Future Concepts in Vision Regeneration
There is a great deal of research on going all over the world especially in the area of macular degeneration as its such a common condition. Unfortunately clinical research tends to be a very slow process indeed – in fact for most major breakthroughs its not unusual for the concept to take 10-15 years in the development and trial phase before being ‘released’. There are three main areas of some interest in managing poor eyesight from macular and retinal disorders that show some promise:
Stem Cell Treatments
Artificial Retinal Implants
- Gene Therapy
Gene therapy refers to the incorporation of new DNA into cells, either to supply a gene that is missing or not functioning in that cell or to supply a therapeutic gene. Several characteristics make the retina an ideal target for gene therapy:
The intraocular environment is accessible through a standard surgical technique – called a vitrectomy.
The intrao-cular environment is relatively isolated from the systemic immune system, providing some degree of tolerance for administered foreign antigens and minimisation of systemic vector spread.
Treatment outcomes can be easily monitored both subjectively (eg, with patient visual acuity) and objectively (eg, with electrophysiology and optical coherence tomography).
The ordered, epithelial architecture of retinal layers allows an administered vector easy access to entire cell populations.
How can this be done?
A way is needed to ‘get the gene’ delivered to the retina. There are currently three most commonly used ‘vector’ systems for retinal gene delivery. A vector is an agent that can act as a postman and deliver the gene to the target tissue – in this case the retina.
The standard vectors used at the moment are viruses. The 3 most common viruses used for this postman delivery are:
- Adenoviral vectors
- Lentiviral vectors and
- Recombinant adeno-associated virus (RAAV) vectors.
The most widely used vectors for ocular gene therapy — RAAV vectors – do not contain viral genes but are engineered to contain specific DNA sequences that can be used for treatment purposes. RAAV can be created in different types that can be used to preferentially target specific retinal cell types, including the photoreceptors, RPE, or ganglion cells.
Some Examples of Conditions that may be helped by Gene Therapy:
Leber Congenital Amaurosis Type 2 (Caused by RPE65 Mutations)
Leber congenital amaurosis (LCA) is a severe, blinding, typically autosomal recessive retinopathy resulting from mutation in one of more than a dozen causative genes. Affected people are usually diagnosed within the first few months of life, typically being born with very poor visual function and experiencing progressive visual decline that often leads to total blindness. Mutations in the RPE65 gene disrupt the visual-retinoid cycle and impair production of the visual pigments rhodopsin and cone opsin leading to toxic accumulation of all-trans-retinyl esters, ultimately causing photoreceptor death and leading to LCA type 2 (LCA2).
Despite its rarity, affecting < 1 in 1 million live births, LCA2 is an ideal pathology for the application of retinal gene therapy because, although photoreceptors degenerate, RPE cells are relatively well preserved; therefore, restoration of RPE65 function in RPE cells was hypothesized to lead to photoreceptor reactivation and restoration of sight.
On the basis of this reasoning, a great deal of research focused on the development of a gene-based therapy for LCA2, and it has been exceptionally successful in a multitude of animal models. In dog, pig, and rat LCA2 models, RAAV vectors have been used to deliver functional retinoid isomerohydrolase, restoring retinal function with dramatic visual improvement.
Building on this success, phase 1 human clinical trials have been performed. For example, 3-year data were reported from a phase 1 study of 15 patients aged 11-30 years who were treated with sub-retinal injection of a RAAV vector expressing RPE65. It revealed no systemic toxicity, good ocular tolerance, and improvement in visual function in all patients — dramatically in some. A 24-patient phase 3 trial is currently recruiting patients in Iowa and Pennsylvania. (1)
Choroideremia is an X-linked recessive retinal degenerative disease affecting about 1 in 50,000 people with loss of night vision beginning in the first decade of life, followed by gradual peripheral visual loss with progression to blindness by the fifth decade in most patients. Retinal degeneration is caused by prenylation deficiency due to absence of Rab escort protein-1 (REP-1) encoded by the CHM gene.
Partial results of a phase 1 study involving 6 men aged 35-63 years who were treated with sub-retinal injections of a RAAV vector expressing REP-1 were recently published (2) Average visual acuity improved by 3.8 letters among all patients, with 2 patients experiencing substantial improvements in visual acuity of 21 and 11 letters (over 4 and 2 lines of visual acuity, respectively).
Neovascular Retinal Diseases (eg wet AMD)
Any retinal disease that could benefit from local production of a specific RNA or protein is a potential candidate for gene therapy.
