Gene therapy

Paediatric ophthalmology is at the forefront of genetic therapy, with clinical trials advancing for the treatment of choroideremia, Miguel Seabra MD, PhD, CEDOC, Lisbon, Portugal, told a session of the WSPOS 2017 Paediatric Subspecialty Day held prior to the XXXV Congress of the ESCRS in Lisbon. “Choroideremia can be regarded as a systemic disease, due to the presence of the defective protein in all cells. However, the disease manifests itself only in the eye,” said Dr Seabra, who has spent the better part of his career researching this disease. This X-linked condition characterised by progressive visual loss affects approximately one-in-50,000 males. Impairment of night vision can occur in early childhood, followed by progressive narrowing of the field of vision and decreased visual acuity. Both the rate of progression and the degree of visual loss are variable. “Genetically speaking, choroideremia is quite a simple disease caused by a loss-of-function mutation in the CHM gene leading to one phenotype,” said Dr Seabra. This gene encodes the Rab escort protein 1 (REP1), which is involved in lipid modification of Rab proteins. The mutation in the RPE greatly accelerates photoreceptor death. The lack of a functional REP1 protein in the retina results in cell death and gradual deterioration of choroid, RPE and photoreceptor cells. The “simplicity” of choroideremia 
stands in contrast to the complexity 
of other genetic ocular diseases such 
as the ciliopathies. These are diseases 
with many causative gene mutations 
and phenotypes, and present with both 
retinal and extraocular manifestations. “Yet despite choroideremia’s genetic and phenotypic simplicity, there are several things that we still don’t know. For example, what are the exact mechanisms of RPE and photoreceptor cell death? And why is the disease restricted to the retina?” he noted. This is possibly due to the presence of a compensatory protein, REP2, which prevents lethality. The disease itself is a result of dysfunction of the substrates, Rab GTPases. In many inherited retinal diseases, the defective protein is directly involved in the light-sensing function of the eye. This is not, however, the case in choroideremia. But what about treatment? Although there is currently no treatment available, strides have been made in the development of gene therapy for choroideremia. Dr Seabra has played a lead role in the treatment’s development, guiding clinical trials. “The eye is an ideal organ for gene therapy. The eye, and particularly the retina, is small, meaning that only a small volume of cells need to be treated. Compare that with the trillions of cells in the liver or the central nervous system, and the retina is ideal.” Furthermore, the eye is accessible, it enjoys immune privilege and it is not a vital organ, despite its great importance to quality of life. “The primary problem in gene therapy is the introduction of genetic material into the cell. For obvious reasons, cells are resistant to this invasion,” he said. Gene therapy trials for choroideremia have used adeno-associated viruses (AAV) with healthy REP1 DNA (AAV.REP1) as a vector to bind to the cell membrane and inject the healthy gene into the cell’s nucleus. This allows the cell to make protein using the healthy gene rather than the mutated one. “The AAV infects both RPE cells and photoreceptors, resulting in efficient gene expression,” explained Dr Seabra. This method was used in human gene therapy trials for Leber’s congenital amaurosis. Researchers have spent more than 25 years getting to this point. The first 15 years, from 1990 to 2005, were spent doing fundamental research, such as developing animal models for choroideremia. The next five years saw the translational research, while clinical research has been ongoing since 2011. The first choroideremia clinical trial was started in October of 2011. In the study, two doses of the AAV.REP1 vector were injected into the subretinal space in 12 patients with choroideremia. The study demonstrated initial improved rod and cone function. Dr Seabra summarised the results. “The two patients with the most advanced disease had substantial gains in visual acuity. There was improvement of maximal retinal sensitivity in treated eyes, and five patients enjoyed improved mean retinal sensitivity,” he said. Dr Seabra added that the most advanced patients exhibited changes in variable fixation. Several questions remain, such as when the ideal moment might be to administer the injection in terms of disease progression; and how much of the retina should be treated, as doing so induces a temporary detachment of the retina. More recently, the positive results seen in the 32 choroideremia patients treated are thought to be long-lasting. The biopharmaceutical company Nightstar has since received both FDA and EMA orphan drug designation to treat choroideremia. Miguel Seabra: m.seabra@imperial.ac.uk