3.2 Research Potential

  3.2.1 Age-related macular degeneration (AMD)

Susceptibility to AMD is determined partly by a person's genes as shown by a number of family- and twin-based studies. Although many candidate genes have been generated by the study of monogenic disorders (see below), association studies for AMD have so far been negative, although a protective effect of ApoE4 has been suggested. The genetic study of AMD is challenging due to the absence of DNA and clinical data from parents of affected people, the difficulty in classification and quantification of disease and the likely ethnic variability in the disease and the underlying genetic factors. A careful collection of phenotypic data and DNA/RNA and the recruitment of affected sibships is required to make further progress in this challenging area. Studies of many polymorphisms in many distinct candidate genes as well as the identification of further loci using linkage analysis in sibs, will be required to elucidate the genes involved. Following the discovery of any new gene implicated in the disorder further laboratory research is required to elucidate its expression, function and pharmacology (see below - inherited retinal disease).
As well as the need for laboratory research to elucidate molecular mechanisms underlying AMD, the evaluation of novel and established clinical treatments will require further careful evaluation in the future five years. Such treatments involve those aimed at destroying the growth of choroidal blood vessels beneath and within the ageing retina such as photodynamic therapy (PDT), external beam irradiation, transpupillary thermotherapy and vitreoretinal surgery. In the case of PDT, in a multicenter international trial comparing patients who had undergone PDT to control subjects with AMD having sham treatment, the percentage of subjects who experienced moderate loss of vision (three lines or less) was 61% in the PDT group and 46% in the control (untreated) group. This benefit was significant only for patients who had a type of choroidal neo-vascularisation (CNV) lesion defined as "predominately classic". Although statistically significant, the technique requires further evaluation for AMD and other causes and types of choroidal neovascularisation. The understanding of the molecules involved in cell death (apoptosis), scar-formation and neovascularisation, processes which contribute to the destruction of functioning retinal tissue in AMD, has increased recently and there exists real opportunities to examine, in the laboratory and then clinic, the manipulation of these processes through pharmocological means. Unlike the neurosensory retina, which histologically resembles the central nervous system (CNS), the retinal pigment epithelium layer is a monolayer of cells that has the potential to regenerate and can be successfully grown in culture. The exploration of retinal pigment epithelium (RPE) transplantation, in close collaboration between cell biologists and retinal clinicians, will be important to investigate this potential treatment for those cases of AMD in which cell death (atrophy) is the predominant feature.


  3.2.2 Vascular retinal disease

In diabetic retinopathy, unlike AMD, clinical research has identified at least partially effective preventive treatments, including intensive diabetic control, control of hypertension and retinal laser photocoagulation for proliferative diabetic retinopathy and to a lesser extent macular oedema (responsible for 70% of visual loss in diabetic patients). The National Screening Guidelines for Diabetic Retinopathy will lay down, for the first time, countrywide targets for screening and treatment but implementation and optimisation of the proposals remains a major objective. The UK is well placed to investigate screening strategies. Topics of investigation include validation (grading strategies, training), incidence and prevalence (establishing optimum screening intervals, NSF targets), cost-effectiveness, detection systems and automated grading. Diabetic macular oedema, even with timely laser treatment, often leads to a poor visual outcome. The effectiveness of alternative treatments such as vitrectomy/membrane peel will require careful assessment.

Continued investigation of the molecular mechanisms and the role of growth factors such as VEGF and the angiopoietins in diabetic retinal angiogenesis and macular oedema will suggest key molecular targets for pharmacological therapeutic intervention. Inhibition of intracellular molecules upregulated by VEGF, such as Protein Kinase C, will undergo more investigation and clinical trial appraisal before introduction as medical treatments. Finally viral vector introduction of VEGF receptors and other growth factor antagonist genes into the retina provides a method of longterm prevention of retinopathy progression.

Treatment of vein occlusion is currently limited to the use of scatter retinal photocoagulation to prevent neovascularisation, and macular laser treatment has some bearing on visual outcome in branch retinal vein occlusion. The pathogenesis of CRVO remains obscure and future research will continue to examine patients for prothrombotic tendencies and systemic risk factors, in an attempt to develop strategies that will reduce disease incidence. VEGF has been implicated in the occurrence of neovascular complications and inhibitors will likely be used to prevent this. Chorio-retinal anastomosis, either by laser or surgical means to bypass CRVO will be further examined and systemic and intravitreal clot lysis agents refined and reassessed.

