BMJ 2014;348:g269 doi: 10.1136/bmj.g269 (Published 16 January 2014)
Page 1 of 1
Research News
RESEARCH NEWS Gene therapy for inherited blindness shows promise in first clinical trial Ingrid Torjesen London
The first phase I clinical trial of gene therapy for an inherited cause of blindness has shown sustained improvements in visual acuity.
In the trial, funded by the Department of Health for England and the Wellcome Trust, six patients had genes injected into the retinal cells of one eye, with no adverse effects. Six months later all the patients reported improvements in their vision in dim light, and two of the six, who have now been followed up for up to two years, were able to read more lines on an eye chart. The six patients who received the gene therapy had choroideraemia, a rare inherited blindness that affects one in 50 000 people and for which there is no treatment.
A third of eye disorders have a genetic basis, and currently around 195 retinal degeneration genes have been characterised. Choroideraemia is caused by a defective CHM gene on the X chromosome so is more prevalent in men. The CHM gene codes for the Rab escort protein REP1 protein. Without the REP1 protein the choroid and retinal pigment epithelium degenerate, and the photoreceptors stop working and die, exposing the sclera.
Underlying changes to the retina begin in childhood and are associated with reductions in parafoveal sensitivity (manifesting as impaired night vision), but good visual acuity is maintained until degeneration encroaches on the fovea. As choroideraemia progresses, the functioning retina shrinks in size, reducing vision and ultimately resulting in complete blindness in middle age. Gene therapy works by providing cells with a functioning copy of the defective gene. In this study the researchers, from the University of Oxford, spliced the CHM gene into the DNA of an adeno-associated virus and then injected these viral vectors under the retina of one eye of each patient using a very fine needle and a surgical procedure called a vitrectomy (to lift the retina).
The lead researcher, Robert MacLaren, professor of ophthalmology at the University of Oxford, said that the effect of the procedure on the patients’ sight was better than they had expected, because retinal detachment is usually associated with a reduction in visual acuity and night vision.
For personal use only: See rights and reprints http://www.bmj.com/permissions
He said, “It’s a very early stage, but we have six patients with very promising results of improvement of vision verified by independent means that to date has been sustained.” Patients have been followed up for between six months and two years.
The results after six months’ follow-up are reported in the Lancet.1 They show that two patients with advanced choroideraemia and low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision) after treatment. Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters.
Maximal sensitivity measured with dark adapted microperimetry increased in the treated eyes by 2.3 dB (95% confidence interval 0.8 dB to 3.8 dB), from 23 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment. The increase in retinal sensitivity in the treated eyes (mean 1·7 (SE 1·0)) correlated with the concentration of vector administered per mm² of surviving retina (r=0·82; P=0·04). By contrast, small non-significant reductions in maximal sensitivity and mean sensitivity were noted in the control eyes. The researchers are now testing a higher dose of the gene therapy in six patients with earlier stage choroideraemia, with the aim of preserving more functioning retinal cells. More virus is therefore needed for these patients, because they have a greater amount of retinal tissue remaining. MacLaren explained that the gene therapy aimed “to return the function of those cells to normal so that they don’t degenerate—what we can’t do is bring back the cells that have gone.”
Pictures and video of the procedure are available at https://www.dropbox. com/sh/dsw95ejvvrzc3jj/edR0mBo0PZ. 1
MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 16 Jan 2014, doi:10.1016/S0140-6736(13)62117-0.
Cite this as: BMJ 2014;348:g269 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 1
Research News
RESEARCH NEWS Gene therapy for inherited blindness shows promise in first clinical trial Ingrid Torjesen London
The first phase I clinical trial of gene therapy for an inherited cause of blindness has shown sustained improvements in visual acuity.
In the trial, funded by the Department of Health for England and the Wellcome Trust, six patients had genes injected into the retinal cells of one eye, with no adverse effects. Six months later all the patients reported improvements in their vision in dim light, and two of the six, who have now been followed up for up to two years, were able to read more lines on an eye chart. The six patients who received the gene therapy had choroideraemia, a rare inherited blindness that affects one in 50 000 people and for which there is no treatment.
A third of eye disorders have a genetic basis, and currently around 195 retinal degeneration genes have been characterised. Choroideraemia is caused by a defective CHM gene on the X chromosome so is more prevalent in men. The CHM gene codes for the Rab escort protein REP1 protein. Without the REP1 protein the choroid and retinal pigment epithelium degenerate, and the photoreceptors stop working and die, exposing the sclera.
Underlying changes to the retina begin in childhood and are associated with reductions in parafoveal sensitivity (manifesting as impaired night vision), but good visual acuity is maintained until degeneration encroaches on the fovea. As choroideraemia progresses, the functioning retina shrinks in size, reducing vision and ultimately resulting in complete blindness in middle age. Gene therapy works by providing cells with a functioning copy of the defective gene. In this study the researchers, from the University of Oxford, spliced the CHM gene into the DNA of an adeno-associated virus and then injected these viral vectors under the retina of one eye of each patient using a very fine needle and a surgical procedure called a vitrectomy (to lift the retina).
The lead researcher, Robert MacLaren, professor of ophthalmology at the University of Oxford, said that the effect of the procedure on the patients’ sight was better than they had expected, because retinal detachment is usually associated with a reduction in visual acuity and night vision.
For personal use only: See rights and reprints http://www.bmj.com/permissions
He said, “It’s a very early stage, but we have six patients with very promising results of improvement of vision verified by independent means that to date has been sustained.” Patients have been followed up for between six months and two years.
The results after six months’ follow-up are reported in the Lancet.1 They show that two patients with advanced choroideraemia and low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision) after treatment. Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters.
Maximal sensitivity measured with dark adapted microperimetry increased in the treated eyes by 2.3 dB (95% confidence interval 0.8 dB to 3.8 dB), from 23 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment. The increase in retinal sensitivity in the treated eyes (mean 1·7 (SE 1·0)) correlated with the concentration of vector administered per mm² of surviving retina (r=0·82; P=0·04). By contrast, small non-significant reductions in maximal sensitivity and mean sensitivity were noted in the control eyes. The researchers are now testing a higher dose of the gene therapy in six patients with earlier stage choroideraemia, with the aim of preserving more functioning retinal cells. More virus is therefore needed for these patients, because they have a greater amount of retinal tissue remaining. MacLaren explained that the gene therapy aimed “to return the function of those cells to normal so that they don’t degenerate—what we can’t do is bring back the cells that have gone.”
Pictures and video of the procedure are available at https://www.dropbox. com/sh/dsw95ejvvrzc3jj/edR0mBo0PZ. 1
MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 16 Jan 2014, doi:10.1016/S0140-6736(13)62117-0.
Cite this as: BMJ 2014;348:g269 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
