Personalized Therapy of AMD (Age Related Macular Degeneration) Patients: the Clinical Use of Personal Genome

Project location: Italy, Rome
Project start date: September 2014 - Project end date: August 2016
Project number: 2013-072
Beneficiary: Fondazione PTV Policlinico Tor Vergata

 

Age-related macular degeneration (AMD) is the most common irreversible cause of severe vision loss throughout the world in people aged 50 years or older. In the USA it is estimate that the prevalence of AMD is 9% among people 40 years of age or older, with a strong increase in the advanced age. Actually about 8.5 million of American suffers from AMD, but a lot of them are unaware of this disease. First signs of the disease (blurred vision, visual scotomas, decreased contrast sensitivity, abnormal dark adaptation) are characteristically misunderstood, therefore when people arrive to ophthalmologist's attention they have intermediate or advanced disease.

Macular Degeneration can have a severe impact on otherwise healthy people and it reduces the potential daily life's activities such working, driving, reading etcetera. In a Southern European country such as Italy the role of family resources are more important than that of the other social resources. Often older people play a significant role in helping management of the family when both parents work and grandparents can take care of children.
Furthermore vision impairment related to AMD has been associated with depression and mental health; therefore, vision related depression needs to be considered in the provision of low vision care.
In an ageing society, the wellbeing of the elderly is an important area for research and at the top of the public policy agenda.
Age-related macular degeneration affects adults from the age of 50 years and is the leading cause of blindness in people older than 65 years in the developed world [Fine et al., 2000; Kahn et al., 1977].It is estimated that almost 500,000 new cases of neovascular AMD occur each year worldwide [Hyman et al., 1992], and this figure is expected to grow dramatically as the population ages [Pizzarello et al., 1987; Scott et al., 1999]. The disease is rare before the age of 65 years, but its prevalence increases exponentially with age, being present in almost 5% of those aged 75-84 years and reaching a frequency of 13% among those aged 85 or over in population-based studies [Smith et al., 2001]. Early stages range in prevalence from 1.6% in those 52-64 years of age to 27.9% in those over the age of 75 years [Klein et al., 1997]. Legal blindness often develops with time because the disease tends to become bilateral in 30-40% of patients within 5 years [Macular Photocoagulation Study Group, 1997; Garattini et al., 2004]
The main object of this project is to institute an inter-disciplinary network that focuses on patient care, patient-oriented research, and outreach and education in personalized healthcare guided by genetics and genomics. This network is expected to promote our knowledge of genetic and pharmacogenetic basis of Age Related Macular Degeneration (AMD) and to translate these emerging data in significant improvements of diagnosis, treatment and study of that disease.

The main objectives of the project, which received a grant from the Nando Peretti Foundation, will be reached with the active collaboration between the ophthalmologists and the geneticists of the Tor Vergata University.
The activities will be organized in Basic Research (BR), Clinical Research (CR) and Translation Protocols (TP). In particular the patient will be evaluated in the context of his or her personal medical history, family background and physical examination. A full range of genetic consultations will be performed by the geneticists of Tor Vergata University. Specific genetic tests may be developed and/or initiated following the clinical evaluation. Tailored recommendations in terms of education and health planning will be provided, and if appropriate, extended to at-risk family members. Patient-oriented research protocols will be developed following the integration of clinical and genetic data. The specialists will work together in order to optimize the multidisciplinary background required for the project aims.
The activities are structured in different work packages:

WORKPACKAGE 1 (BR). SELECTION OF PATIENTS AND COLLECTION OF BIOLOGICAL MATERIAL, CLINICAL DATA, AND FAMILY HISTORY
Participants will be recruited from the UOSD Retinal Pathologies (the retina unit) of the PTV Foundation.
The inclusion criteria are: male or female subjects over the age of 50 years; written informed consent; presence or history of AMD both atrophic and exudative; presence of CNV secondary to AMD in treatment or treated with anti-VEGF injections; clear media in order to guarantee good quality images.
The exclusion criteria are: signs of any other macular condition predisposing to CNV (similar to what reported by Unit 3); any previous intraocular treatment, including laser photocoagulation and photodynamic therapy with verteporfin (PDT); failure to complete 6 months of intravitreal therapy; cataract surgery in the study eye any time from 3 months before until 6 months after the initiation of intravitreal anti-VEGF therapy; allergy to fluorescein.
Participants will be asked to give a blood sample for genetic purposes. For the collection of biosamples, full written informed consent will be required for each subject participating in the study, obtained only after the study has been explained to them and they have had an opportunity to ask, and have answered, questions concerning the study. In addition, the subjects can have their samples and records permanently removed from the study at any time.
The data treatment will be conduct in respect with the highest ethical standards and within full compliance with the requirements of the latest version of the Declaration of Helsinki.

WORKPACKAGE 2 (CR). PHENOTYPING AMD LESION, IN PARTICULAR ATROPHIC AMD THAT PROGRESS TO NEOVASCULAR LESION, AND CHOROIDAL NEOVASCULARISATION (CNV) SUBTYPES ON THE BASIS OF THE ANGIOGRAPHY WITH FLUORESCEIN
The Clinical Unit will use the classification for choroidal neo-vascularization (CNV) based on fluorescein angiography (FA), identifying occult lesions, classic lesions or predominantly or minimally classic lesions.
A minimum standardized imaging protocol will be performed in all patients, after pupil dilation and prior to dye injection, which includes: color stereoscopic pairs of photographs of the retina of both eyes, acquisition of near-infrared reflectance, fundus autofluorescence and simultaneous SD-OCT scanning using a second, independent pair of scanning mirrors.
The phenotypic characteristics will be then correlated to the response to treatment with different anti-VEGF drugs.

WORKPACKAGE 3 (TP). TREATMENT OF NEOVASCULAR AMD PATIENTS WITH BIOLOGICAL DRUGS AND FOLLOW UP.
The treatment regimen will be arranged according to the international guidelines and the specific requirements of patients. However follow-up visits will be time scheduled both for treated patients and non-treated patients.

WORKPACKAGE 4 (CR;TP). MONITORING OF NON EXUDATIVE AMD.
Patients with atrophic AMD, characterized by the presence of drusen, pigmentary changes, and geographic atrophy, will be monitored for possible progression to the neovascular form. Specific biomarkers will be associated with this peculiar condition and compared with atrophic AMD cases that remain stable.

WORKPACKAGE 5 (TP). IDENTIFY FAMILIES WITH AMD OR SPORADIC CASES
Accurate family history will be collected from each subject enrolled in the study. When the patient reports that other members of the family are affected with AMD, the ophthalmologist will address the family to genetic counseling. The geneticist will record the familial data and inform the members about their risk to develop AMD. Furthermore, the geneticist will collect familial information for statistical and genetic correlation to progression of the disease and to response to treatment.

WORKPACKAGE 6 (BR). COLLECTION OF BIOLOGICAL MATERIAL FROM A GROUP OF AGE-MATCHED SUBJECTS WITH NO SIGNS OF AMD THAT UNDERGO TO CATARACT SURGERY AS CONTROL GROUP.
In the literature there is no evidence of possible correlation between cataract extraction and AMD occurrence or progression in subjects of age > 55 years. Therefore, a screening program will be performed on such group of patients. In particular, subjects undergoing to cataract surgery will be screened for the presence of early AMD signs. Blood will be collected from these patients, after signed informed consent, in order to have a control group for our study.