  3.2.3 Inherited retinal disease

Each newly discovered gene generates further research opportunities. Downstream projects include determining the expression profile of the gene in different tissues; characterising the structure of the expressed protein and localisation of the protein within the cell, the identification of interacting and homologous proteins; and the effect on protein function; structure and interaction of the genetic mutations found in families from the clinic. Only with the further investigation of gene function and protein biochemistry will understanding emerge to develop therapeutic strategies. Further genes and loci remain to be found for retinal disease, and although the techniques for linkage analysis and positional cloning have improved, the standard technologies of DNA and RNA analysis and sequencing remain expensive and hence the costs of such research remain large. The experimentation needed to realise those laboratory projects downstream of gene discovery include the use of animal models. Animal models with naturally occurring mutations in retinal genes or those with generated knock-out mutations, allow the assessment of novel treatment approaches. Such techniques include gene-replacement therapy in which the missing gene is inserted into a viral vector and injected into the animal (for instance the sub-retinal space or vitreous cavity). Encouraging results have been shown for the replacement of the rds gene in rds -/- mice, and more recently the RPE65 gene in RPE65 -/- dogs (Nature Genetics May 2001) and this approach is a paradigm for the treatment of disorders that occur due to reduced gene dosage in the retina in humans (the majority of autosomal and X-linked recessive retinal disease). Other approaches include the insertion of genes designed to express ribozymes capable of catalysing mutant alleles in vivo such as those with missense mutations that cause the majority of autosomal dominant retinal disease. Also, the use of genes and proteins designed to interfere with and suppress apoptosis of retinal cells (such as ciliary neurotrophic factor - CNTF) is a promising strategy. Novel drugs designed on the basis of the laboratory investigations described above will also require evaluation in animal models as in the recent evaluation of systemic diltiazem on the retinal degeneration of mice lacking rod photoreceptor phosphodiesterase (rd-/-).

Following the determination of causative genes, in parallel with further laboratory investigation, there remains an important opportunity to study the clinical phenotype of resulting disease in the light of genetic discovery. The work of the interested clinician, in concert with the genetic laboratory, can identify subsets of patients with particular molecular diagnoses and carefully characterise the disease phenotype given such specific molecular data. Only with these phenotype-genotype correlation studies will the ultimate effect of genetic mutation on human biology be elucidated and the appropriate families and individuals for future novel therapies be identified. Such careful clinical characterisation of selected patients and families in terms of retinal imaging, psychophysics and electrophysiology is not inexpensive and requires substantial devoted funding.

  3.2.4 Inflammatory retinal disease

The research priority in this area is to devise novel therapeutic strategies which are more effective at controlling the inflammation and thereby preventing visual loss. A greater understanding of the disease mechanisms can be achieved by examination of the cells that infiltrate the eye and are present in the ocular fluids. This may identify a cytokine profile produced by the cells which results in aggressive disease and switching these off may be achieved by using other downregulatory cytokines. In some types of retinal infection, implants containing the therapeutic agent are inserted into the eye and deliver the drug constantly over 6 months. To be able to treat eye inflammation inside the eye has many advantages in that it is likely to be more effective as reliable drug levels are achieved where the drug is needed and all the systemic side effects are avoided.

New immunosuppressive drugs can be assessed against current therapy in clinical trials. Many patients are young and healthy apart from their chronic eye problem and therefore it is of major importance that the side effect profile is acceptable for long term treatment. Drugs which could induce disease remission, as has been suggested for interferon alpha, and/or could considerably reduce or replace the need for corticosteroids, which are the mainstay of treatment, would be ideal.

Patients with the same clinical phenotype of disease can have very different responses to treatment and visual outcome. Although few types of intraocular inflammation have a strong HLA association, there must be other genetic factors which determine disease out come. This maybe genes that control levels of cytokine production or other immune signals or genes which control processes that metabolise drugs or a myriad of other processes which are involved. By dissecting out these parameters in carefully phenotyped patients, it may be possible to identify patients who will do badly and lose vision. The aim then would be to target these patents for earlier more aggressive treatment to try and prevent this from occurring.

  3.2.5 Ocular oncology

Uveal melanomas are the most common primary intraocular malignancy in adults and pose a significant threat with approximately 50% of patients ultimately dying from their disease. In the past two decades there has been considerable progress in developing therapeutic options which avoid the need for removal of the affected eye. Whilst this has, in many cases, led to the preservation of a cosmetically acceptable eye and/or useful vision there has been no impact on patients' survival. The identification and treatment of high risk patients with adjuvant therapy at the time of their initial diagnosis may ultimately lead to improved survival in these patients.

In the last few years certain cytogenic abnormalities have been detected within uveal malanomas and these have been found to have a profound prognostic significance. Further research is directed into the characterisation of these and other abnormalities within the tumour genome. Increasing our understanding of the molecular genetic events which lead to the genesis of these tumours may provide us with greater means for identifying high risk individuals. In addition, an increased understanding of the molecular mechanisms responsible for the development of these tumours may provide us with opportunities to control tumour growth at a molecular level.

Adjuvant therapies must be developed to address the problem of micrometastatic disease present at the time of primary therapy. Such therapeutic options may include: immunotherapy, anti-angiogenic therapy, chemotherapy and gene therapy.

Retinoblastoma is the commonest intraocular tumour in childhood with a frequency of approximately 1 in 20,000 - 1 in 30,000 liver births. Present treatment is highly successful in controlling the primary tumour and survival rates in affected children is extremely high. Primary treatment that may include radiotherapy, laser therapy, cryotherapy and chemotherapy may have a secondary adverse affect on visual function. Future treatment strategy will aim to eradicate the primary tumour, but at the same time minimise normal tissue damage. Again, in recent years there has been a considerable increase in our understanding in the genetic and molecular events that determine the development of retinoblastoma. Future research should be directed at increasing our understanding of these molecular genetic events that in turn may provide us with therapeutic options for eradicating the primary tumour with a minimal disturbance of normal tissues.

   3.1 Background // 3.3 Research Priorities