Currently, therapies applied for wet AMD involve pharmacologic agents that block vascular endothelial growth factor (VEGF) – e.g Lucentis, Eyelea or Avastin. These medications achieve VEGF suppression remarkably well, but the relatively short duration of action of these biological proteins, often means monthly administration for maximal clinical effect and visual benefit, especially in resistant cases. Repeated treatments incur additional patient risks, cost for the health services and inconvenience.
The need for longer-acting therapeutics may be fulfilled with gene therapy. For example, an adenoviral vector expressing pigment epithelium-derived factor (PEDF) that inhibits angiogenesis was used with success in a phase 1 trial (3). Currently, a phase 1 trial is under way to evaluate an intra-ocular administered RAAV vector expressing a soluble portion of a VEGF receptor intended to block VEGF (sFlt01) (4)
Future Gene Therapy Targets
Early results of gene therapy studies for inherited retinopathies are compelling; phase 1 human clinical trials have demonstrated safe and successful targeting of mutant genes involving the RPE (LCA2) and photoreceptors (choroideremia). If ongoing trials, including a phase 3 trial for LCA2 treatment, are successful, other ‘monogenic’ retinopathies will certainly be targeted as treatment horizons expand.
Ideally, retinal gene therapy targets will be expanded to include multigenic diseases, such as dry AMD. Dry AMD has a substantial genetic component but many involved loci,(5) and the only current treatment options involve lifestyle modifications, such as smoking cessation,(6) cardiovascular risk factor optimization, and AREDS2 (Age-Related Eye Disease Study 2) vitamin supplementation (7) aimed at slowing disease progression.
There is no doubt that the future is getting brighter when considering gene therapy for retinal diseases. However at the present time (2014) – only the tip of the therapeutic iceberg is still visible today, with many challenges remaining. Continued research and development with refinement of these technologies should lead to the clinical application of gene therapy vectors becoming a realistic possibility in the next decade or so.
1) Jacobson SG, Cideciyan AV, Ratnakaram R, et al. 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. Abstract
2) ClinicalTrials.gov. Gene therapy for blindness caused by choroideremia. NCT01461213. http://www.clinicaltrials.gov/ct2/show/NCT01461213?term=NCT01461213&rank=1 Accessed April 4, 2014.
3) Campochiaro PA, Nguyen QD, Shah SM, et al. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther. 2006;17:167-176. Abstract
4) Maclachlan TK, Lukason M, Collins M, et al. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration. Mol Ther. 2011;19:326-334. Abstract
5) Grassmann F, Fritsche LG, Keilhauer CN, Heid IM, Weber BH. Modelling the genetic risk in age-related macular degeneration. PloS One. 2012;7:e37979.
6) Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP. Smoking and age-related macular degeneration: a review of association. Eye (Lond). 2005;19:935-944. Abstract
7) Age-Related Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309:2005-2015. Abstract
- Stem Cell Treatments
Stem cell treatments are currently being investigated within rigorously controlled clinical trials. The basic idea is to attempt replacement of worn out retinal pigment epithelial cells (RPE) with fresh cells. The RPE cells form a single layer of cells behind the retina and are critical to proper working of the retina and especially the macula. Worn out RPE cells in AMD conditions ultimately lead to poor sight because of the impact on the retinal photoreceptors that sit on top of the RPE cells.
RPE cells could be replaced with cells taken from stem cells from a human embryo or from stem cells from the adult patient. Both approaches are under evaluation and it is far too early to be able to tell which approach is most feasible. At this stage there is insufficient clinical trial data to draw any conclusions from but the concept of replacing worn out RPE cells in AMD and other such conditions is certainly worthy of further research which is on going.
Questions we would need to be able to answer for stem cells to become viable options in treatment are :
- How safe is it to replace RPE cells with either human embryo derived stem cells or adult human stem cell derived RPE cells ?
- How effective are these techniques in regenerating the tissue on a medium to long term basis ?
- How effective are these techniques in restoring lost vision after treatment ?
- Is the degree of vision change ‘worth it’ for the risks and costs involved ?
- Are there any longer term risks such Cancer arising from the stem cells ?
As can be seen from this (non exhaustive list) there are many questions yet to be answered on stem cell research and Bettersights view is that we are still at least half a decade away from a realistic prospect of clinical implementation even were the answers to the above questions to be highly positive.
- Retinal Prosthetic Implants
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