AAV2/2-hRPE65p-hRPE65 (UCL 06/061)

UCL

Gower St, London, United Kingdom, WC1E 6BT

Ctimps@ucl.ac.uk, University College London, Gower Street, London, 0044 020 7679 6481, ctimps@ucl.ac.uk

Professor James Bainbridge Professor Robin Ali UCL Institute of Ophthalmology, UCL Institute of Ophthalmology 11-43 Bath St, London EC1V 9EL, 0044 020 7566 2576, j.bainbridge@ucl.ac.uk

No

No

No

Final

30 Apr 2015

Yes

30 Apr 2014

Yes

24 Jul 2014

No

The main objective of the trial was to determine the efficacy and safety of subretinal administration of a recombinant adeno-associated viral vector (rAAV 2/2.hRPE65p.hRPE65) in individuals with autosomal recessive severe early-onset retinal degeneration due to mutations in RPE65.

An important ethical consideration relevant to this study was the application of gene therapy technology for the treatment of a condition that is not life threatening. A gene therapy trial in human subjects should not put subjects at disproportionate risk and for this reason should be restricted to individuals with serious disorders where effective treatments are not available. Although RPE65-related retinal degeneration is not life threatening, there is no effective treatment for the disorder that results inevitably in profound visual impairment. Whilst pre-clinical data suggest that the likelihood of adverse systemic side effects following ocular gene transfer is low, there is a real possibility that this approach will offer a significant benefit in terms of improved visual function and quality of life. The potential risk of gene therapy to existing vision was minimised by restricting intervention to only one eye of each affected individual. Patients were screened to ensure there were no contra-indications for transient immune suppression, in particular, a history of hypertension, diabetes mellitus, tuberculosis, renal impairment, immunocompromise, osteoporosis, gastric ulceration or severe affective disorder. A detailed assessment of visual function and imaging was performed on both eyes preoperatively. Blood was sampled in order to assess baseline levels of circulating antibodies against AAV2 and RPE65 so that following intervention, immunological responses to vector capsids and transgene product could be determined. Responses in the first 4 subjects were assessed before subsequent subjects received escalated doses of vector suspension involving larger proportions of the retinal area.

01 Feb 2007

No

Yes

United Kingdom: 12

12

12

0

0

0

0

5

3

4

0

0

Overall Trial (overall period)

Not applicable

This is not a blinded study.

rAAV2/2.hRPE65p.hRPE65

Suspension for injection

Intraocular use

1x10e11vg; 1x10e12 vg

Overall Trial

Intervention

The primary safety outcome was the incidence of a grade 3 adverse event at 3 years, defined as either the loss of visual acuity by 15 or more letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart or severe unresponsive intraocular inflammation.

Primary

Within 3 years of intervention

The outcomes for efficacy were descriptive in nature and were defined as any improvement in visual function greater than the test–retest variability for any assessment, determined by means of one-way analysis of variance with the use of multiple baseline measurements. Microperimetry data were analysed using a volumetric approach, Visual Field Modelling and Analysis (VFMA). VFMA can be applied to any static field data where the test locations and associated sensitivity data in dB can be exported. A thin-plate spline is fit through the sensitivity data points and the volume in dB-steradian (dB-sr) is determined by integration of the sensitivity of the visual field with the solid angle beneath the envelope. Test-retest variability was determined by ANOVA.

Secondary

0 - 3 years

The recording and follow up of all adverse events was carried out until the end of the trial, which was the 3 year follow up visit of the last patient

Adverse events were recorded for all patients.

17.1

Active treatment