WORKPACKAGE 7 (BR). DEVELOPMENT OF A BIOREPOSITORY FOR THE COLLECTION OF DNA SAMPLES, CLINICAL DATA, INSTRUMENTAL RESULTS AND FAMILIAL HISTORY
This biorepository will be dedicated to the collection of clinical data and samples (whole blood, plasma, DNA). The biorepository aims to develop a facility to support research programs in Italy as well as throughout the world. This biorepository is expected to facilitate and accelerate the rate of progress in understanding the biological basis of AMD. The major thrust of this biobank activities focuses on the collection of DNA from selected patients, controls and general population. DNA sample and matching clinical data as well as data arising from follow-upstages will be rendered anonymous and available to the genetic laboratory in the Tor Vergata University for scientific programs. In addition to biological samples, this biorepository will include clinical and instrumental data to support longitudinal and retrospective studies and to assist the identification of biomarkers. The biorepository will support the principles and measures, consistent with ethics policy guidelines, to protect the privacy and the confidentiality of an individual's data obtained from genetic research in the following ways. The data will be managed according to the current ethical standards and within full compliance with the requirements of the latest version of the Declaration of Helsinki. For the collection of both tissue and DNA samples, full written informed consent will be required for each subject participating in the study. This informed consent will be obtained only after the study has been extensively explained giving full opportunity to ask, and have answered, questions concerning the study. In addition, the subjects can have their samples and records permanently removed from the study at any time.

WORKPACKAGE 8 (TP). DEVELOPMENT OF AN INTEGRATED INTERACTIVE PLATFORM
A specific web-based interface will be developed, in collaboration with e-learning Companies, to promote data collection (surveys, experiment results, available tests, clinical data collection) and data sharing. Although in a first phase of this project, the interface will assist the connection and data sharing between the specialists, it is important to outline that, in a second phase it is expected to become a multidisciplinary network to promote national and international web-based data collection as well as the record of experiments and results. The interface will benefit from communication throughout the genetic and ocular studies by establishing a network bringing together molecular scientists, clinical surveys and data collection. It will tackle several clinical and biological problems and discuss scientific validity. In our opinion such platform can generate innovative ideas, address the latest technological options, synergize knowledge, encourage cross-national research proposals and finally provide new tools and guidance for researchers, official bodies and scientific institutes.

WORKPACKAGE 9 (BR). CONFIRMATION OF SUSCEPTIBILITY GENES AND VARIATIONS IN A LARGE COHORT OF SAMPLES AND SAMPLE STRATIFICATION
The recruitment of samples affected by AMD will be carried out by the UOSD Retinal Pathologies of the PTV Foundation. All SNPs and genetic variation identified so far will be confirmed in a large cohort of samples to verify the presence of genetic heterogeneity in Italian samples and to assess the penetrance of these genes in our patients. Particular attention will be paid to the differential analysis of endophenotypes in order to disclose specific effects in different classes of patients. Extreme phenotypes will be compared and characterized (i.e. early onset vs late onset; stable AMD vs advanced AMD; patients switched from dry to exudative AMD vs stabilized dry AMD, patients with positive family history vs sporadic patients with well documented negative family history).
New genetic variants will be selected from large genome-wide studies conducted around the world and typed in the cohort of patients, controls and general population. Genetic data will be correlated to clinical phenotypes and treatment response: Early onset patients, late onset patients; patients with stable AMD, patients with advanced AMD; patients switched from dry to exudative AMD, patients with stabilized dry AMD; responders to biological treatments (subdivided in different classes, each for biological drug) and not responders.

The following goals represent the scientific priorities of the project:
1) Web based facility to support studies on AMD genetic associations, endophenotypes-gene associations and gene-environment interaction;
2) Development of a biorepository and database to improve our ability to define individual risk, to identify biomarkers and to predict response to therapies;
3) Genome-based protocols for AMD prevention, management and prognosis
4) Development of an epidemiology/clinic/genetic consortium to translate genomic information into promising applications, protocols and further research;
5) Pharmacogenomic dissection of AMD, to identify and characterize validity and utility of genetic markers for AMD care and prevention

