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Cambridge University Science Magazine
Restoring sight to the blind may sound like a task of biblical proportions, but researchers at the University of Cambridge and the University of Pittsburgh have employed a breakthrough gene therapy that can ‘reverse’ the effects of lost vision.

As part of a clinical trial, aptly named the ‘REVERSE’ trial, researchers have successfully used viral gene therapy to target a rare genetic disease known as Leber hereditary optic neuropathy, or LHON, representing a great leap ahead in efforts to restore lost sight. The disease is somewhat distinct from other causes of blindness in that it often affects younger individuals, with symptoms most commonly presenting in a person’s 20s and 30s. The disease itself is characterised by the destruction of retinal ganglion cells and rapid degradation of the optic nerve. Progression can be severe — what begins as just cloudy or blurred vision can lead to near-complete blindness in one or both eyes just weeks later.

Despite the early onset and devastating consequences of LHON, the search for treatments has thus far been limited. ‘As someone who treats these young patients, I get very frustrated about the lack of effective therapies,’ said senior investigator Dr José-Alain Sahel, a professor of ophthalmology at the University of Pittsburgh. This frustration is what motivated Dr Sahel and Dr Patrick Yu-Wai-Man from the University of Cambridge to begin clinical trials of a new targeted therapy to combat the disease.

The treatment harnesses the power of targeted gene therapy, a technique that is gaining popularity in treating diseases with a strong genetic component, like LHON. Gene therapy involves re-programming a type of virus known as an adenovirus, a common (and often harmless) human pathogen known to inject its own viral DNA into the DNA of the host cell it infects. This injection mechanism is hijacked by researchers, who remove nearly all of the adenovirus DNA and instead equip the empty viral shells with a corrected copy of the diseased individual’s mutant gene, with instructions on where to deliver it. The therapy is common practice in the treatment of some cancers, and now famously also behind the Oxford-Astra Zeneca COVID-19 vaccine.

The majority of patients affected by the disease carry one of three mutations in the MT-ND4 gene, a mitochondrial gene whose protein is required for the normal function of the mitochondria. Using gene therapy, the researchers were able to inject the corrected copy of MT-ND4 into the eyes of 37 patients suffering from LHON. This was no easy task, as the dense matrix of proteins and membranes surrounding the mitochondria makes targeting therapies more challenging and required the use of a special target sequence specific to the mitochondrial genome. Notably, the treatment led to a vast improvement in the vision of 78% of patients, even after two years of follow-up.

Encouragingly, despite only injecting one eye with the gene therapy, the researchers observed improvements in the vision of both eyes, as well as the presence of the ‘fixed’ gene in areas distant from the initial point of treatment. This finding was then confirmed in a follow-up study with rhesus macaques, proving the utility of this treatment and offering important insights into how this therapy may be rolled out in everyday practice. ‘Saving sight with gene therapy is now a reality’, said Cambridge researcher Dr Yu-Wai-Man. ‘The treatment has been shown to be safe and we are currently exploring the optimal therapeutic window.’


Patrick Yu-Wai-Man et al. Bilateral Visual Improvement with Unilateral Gene Therapy Injection for Leber Hereditary Optic Neuropathy. Science Translational Medicine; 9 December 2020: DOI:10.1126/scitranslmed.aaz7423

Juli Cudini is a PhD student at the Wellcome Sanger Institute studying infection genomics.