• Improved effectiveness and safety.

New Directions of Investigation

The future of gene therapy is promising, but requires further research that should focus on hitherto little explored areas.

• Mechanisms of action at the cellular level: Studying how genes influence target cells.
• Pathways of gene diffusion: To better understand how genes spread through the body.

I vascular and lymphatic tissues could play a crucial role in the spread of the corrective gene. Scientists are exploring whether these tissues can be used as natural vectors for gene distribution.

The identification of new gene transfer circuits could revolutionise the way treatments are designed.

Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Biousse V, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Barboni P, DeBusk AA, Girmens JF, Rudolph G, Karanjia R, Taiel M, Blouin L, Smits G, Katz B, Sahel JA; LHON Study Group. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset. Ophthalmology. 2021 May;128(5):649-660. doi: 10.1016/j.ophtha.2020.12.012.