IMPACT ON PUBLIC HEALTH
The researchers will develop a web-based tool supporting research programs on AMD. This facility will be implemented with genomic and pharmacogenomic data as well as traditional clinical measurements as family history, clinical outcomes and instrumental data. It is expected to provide an innovative, end-to-end, outsourced service model, enables researchers and clinicians to conduct complete human genome studies. The ultimate goal of the platform is to support integration of different expertise providing new opportunities for AMD prevention and treatment as well as for applied science. Refinement of risk assessment and diagnosis individualization based on these interdisciplinary data should be used to target high risk populations with personalized primary prevention health information about diet, lifestyle modification, risk factor management and current screening recommendations.
Major fields of impact on public health:
- Lifestyle improvement. The identification of new susceptibility biomarkers will support the development of more efficient prevention strategies, individualized according to genetic/epigenetic and environmental factors.
- Pharmacogenomics. The development of "personalized medicine" is considered as a major objective for the next decade in the European Union. The integration of genomic data and the availability of large-scale biorepository and database are expected to improve our ability to define individual risk and to predict response to therapies.
- Protocols. The development of specific guidelines and protocols, assessed by both clinical and genetic expertise, will improve the management of AMD patients as well as the prevention for at-risk subjects.

SOCIO-ECONOMIC IMPACT
The emotional and economic burden of age-related macular degeneration (AMD), the leading cause of severe visual impairment in the Western world, is often under-recognized. The economic impact of AMD on society is expected to increase in the near future as populations' age and the prevalence of AMD increases. With new AMD therapies, healthcare decision makers will require reliable quantitative data on AMD-related resource utilization to evaluate alternatives. Insufficient documentation of the impact of AMD on patients and caregivers limits our understanding of the disease burden impact, and undermines our ability to make rational policy decisions when considering alternative treatment strategies.
Cruess and coworkers in 2008 [Cruess et al., 2008] make an examination of the healthcare costs of neovascular age-related macular degeneration (NV-AMD), which constrains the understanding of the economic impact of this condition. Cruess suggests that the mean annual cost per bilateral NV-AMD patient ranged from €5300-12445, the annual direct medical costs for NV-AMD in 2005 were estimated to be €597 million in Canada, €926 million in France, €1155 million in Germany, €500 million in Spain and €662 million in the UK, which correspond to approximately 0.5-0.6% of the total health-related expenditures in these countries. [OECD 2006]
In Italy, the mean annual total cost borne by the Italian National Health Service was euros 383.2 per patient, with patients with drusen or geographic atrophy having substantially lower costs (158.1 and 147.9 respectively) that patients with CNV (540.1). Out-of-pocket costs, including over-the-counter supplements and eye drops, averaged euros 51.7 over the year, with geographic atrophy patients having higher out-of-pocket costs than either of the other two groups. The higher rate of use and cost of supplements among patients with early and intermediate disease is consistent with recommendations that these supplements are most effective when taken early in the disease course. No indirect costs were included in this study. [Schmier et al., 2006]

In Italy, SSN focuses the attention on prevention and treatment of AMD, encouraging lifestyle improvements for primary prevention and careful choice of treatment. To date no genetic or biological data can influence the treatment and the prognosis of patients, treatment is established mainly (if no exclusively) on the "evidence based medicine". Despite the large amount of research programs and the guidelines of "evidence based medicine" the economic and social impact of AMD remains high.
Based on these data, the proponents aim to combine current knowledge in "evidence based medicine" with genetic, clinical, epidemiological and biochemical data for a target treatment of these patients reducing the economic and social burden on such disease. The establishment of a biorepository integrated with clinical, epidemiological, biochemical and instrumental data will provide an invaluable resource for research in AMD, including studies of etiology, progression, and prognosis, as well as development of biomarkers for early detection and treatment safety and/or efficacy. The measurement of such biomarkers in blood is an integral component of translational research, with applications to studies on genetic susceptibility and individualized medicine.

 


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