Gene therapy of choroideremia on the horizon

Ian MacDonald, MSc, MD, talked about the future of gene therapy trials in choroideremia, a single-gene disorder that primarily affects the eye.


Edmonton, Canada-Gene therapy trials in choroideremia may be on the horizon. Ian MacDonald, MSc, MD, talked about the future of this therapy.

“Choroideremia has long been seen as the next target for gene therapy. Gene therapy in this disease makes sense because the genetics of the disease are known, there is an understanding of the pathophysiology, suitable viral vectors can be used, and the vitreoretinal surgical techniques have been refined to deliver the vector to the subretinal space,” Dr. MacDonald explained. He is chair, Department of Ophthalmology, University of Alberta, Edmonton, Canada.

Choroideremia is a single-gene disorder that primarily affects the eye. The mutations cause a relative deficiency of rab escort protein-1 (REP-1), which is needed for intracellular trafficking in the eye.

Subretinal gene delivery of REP-1 will replace REP-1 missing from the photoreceptors and the retinal pigment epithelium. It is presently unknown if the choroid needs to be transduced. The delivery of the gene therapy to the submacular region is thought to be safe based on the results in six patients who underwent gene therapy with an adeno-associated virus that contained REP-1, Dr. MacDonald commented.

A gene therapy trial of choroideremia requires genotyping of the patients, with vision as the primary outcome in the selected patients. The secondary measures would include microperimetry, optical coherence tomography, electrophysiology, and autofluorescence to determine if gene therapy is effective in choroideremia. Choroideremia is characterized by marked decreases in central vision when the patients reach their sixth decade of life. 

When physicians and patients were interviewed about their perspectives on gene therapy for choroideremia, the results indicated that patients were well informed and understood the risks and benefits of the technology. However, there were gaps between clinician communication and the patient perspectives.

“Communication about gene therapy with trial participants must carefully represent the risks for informed consent,” he emphasized.

While most patients hoped that gene therapy would stop visual loss and perhaps reverse some loss, some patients considered gene therapy to be curative. The patients’ optimism about the therapy resulted in their minimization of the risks, with their main concern being access to a clinical trial. A major discrepancy was the difference between the physician and patients regarding when gene therapy could be implemented clinically.

This article is adapted from Dr. MacDonald’s presentation during Retina Subspecialty Day at the 2012 American Academy of Ophthalmology annual meeting.

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