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Follow up clinical trial data on gene therapy chorideremia treatment continues to show potential

Following three and a half years of clinical data on a choroideremia gene therapy study among 6 UK patients, results to date appear to indicate that earlier positive observations continue to persist over the 42-month duration. In a letter published in the New England Journal of Medicine, the study’s principal investigator, Prof. Robert MacLaren, reported that visual acuity in two of the six participants continued to show therapeutic benefit in the study eye, compared to a continuing degeneration in the control eye. Two patients in the study, each with advanced disease and visual acuity scores several lines below normal at baseline on the ETDRS chart, showed clear improvement. In the first patient (Patient 1), the treated study eye had increased by 21 letters (>4 lines) compared to baseline while in a fourth patient (Patient 4) an increase of 18 letters (>3 lines) was recorded. In contrast to the treated eyes in these two patients, visual acuity in the control eyes decreased by 18 letters in Patient 1 and by 6 letters in Patient 4.


Choroideremia is an X-linked recessive disease with an estimated prevalence of 1 in 50,000 and is currently incurable. Successful proof-of-concept holds significant implication not only for treatment of choroideremia but also for treatment of a number of other retinal degenerations including retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The Phase I/II trial conducted by Prof. MacLaren and colleagues from Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, and Imperial College London, UK, uses an adeno-associated virus (AAV) as the delivery vehicle to transport a copy of a functioning choroideremia gene (CHM) encoding the Rab escort protein-1 (REP1). The therapeutic transcript is flanked upstream by a chicken-derived beta actin promoter to ensure constitutive expression and a downstream woodchuck viral hepatitis regulatory element to enhance gene expression. The prospective therapy was delivered surgically by sub-foveal 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 involves 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). Two-year results showed that the responding patients (Patients 1 and 4), with advanced disease and low baseline BCVA, gained 18 letters and 8 letters, respectively, while a further patient (Patient 3) gained 5 letters. The three remaining patients recorded a loss in visual acuity. 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 initial 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 had earlier 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]).


In concluding their letter on data out to month 42, the authors of the study commented that, “In contrast to Leber’s congenital amaurosis, in which visual acuity is generally profoundly affected early in life, choroideremia and most types of retinitis pigmentosa are characterized by progressive loss of the visual field, with visual acuity remaining close to normal levels until the very late stages of disease. Therefore, in some patients, the effect of preserving visual acuity with the use of retinal gene therapy may take several years to become apparent.”