Leber Hereditary Optic Neuropathy - The Gene Therapy race to treatment

GenSight Biologics, which is in advanced stages of clinical development of gene therapy for Leber Hereditary Optic Neuropathy, has a new Chief Medical Officer. Barrett Katz, M.D., M.B.A., who until recently was the Professor of Ophthalmology, Neurology and Neurosurgery at the Montefiore Medical Center and the Albert Einstein College of Medicine in New York. Dr. Katz has worked in both academic medicine and the industry as a neuro-ophthalmologist, working as CEO of ophthalmic biotech Danube Pharmaceuticals, as well as CMO of Fovea Pharmaceuticals and VP of medical affairs and strategy at Eyetech.

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Leber's hereditary optic neuropathy (also referred to as Leber hereditary optic atrophy) is a mitochondrially inherited (i.e., transmitted from mother to offspring) degeneration of retinal ganglion cells and their axons that leads to an acute or subacute loss of central vision; this predominantly affects young adult males. To read more about LHON, click here.

(c) National Institutes of Health

LHON is caused by defects in mitochondrial genes encoding for proteins called NADH dehydrogenase. 95% of LHON cases are due to mutations in ND1, ND4 and ND6 mitochondrial genes that encode proteins of the respiratory chain Complex I, an important component of energy production within the mitochondrion and therefore the cell. The ND4 mutation is responsible for the majority of cases (representing around 70% in Europe and North America and 80 to 85% in Asian countries).

Although the genetic defect is present throughout the body, LHON symptoms are almost uniquely limited to retinal ganglion cells, or RGCs, dysfunction and optic nerve atrophy. RGCs are located near the inner surface of the retina. They receive visual information from photoreceptors. RGCs collectively transmit image-forming and non-image forming visual information from the retina to several regions in the brain. Once the RGCs degenerate, signals can no longer be transmitted to the brain and the patient turns blind.

Onset of vision loss due to LHON typically occurs between 15 and 35 years of age. Vision loss often occurs in a bilateral sequential fashion, the second eye being affected after the first one with a median delay of two months.

Management of LHON: Without a known family history of LHON, the diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mitochondrial DNA assessment. It is considered to be a diagnosis of exclusion in most hands, and hence it is important to exclude other possible causes of vision loss. 

The prognosis for those affected left untreated is almost always that of continued significant visual loss in both eyes. 

Currently, available treatments are limited in their benefit. Usually, the following is advised to patients:

• Regular corrected visual acuity and perimetry checks
• Early onset disease may show some benefit with treatment
• Genetic counseling
• Health and lifestyle choices should be reassessed particularly in light of toxic and nutritional theories of gene expression - avoid tobacco and alcohol.
• Vision aides assistance and work rehabilitation should be used to assist in maintaining employment.
• Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk; e.g. Ethambutol, Nitroprusside, etc.

For those who are carriers of a LHON mutation:

• Preclinical markers, such as fundus photography (monitor nerve fiber layer swelling) and Optical coherence tomography (OCT) (retinal nerve fiber layer thickness) may be used. 
• Red green color vision testing may detect losses. 
• Contrast sensitivity may be diminished. 
• Electroretinogram or visual evoked potentials may be adnormal. 
• Neuron-specific enolase and axonal heavy chain neurofilament blood markers may predict conversion to affected status.

Idebenone has been shown in a small placebo controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.

α-Tocotrienol-quinone, a vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss.

Other drugs evaluated include brimonidine, minocycline, curcumin, glutathione, etc., with minimal to no effect. 

Currently, Idebenone (wherever approved), with doses spaced out in a day rather than at one time to achieve a dose of 900 mg per day, combined with avoidance of smoke and limitation of alcohol intake, is considered the preferred standard treatment protocol for patients affected by LHON. The drug should be taken with a moderate amount of dietary fat in each meal to promote absorption, while patients also take vitamin C 500 mg daily to keep idebenone in its reduced form, as it is most active in this state.

Current Research:

Currently, human clinical trials are underway at GenSight Biologics (clinicalTrials.gov # NCT02064569) and the University of Miami (clinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in LHON.

In GenSight trials,  phase 3 clinical trial focused on either RESCUE (vision Loss up to 6 Months from onset) or REVERSE (vision loss from 7 months to 1 year from onset) in currently underway. In both trials, GS010 is injected into one eye of each participant, while the other eye receives a sham injection. The trials are 6 months away from topline results.

In the clinical trial from University of Miami, John Guy, MD, and his team have demonstrated that allotopic gene therapy for LHON at low and medium doses seems to be safe and does not damage the temporal retinal nerve fiber layer. (Read the paper here.)

Stealth BioTherapeutics is presently investigating the potential use of twice-daily topical eye drop formulation of elamipretide (MTP-131) as a therapy for LHON in a Phase 2 clinical trial (clinicalTrials.gov # NCT02693119).

There is developmental work currently on-going in China as well.

Note: Top image (c) Healio