Researchers at the University of Alberta, Canada have announced the initiation of enrolment and dosing in a Phase II clinical trial of a novel gene therapy for the treatment of choroideremia (CHM). The therapeutic approach will use a viral vector, adeno-associated virus (AAV), to deliver a wild-type copy of the Rab-escort protein 1 (REP-1) gene into retinal cells. The clinical study represents the first ocular gene therapy trial to be conducted in Canada and is supported by a UK based gene therapy company, NightstaRx Ltd., a recent biotech enterprise spun out of Oxford’s Nuffield Laboratory of Ophthalmology by Professor Robert MacLaren and colleagues. Choroideremia is an inherited X-linked recessive disease arising from mutations to the CHM gene, encoding Rab-escort protein 1. The disorder is estimated to affect approximately 1 in 50,000 people and is characterized by initial impairment of night vision followed by progressive narrowing of the visual field often leading to blindness in late adulthood.
Previous research findings published by the academic group behind NightstaRx Ltd reported success for the treatment in 6 male patients with choroideremia. The Phase I/II trial conducted by the Oxford University team used an AAV as the delivery vehicle to deliver a copy of a functioning choroideremia gene encoding REP1. The prospective therapy was delivered surgically by subfoveal injection and comprised 0.6–1.0 X 10^10 AAV.REP1 genome particles in a fixed volume of 0.1mL. Assessment of therapeutic benefit involved a variety of functional tests including best-corrected visual acuity (BCVA), micro-perimetry and retinal sensitivity assays to compare pre- and post-surgical values (6 months after surgery). The results showed that two patients with advanced disease and low baseline BCVA gained 21 letters and 11 letters (> two and four lines of vision) while four patients with near normal BCVA at baseline recovered to within one to three letters. The mean gain in visual acuity overall was reported to be 3.8 letters (SE 4.1). Measurements of dark-adapted micro-perimetry indicated that maximal sensitivity increased in treated eyes from 23.0 dB (SE 1.1) at baseline to 25.3 dB (1.3) after treatment (increase 2.3 dB [95% CI 0.8–3.8]). Over the 6-month period of assessment all patients showed an increase in retinal sensitivity in the treated eyes (mean 1.7 [SE 1.0]) which additionally appeared to correlate with the AAV dose administered per millimetre of surviving retina (r=0.82, p=0.04). In comparison, in the control eyes, the research group reported small non-significant reductions (p>0.05) in both maximal sensitivity (–0.8 dB [1.5]) and mean sensitivity (–1.6 dB [0.9]).
The Canadian research is supported by a variety of governmental and private agencies, including Alberta Innovates – Health Solutions (AIHS); Canadian Institutes of Health Research (CIHR); NightstaRx; Canada Foundation for Innovation; Alberta Innovates (Alberta Innovation and Advanced Education); The Foundation Fighting Blindness (FFB); Choroideremia Research Foundation Canada (CRFC); and additional private donors. Commenting on the milestone, Ian MacDonald, Professor of Ophthalmology and Visual Sciences, University of Alberta stated, “We are very excited to be working with Nightstar and to have treated our first choroideremia patient. Choroideremia is a devastating condition for individuals and families, but we believe our new gene therapy will arrest any further deterioration of vision and will provide long lasting benefit. The next challenge will be making this therapy available to all individuals with the condition as soon as we possibly can.”