1. Background to Programme Area

1.1 The recent past has seen an upsurge of interest in the function and dysfunction of the macular retina. This small region of the retina centred around the visual axis is responsible for fine and discriminant vision encompassing the functions of resolution, colour perception, contrast sensitivity, scanning, reading and detection of motion. Diseases of the macula, which were previously under-researched are now the focus of attention owing to the identification of degenerative age-related macular disease as the major visual public health problem of the 21st century.

1.2 The disease is responsible for over 50% of all blind and partially-sighted registration in the UK and is estimated to affect over three million people in the UK. The magnitude of the problem will grow significantly as the number of elderly people increases; one study projects an increase of over 29% in the number of people over the age of 65 years in the next 20 years in the UK. Moreover, the disease may be increasing in prevalence in real terms over and above that due to changing demographics.

1.3 The fact that the disease is untreatable and non-preventable increases the frequency of the contact of sufferers with the medical and social professional services. Although not life threatening, age-related macular degeneration (AMD) has been judged, on the basis of a spectrum of measures of patient disability, as the third most disabling disease in the US population after diabetes and cancer. For these reasons, funds into AMD research have been targeted recently as a high priority in the distribution of US NIH/NEI national funding. Clearly, the development of measures to prevent, or a strategy to treat even a small proportion of sufferers of AMD, will produce a large saving in health care costs and a substantial reduction in disability of a large proportion of the population. Research into the genes and proteins underlying the disorder offers the most promising hope for development of such novel treatment strategies

  2. Programme plan

2.1 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 programme 3).

2.2 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 multicentre 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.

2.3 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.

2.4 Epidemiological and Service Issues
· Evaluation of novel, and improvement of existing treatments in AMD including:
· Photodynamic therapy
· External beam radiation, proton beam irradiation
· Transpupillary thermotherapy
· Chorioretinal anastomosis (surgical and laser)
· Intraocular administration of tissue plasminogen activator, other clot-lysis agents and anti-angiogenic, anti-scarring agents

2.5 Clinical and Laboratory Issues
· Phenotype-genotype characterisation of monogenic retinal disorders
· Characterisation of phenotype of AMD genetic polymorphisms (eg ApoE4).
· Development of RPE transplantation strategies in AMD
· Characterisation of molecules involved in neovascularisation occurring in AMD
· Elucidation of novel therapies including gene replacement therapy, modulation of retinal cell apoptosis, catalysis of harmful gene mutations in vivo (ribozymes) and retinal cell transplantation.
· Evaluation of gene function, protein structure, chemistry and interaction in cell systems and animal models.

  3. Future Development Work in the Programme During 2002/3

3.1 Genetics, genotyping and risk factors

· Continue the molecular genetic studies of patients with AMD using blood collected from our patients, and their siblings.

· Segregate according to their phenotype using photography, fluorescein angiography and autofluorescence imaging. Spouses of patients
free of AMD provide a comparison group.

· Continue, in parallel, histological studies undertaken to document the variation of age-changes at the macula, compatible with the concept that several genes are involved in conferring risk of visual loss.

3.2 Prevention and surveillance

· Pursue funding to establish an AMD specific disease register

3.3 Symptoms, presentation and referral

· develop further epidemiological studies to improve information about the incidence and prevalence of AMD

3.4 Phenotyping, information and communication

· Continue the collection of phenotyping data in the Phenotyping Unit

3.5 Diagnosis, investigations and pathology
· Elucidation of novel therapies including gene replacement therapy, modulation of retinal cell apoptosis, catalysis of harmful gene mutations in vivo (ribozymes) and retinal cell transplantation.

3.6 Interventions -surgery, medical, radiological

· Evaluation of novel, and improvement of existing treatments in AMD including:
Photodynamic therapy
Transpupillary thermotherapy
External beam radiation, proton beam irradiation
Chorioretinal anastomosis (surgical and laser)
Intraocular administration of tissue plasminogen activator, other clot-lysis agents and anti-angiogenic, anti-scarring agents
Retinal translocation surgery

3.7 Nursing, community care, rehabilitation - see programme 15