Retinal disease therapy

Multi-pronged attack on underlying retinal disease processes drives 
current research

Leigh Spielberg

Posted: Wednesday, March 1, 2017

Gisbert Richard receives the certificate for the inaugural Gisbert Richard Lecture from EURETINA President
Ursula Schmidt-Erfurth 
at the 16th EURETINA Congress in Copenhagen in September 2016


Dr Gisbert Richard’s keynote lecture at the 16th EURETINA Congress in Copenhagen, Denmark, examined the prospects and limitations of artificial vision and stem cell therapy.
“About two million people worldwide suffer from photoreceptor degenerative diseases,” said Dr Richard in his inaugural Gisbert Richard Lecture. “With a prevalence of approximately one in 4,000, these diseases are not so uncommon. It is therefore crucial that research continues, and that we continue trying to solve the primary problems inherent to the treatment of these diseases,” he added.
“The first problem is the interdependence of different layers of the retina. Retinal pigment epithelium (RPE) degeneration leads to both degeneration of the choriocapillaris and focal necrosis of photoreceptor cells. The second problem is the question of timing of a therapeutic intervention. Namely, is it better to intervene early, before the damage has occurred? Or later, when the risks of making it worse have lessened?” he asked.
As it turns out, that depends on which type of therapy is administered. Gene therapy should be administered in an early stage, cell therapy in any stage, and the retinal prosthesis in the late stage.
The third problem is that of additive RPE ageing. This refers to the various ways in which RPE cells degenerate, losing their typical cell morphology and undergoing atrophy and hyperpigmentation. This physiologic ageing also causes secondary alteration of the choriocapillaris and retina.
Dr Richard discussed the treatment options in depth. Broadly speaking, there are three therapeutic categories: cell therapy, gene therapy, and retinal prostheses.

Cell therapy refers to the transplantation of either HLA-typed RPE cells or stem cells, or a more pharmacologic approach to the diseased cells.
“Cell therapy requires the establishment of an RPE cell bank in order to isolate and cultivate human adult RPE cells. HLA-typed RPE transplantation has been shown to be a safe procedure, with no rejection of transplanted cells and improvement of visual acuity, albeit limited. However, there remains the problem of progression of geographic atrophy,” said Dr Richard.
Stem cell therapy, which involves undifferentiated, multipotent cells with the capacity for self-renewal, aims to transfer therapeutic gene products to the retina, or to substitute or replace dysfunctional or degenerated retinal cell types.
Grafted primary retinal cells develop the morphology of fully mature photoreceptors when incorporated into an otherwise healthy retina. These cells also express photoreceptor-specific antigens. There is, however, no proof of therapeutic value to date, he noted.

Cell therapy refers to the transplantation of either HLA-typed RPE cells or stem cells, or a more pharmacologic approach to the diseased cells.

Gene therapy focuses on treatment of early-stage disease. Because these diseases are monogenetic, they are ideal candidates for gene therapy. The goals include replacing or knocking down a defective gene, controlling gene expression, delivering a suppressor or correcting a mutation that misdirects splicing. With 204 causative genes identified and 244 retinal dystrophy loci mapped, there is clearly no shortage of targets.
“Ongoing and anticipated gene therapy trials include treatments for Leber’s congenital amaurosis (LCA) Type 2, choroideremia, Leber’s hereditary optic neuropathy (LHON), Stargardt and Usher syndrome Type 1B,” said Dr Richard.

Dr Richard then turned his attention to retinal implant (prosthetic) technology. This incorporates two primary external components: a camera chip and a retina encoder; and an implanted component: the retinal stimulator, which receives pulse sequences and transmits them to the retina.
“Visual improvement by retinal stimulation is definitely possible. However, high-resolution implants are difficult to achieve,” said Dr Richard.
This was evident in the five-year trial of the Argus II implant, in which patients were clearly able to recognise and use shapes for orientation and environmental information, but do not have any fine resolution.
This is because the current maximum number of electrodes per square millimetre is 37. Each electrode generates one phosphene. However, to obtain normal reading speed, more than 5,000 phosphenes are needed per square millimetre.
Dr Richard remains very optimistic. “Who knows what the future holds?”

Gisbert Richard: