Research advances understanding of Leber Hereditary Optic Neuropathy
Gene therapy research conducted by Emory Eye Center neuro-ophthalmologist Nancy J. Newman, MD was recently singled out for high praise by the American Academy of Neurology (AAN) Her abstract, The Phase III REFLECT Trial: Efficacy and Safety of Bilateral Gene Therapy for Leber Hereditary Optic Neuropathy (LHON)
summarized the results of a multinational clinical trial for which Newman was the international coordinating principle investigator.
Newman's was one of three scientific abstracts chosen for the Top Science
honor from AAN's Science Committee, which received more than 2,400 submissions.
Announcement of the three Top Science awardees was made just days before the American Academy of Neurology's 74th Annual Meeting in Seattle, by Dr. Natalia S. Rost, the AAN Science Committee chair.
I want to thank you Dr. Newman for truly pioneering work in neuro-ophthalmology, now, for many decades,
said Rost. And now, with this, you are bringing the reality of the most-recent cutting-edge gene therapy to patients with this devastating disease and disability.
The subject of Newman's investigation - Leber Hereditary Optic Neuropathy - is a rare but devastating disease that starts in one eye and invariably leads to bilateral blindness. It typically affects young otherwise healthy men. Researchers have traced the cause to point mutations in the mitochondrial DNA, causing the disorder to be passed down through the mother. While not every individual who has the disease will lose vision, when it does affect one eye, it invariably involves the other as well.
The most common point mutation that severely affects the patient is the 11778 mutation in the ND4 gene,
said Newman.
We have shown that one can apply gene therapy with a viral vector and inject a complement of the abnormal gene into the eye where, hopefully, it is taken up by the retinal ganglion cells and makes up for the abnormality.
This therapy, called lenadogene nolparvovec, has been shown to improve LHON patients' visual acuity in the affected eye. Surprisingly, these experiments found that the uninjected eye also improved more than would naturally be expected of a LHON patient. This implies that there is some migration of the therapy to the other eye and optic nerve.
Following two phase-3 studies of unilateral gene therapy in LHON patients, a bilateral trial of the gene therapy (the REFLECT study) injected all patients with the gene therapy in one eye; injections into the second eye were randomly split between gene therapy and a placebo.
And indeed, all second affected eyes improved, whether they received an injection of the drug or the placebo. And they improved more than we would have expected from the natural history of the disease,
she said.
But what we also noted was that the eyes that received the placebo did not improve as much as the eyes that received the true gene therapy injection. And patients who received true injections in both eyes did better, overall, which seems to suggest a dosing effect.
Newman noted that some findings were counter intuitive. For instance, findings from REFLECT and the two previous unilateral gene therapy trials suggest that early introduction of the gene therapy - when only one eye is affected - does not prevent the second eye from being affected, even if that eye receives the therapy.
And, secondly, gene therapy seems to work best when it is introduced six months after patients first experience vision loss. This contradicts the typical reliance on early intervention. Newman and her colleagues have hypothesized that the initial swelling of axons from the retinal ganglion cells may create a barrier that hinders adequate uptake of the therapy during the first few months of vision impairment. As the swelling subsides, the gene therapy may be more effective.
We still have a lot to do, but for the patients who suffer from this devastating disease, this is a step in the right direction,
Newman said.
-Kathleen E. Moore