Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial
Robert E MacLaren, Markus Groppe, Alun R Barnard, Charles L Cottriall, Tanya Tolmachova, Len Seymour, K Reed Clark, Matthew J During, Frans P M Cremers, Graeme C M Black, Andrew J Lotery, Susan M Downes, Andrew R Webster, Miguel C Seabra, Robert E MacLaren, Markus Groppe, Alun R Barnard, Charles L Cottriall, Tanya Tolmachova, Len Seymour, K Reed Clark, Matthew J During, Frans P M Cremers, Graeme C M Black, Andrew J Lotery, Susan M Downes, Andrew R Webster, Miguel C Seabra
Abstract
Background: Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease.
Methods: In a multicentre clinical trial, six male patients (aged 35-63 years) with choroideremia were administered AAV.REP1 (0·6-1·0×10(10) genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213.
Findings: Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the 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]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm(2) of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (-0·8 dB [1·5]) and mean sensitivity (-1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector.
Interpretation: The initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning.
Funding: UK Department of Health and Wellcome Trust.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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References
- Mauthner L. Ein Fall von Choroideremie. Ber Naturwissensch-med Ver Inssbruck. 1872;2:191–197.
- Sankila EM, Tolvanen R, van den Hurk JA, Cremers FP, de la Chapelle A. Aberrant splicing of the CHM gene is a significant cause of choroideremia. Nat Genet. 1992;1:109–113.
- Cremers FP, van de Pol DJ, van Kerkhoff LP, Wieringa B, Ropers HH. Cloning of a gene that is rearranged in patients with choroideraemia. Nature. 1990;347:674–677.
- van Bokhoven H, van den Hurk JAJM, Bogerd LPM. Cloning and characterization of the human choroideremia gene. Hum Mol Genet. 1994;3:1041–1046.
- Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science. 1993;259:377–381.
- Jacobson SG, Cideciyan AV, Sumaroka A. Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations. Invest Ophthalmol Vis Sci. 2006;47:4113–4120.
- Sieving PA, Caruso RC, Tao W. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA. 2006;103:3896–3901.
- Syed R, Sundquist SM, Ratnam K. High-resolution images of retinal structure in patients with choroideremia. Invest Ophthalmol Vis Sci. 2013;54:950–961.
- Jacobson SG, Cideciyan AV, Ratnakaram R. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130:9–24.
- Maguire AM, Simonelli F, Pierce EA. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240–2248.
- Loeb JE, Cordier WS, Harris ME, Weitzman MD, Hope TJ. Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element: implications for gene therapy. Hum Gene Ther. 1999;10:2295–2305.
- LeWitt PA, Rezai AR, Leehey MA. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011;10:309–319.
- Anand V, Barral DC, Zeng Y. Gene therapy for choroideremia: in vitro rescue mediated by recombinant adenovirus. Vision Res. 2003;43:919–926.
- Tolmachova T, Tolmachov OE, Barnard AR. Functional expression of Rab escort protein 1 following AAV2-mediated gene delivery in the retina of choroideremia mice and human cells ex vivo. J Mol Med (Berl) 2013;91:825–837.
- Bennicelli J, Wright JF, Komaromy A. Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008;16:458–465.
- Klein R, Klein BE, Moss SE, DeMets D. Inter-observer variation in refraction and visual acuity measurement using a standardized protocol. Ophthalmology. 1983;90:1357–1359.
- Chen FK, Patel PJ, Xing W. Test-retest variability of microperimetry using the Nidek MP1 in patients with macular disease. Invest Ophthalmol Vis Sci. 2009;50:3464–3472.
- Cideciyan AV, Jacobson SG, Beltran WA. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci USA. 2013;110:E517–E525.
- Bennett J, Ashtari M, Wellman J. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4:120ra15.
- Cideciyan AV, Hauswirth WW, Aleman TS. Vision 1 year after gene therapy for Leber's congenital amaurosis. N Engl J Med. 2009;361:725–727.
- Endo K, Yuzawa M, Ohba N. Choroideremia associated with subretinal neovascular membrane. Acta Ophthalmol Scand. 2000;78:483–486.
- Bowne SJ, Humphries MM, Sullivan LS. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011;19:1074–1081.
- Tolmachova T, Wavre-Shapton ST, Barnard AR, MacLaren RE, Futter CE, Seabra MC. Retinal pigment epithelium defects accelerate photoreceptor degeneration in cell type-specific knockout mouse models of choroideremia. Invest Ophthalmol Vis Sci. 2010;51:4913–4920.
- Vandenberghe LH, Bell P, Maguire AM. Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med. 2011;3:88ra54.
- Maguire AM, High KA, Auricchio A. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374:1597–1605.
- van den Hurk JA, Schwartz M, van Bokhoven H. Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene. Hum Mutat. 1997;9:110–117.
- MacLaren RE. An analysis of retinal gene therapy clinical trials. Curr Opin Mol Ther. 2009;11:540–546.
Source: PubMed