Companies are exploring light-sensitive proteins method in patients with advanced disease.
When introducing genetic material into the target cell of a patient to prevent or cure a disease, one approach is to replace an otherwise mutated or missing gene with the correct coding sequence. Another is to inactivate or silence a mutant copy of the gene with a dominant negative or toxic effect (for example, using endonuclease/CRISPR-Cas9, ribozyme or antisense RNA). It is also possible to introduce therapeutically beneficial genetic material such as a ‘killer gene’ into tumours.
These three approaches were introduced by Prof. Isabelle Audo in one of her presentations at this year’s European Society of Retinal Specialists (EURETINA) Meeting on 3rd September in Hamburg, Germany, in the Session on “Inherited Retinal Diseases”. Prof. Audo is based at the Department of Genetics, Institut de la Vision, Paris, France.
However, there is another promising avenue available in gene therapy: optogenetics. In this case, the genetic material consists of light-sensitive proteins which can induce a biological process when exposed to light of a certain wavelength. This has potential in the progressive, inherited disease retinitis pigmentosa (RP), Prof. Audo explained.
The ongoing PIONEER Phase I/II study is a first-in-human dose escalation study that is investigating the optogenetics approach with the AAV2-based candidate GS030 (GenSight Biologics), which is delivered by a single intravitreal injection in the worst-seeing eyes of RP patients.
GS030 encodes the light-sensitive protein red-shifted channelrhodopsin. According to Prof. Audo, the gene is stimulated with an optoelectronic device consisting of a pair of engineered glasses, to transform an external light stimulus into a signal to activate the retinal ganglion cells and the retinal output is sent to the brain for image processing.
The clinical trial is being undertaken at is being at three sites in the United Kingdom (London), Paris (France) and United States (Pittsburg, Pennsylvania) and has enrolled 18 subjects between the ages of 18 and 75 with non-syndromic RP into three cohorts. Patients eligible for the study were affected by end-stage RP with no light perception or light perception levels of visual acuity. An extension cohort expanded the inclusion criteria by recruiting patients with hand motion and counting fingers levels of visual acuity.
The first cohort of patients (n = 3) received a dose of 5.0 x 1010 vector genomes, the second (n = 3) received 1.5 x 1011 vector genomes and the third cohort (n = 3) were administered with a dose of 5.0 x 1011 vector genomes. Dosing in these three cohorts has been completed and, following review by the independent Data Safety Monitoring Review Board, no safety issues were found. Based on this, the Board advised that the highest dose could be selected for the extension cohort, and one patient in this cohort is currently being reviewed in France.
In terms of efficacy data to date, Prof. Audo described by way of a video how a patient with late-stage RP in the second cohort partially recovered her visual function following treatment with a single dose. The patient had been diagnosed with RP 20 years prior to enrolment and, 12 months following injection in her worse-seeing eye, she could correctly locate objects of different sizes and contrasts on a white table in front of her, with a 57% success rate when wearing the light-stimulating goggles, versus 24% without the device.
The optogenetic candidate has been granted orphan drug designation in Europe and the United States.
Another company that is investigating the optogenetic approach in RP patients is Nanoscope Therapeutics. According to Prof. Audo, enrolment is complete in a Phase IIb trial, RESTORE, in 27 adult patients with a diagnosis of advanced RP.
In this trial, the experimental treatment is the ambient-light activatable multi-characteristic opsin MCO-010, delivered in a single intravitreal injection. There are two dose groups that comprise patients over the age of 18-years-old who have a confirmed diagnosis of advanced RP based on clinical examination, dilated fundus examination and genetic testing.
Enrolled patients had a best-corrected visual acuity worse than 1.9 LogMAR (Snellen equivalent of 20/1600), counts fingers/hand motion in the study eye and no better than 1.6 LogMAR (Snellen equivalent 20/800) in the fellow eye during screening. Patients also had the presence of retinal inner nuclear and nerve fibre layers detected on optical coherence tomography testing in the study eye during screening as determined by the investigator and confirmed by the sponsor or designee.
Patients will be assessed over 52 weeks and the primary outcome measures are the efficacy of a single intravitreal injection of vMCO-010 assessed by Y-Mobility test, and the type, severity and incidence of ocular and systemic adverse events, specifically those related to intravitreal injection of the candidate.
Dr Audo concluded by stating that in the future it should be possible to fine-tune the vectors to improve sensitivity and simulation and to target dormant cones to help restore vision.