GenSight Biologics

GenSight Biologics is a clinical-stage biotechnology company discovering and developing novel therapies for neurodegenerative retinal diseases and diseases of the central nervous system.

The London-based biotech company leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics for retinitis pigmentosa, to help preserve or restore vision in patients suffering from severe degenerative retinal diseases.

Drug Development pipeline

GenSight, has two lead product candidates for the treatment of sight-threatening retinal degenerative diseases, together with products in preclinical development targeting ophthalmic and neurodegenerative diseases. 

LHON-ND4

LHON-ND4 is a drug for the treatment of Leber Hereditary Optic Neuropathy. The ND4 gene is normally located in the mitochondria where ND4 proteins are synthesized. GS010 allows allotopic expression of the mitochondrial gene ND4 in the nucleus thanks to a proprietary Mitochondrial Targeting Sequence that shuttles the messenger RNA from the nucleus directly to the outer membrane of the mitochondria. There, the ND4 proteins are synthesized and incorporated into the mitochondria. Wild-type ND4 proteins then integrate into Complex I of the respiratory chain and rescue the deficiency.

The drug is currently in phase III trials in both the USA and EU. ClinicalTrials.gov Identifier: NCT03293524

LUMEVOQ

GenSight Biologics is developing LUMEVOQ (GS010), a therapy that causes ND4, a mitochondrial protein, to be expressed in the nucleus and shuttled to the mitochondria. This concept of moving mitochondrial DNA into the nucleus, where it is better protected, is a key approach for combating mitochondrial dysfunction, one of the hallmarks of aging. The company has taken LUMEVOQ into multiple Phase 3 clinical trials for the treatment of Leber Hereditary Optic Neuropathy (LHON), a disease that causes blindness.

This company has had some issues with clinical trials in the past, as each patient had a single treated eye to test the efficacy of GS010 and the other eye was left untreated to serve as the control group. The problem was that administering this therapy seemed to affect the untreated eye along with the treated eye, leading to a lack of difference between the experimental group and the control group – thus possibly making an effective therapy seem ineffective.

In December 2020, the Phase 3 REVERSE clinical trial was a success, representing the moment when mitochondrial gene therapy became a reality in humans. The researchers report that by week 96 of the study, 25 participants showed a significant improvement of best-corrected visual acuity (BCVA) in at least one eye compared to the baseline taken before treatment. 29 of the 37 participants showed an improvement of vision in both eyes. They discovered that eyes were about three times more likely to regain 20/200 vision or better following treatment.

In June 2021, Gensight reported key efficacy and safety results at 78 weeks post-treatment in the REFLECT Phase 3 clinical trial for LUMEVOQ. The results show better BCVA improvements from bilateral intravitreal injections of the gene therapy compared to a unilateral injection.

In September 2021, results from the long-term follow up of the RESCUE & REVERSE Phase 3 clinical trials were published, which showed continued improvement in BCVA between 2 to 3 years post treatment.

LUMEVOQ has received a Cohort Temporary Authorization for Use in France, and EU marketing authorization is expected in H1 2022.

The researchers are also interested in using the same approach to treat other mitochondrial diseases.

GenSight is also developing GS030, a gene therapy that allows retinal cells to detect the presence of light, which is currently in a Phase 1/2 dose-escalation study.

GS030

GS030 is a unique combination of two parts. The first is a gene therapy that includes a gene for a light-sensitive protein. It’s delivered using a specially modified virus called AAV2 7m8. The second part is a pair of special goggles that stimulate the cells in the retina that have been altered by the gene therapy. The goggles project images onto your retina using a specific type of light. This approach, called optogenetics, involves inserting a gene for a light-sensitive protein into cells, which makes these cells respond to light.

GS030 uses a bio-engineered virus to put the gene of this light-sensitive protein into the target cells in the retina, known as retinal ganglion cells (RGCs). This makes these cells sensitive to light, regardless of the genetic mutation that caused their initial damage. However, these altered cells aren’t as light sensitive as normal cells in the retina, so regular vision in normal daylight probably won’t be possible without the special goggles. These goggles work by capturing visual information and boosting the light signal to the altered cells in the retina, allowing them to function more like normal cells. GS030 is being tested as a treatment for retinitis pigmentosa