Unilateral gene therapy surprisingly improves visions in both eyes

gene therapy restores vision

Date: 14th December 2020

Leber hereditary optic neuropathy (LHON) is the most common inherited mitochondrial disorder affecting around 1 in 30,000 to 50,000 people. It is characterised by selective loss of retinal ganglion cells (RGCs) and their axons, which causes optic nerve degeneration and can lead to vision loss in just a few weeks after disease onset.  Now, scientists have reported they have successfully administered gene therapy to 37 patients to correct LHON in a Phase 3 trial. Surprisingly 78% experienced a significant visual improvement in both eyes, even though only one eye had been treated.

Three mitochondria DNA (mtDNA) point mutations account for about 90% of all LHON cases, and affect the complex I subunits of the mitochondrial respiratory chain, impairing mitochondrial function and increasing the production of reactive oxygen species.  Whilst, LHON is amenable to gene therapy as it has well-defined onset and progression, and RGCs are easily accessible, it is challenging as mitochondria disorders add a layer of complexity as the wild type therapy protein has to reach the mitochondrial compartment.

Now a team of scientists led by Patrick Yu-Wai-Man from the University of Cambridge, UK, and José-Alain Sahel from the University of Pittsburgh, US, and the Institut de la Vision, France, have used a recombinant replication-defective adeno-associated virus, AAV, to deliver a modified complementary DNA encoding NADH-ubiquinone oxidoreductase chain 4 (ND4) into one eye of LHON patients.  The team unexpectedly found significant vision improvement in both eyes, and showed in non-human primates this may be due to viral vector DNA transfer between the eyes.

The team enrolled 37 subjects with LHON due to one specific mutation (m.11778G>A) who had experienced vision loss between 6 to 12 months.  The participants were injected into the vitreous humour of one eye with an AAV carrying DNA encoding the human wild-type mitochondrial ND4 protein.  This also contained a specific mitochondrial targeting sequence (MTS) that allowed translocation of the protein in to the mitochondrial matrix.  The unilateral treatment-injection was performed under the assumption that the therapeutic effects of treated versus untreated/sham injected eyes would be compared.

The participants were examined after 96 weeks and whilst the team found a clinically relevant response was higher in the treated eyes (62%) compared with the sham eye group (42%) they were surprised to find around 78% of participants had increased vision in both eyes.  To put this in perspective this accounted for a mean improvement in best-corrected visual acuity (BCVA) of 15 letters on an ETDRS chart (a standard test) for the treated eyes – representing three lines of vision, while a mean improvement of 13 letters was observed in the sham treated eyes.

Intrigued by increased vision in both eyes, the team went on to investigate this further in a non-human primate model, cynomolgus macaques, as this species has a similar vision system to us.  Here, they found that there was evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral non-injected eye providing a mechanistic explanation for vision improvement in both eyes.

Conclusion and future applications

The team here have shown bilateral improvement of visual function in LHON subjects treated with a unilateral intravitreal injection with ND4-AAV, likely due to viral DNA transfer between the eyes.  Although this underlying transfer needs further investigation, it could have profound implications for gene therapy clinical trial design and outcome measures.

The team hope this method of preserving RGC function and improving the patient’s visual prognosis will be life-changing for patients and that sight-saving gene therapy is now a reality.  The treatment has been shown to be safe and the team are now exploring the optimal therapeutic window.

This work adds to the flurry of recent gene therapies designed to restore vision. From reprogramming retina cells, to restore youthful DNA methylation patterns, which promoted axon regeneration – to gene therapy to deliver an adapter molecule, Protrudin, into the eye which stimulated axon regeneration of the damaged nerve fibres, and protected them from cell death after injury – or the delivery of a highly photosensitive multi-characteristic opsin (MCO1) protein into retina bipolar cells.

However, whilst these preclinical trials are showing promising results in mice, this Phase 3 trial in humans offers a tangible therapy that should translate into a treatment in the not so distant future, offering hope to LHON sufferers. From a wider perspective this approach could also be applied to treating other types of mitochondrial diseases.


For more information please see the press release from the University of Cambridge


Yu-Wai-Man, P., N. J. Newman, V. Carelli, M. L. Moster, V. Biousse, A. A. Sadun, T. Klopstock, C. Vignal-Clermont, R. C. Sergott, G. Rudolph, C. La Morgia, R. Karanjia, M. Taiel, L. Blouin, P. Burguière, G. Smits, C. Chevalier, H. Masonson, Y. Salermo, B. Katz, S. Picaud, D. J. Calkins and J.-A. Sahel (2020). “Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.” Science Translational Medicine 12(573): eaaz7423.