Qualifying mouse models of spontaneous, progressive age-related macular degeneration

Lead Research Organisation: University College London
Department Name: UNLISTED

Abstract

Age-related macular degeneration (AMD) is a chronic disease of the retina, which results in the loss of central vision and is the main cause of blindness in the Western World in people over 55 years age. More than 30 million people in the developed world suffer from AMD and with increasing life expectancy and changing environmental factors the incidence of AMD continues to increase. Though several treatments for AMD exist, they target ~ 20% of patients with the disease and are effective at restoring vision to a minority of those treated. Those with visual impairment or blindness have a significant impairment in quality of life and functional independence and are a considerable burden on healthcare resources. Recent scientific studies have led to the discovery of several genes linked to inflammation and the immune system, termed the complement pathway, that appear to play a major role in the onset and progression of AMD. However, there are many different abnormalities associated with AMD, including alterations to the neurons and support tissues of the retina, improper removal of waste products and in the most severe stage, growth of chaotic and sight-threatening blood vessels and oedema. Researchers are now focused on determining which of these abnormalities are caused by the complement pathway, and therefore could be targeted by new medicines that are now being developed by pharmaceutical companies. Animal models that mimic human AMD are urgently needed to begin testing these new potential medicines. By identifying animal models that accurately reflect the abnormalities observed in AMD, we hope to test the new therapies and identify at which stage of the disease, and for which abnormalities we should focus on in human clinical trials. We propose to work in partnership with a pharmaceutical company named Jerini Ophthalmic to evaluate two mouse models of AMD, compare them to the human condition, and use the models to test an inhibitor of the complement pathway that Jerini Ophthalmic hopes to test in human clinical trials within the next 1-2 years.

Technical Summary

Age-Related Macular Degeneration (AMD) is a chronic, progressive disease of the central retina, called the macula, which results in the loss of central vision. It is the leading cause of severe vision loss and blindness in patients over the age of fifty in the developed world. A major breakthrough in AMD research occurred following recent publication of several human genetic studies linking 3 different gene loci encoding components of the complement pathway to AMD. These data implicate the complement cascade as the first molecular pathway to target in therapeutic strategies aimed at the prevention of advanced AMD. This new therapeutic approach will hopefully improve the outcomes for the large majority of AMD patients who have no treatment options (i.e. geographic atrophy) or who do not respond to current ?wet? AMD treatments targeting Vascular Endothelial Growth Factor (VEGF). Remarkably, several complement cascade antagonists are already in early clinical testing or late-stage pre-clinical development. Yet, despite having a highly validated biological pathway to target, and several potential antagonists in drug development, the pathogenic mechanisms by which the complement cascade triggers progression from early stages of AMD to either of the sight-threatening forms, geographic atrophy or choroidal neovascularisation, are ill-understood. Clarity around at which stage of AMD progression complement-induced dysfunctions play a role will be critical for designing effective clinical trials to test this promising area of disease prevention. Progress in meeting the challenges outlined above is hampered by the lack of qualified, validated animal models that enable credible comparative studies to pinpoint a therapeutic window for the application of complement antagonists in clinical trials. In collaboration with Jerini Ophthalmic, a small ophthalmic biotech, we propose to evaluate and qualify the suitability of two mouse genetic models which together appear to recapitulate most of the pathologies associated with the progression of AMD, and to determine the comparative efficacy of VEGF and complement antagonism on disease progression.
 
Description NIHR BRC
Amount £260,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2012 
End 02/2015
 
Title TJL mouse model of CNV 
Description A new, quantitative model of spontaneous choroidal neovascularization for assessment of drug candidates for AMD without the need for laser 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact Proof of concept studies for new drugs entering clinic. Has led to clinical track nomination of 2 drug candidates with GSK 
 
Description GSK-IoO collaboration 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution The lab and many other researchers at the Institute have performed POC studies on new compound candidates using our animal models and biology expertise
Collaborator Contribution Provision of compounds for lab studies; involvement in POC and transitioning of new compounds into clinic for ophthalmic use
Impact Our POC efforts have led to the movement of compounds into clinical candidate status and have led to design and execution of one clinical trial
Start Year 2009
 
Description New GSK collaboration 
Organisation GlaxoSmithKline (GSK)
Department Institute of Ophthalmology
Country United Kingdom 
Sector Academic/University 
PI Contribution Using the novel animal model, we have validated 2 new targets and cognate compounds, which are currently being scheduled for entry to the clinic in 2011-2012
Collaborator Contribution Through research in the animal model, we have jointly moved 2 novel compounds/formulations to clinical trials
Impact Using the novel animal model, we have validated 2 new targets and cognate compounds, which are currently being scheduled for entry to the clinic in 2011-2012
Start Year 2011
 
Description New Roche collaboration 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution Using the model, we have achieved POC studies in preclinical assessments that have led to Clinical trial initiation in Nov 2013
Collaborator Contribution Provided compounds for testing
Impact Multi-disciplinary Led to initiation of a clinical trial for a new therapeutic antibody to treat neovascular AMD
Start Year 2010
 
Description Roche 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution Using the novel model, we have validated novel therapeutic strategies for treating AMD
Collaborator Contribution Opened new lines of investigation by introducing novel targets
Impact Novel target validated using a drug currently in human clinical trials
Start Year 2011
 
Title CCR3 antagonists for AMD 
Description Use of the mouse model of AMD to determine the mechanism of action and efficacy of an NCE that entered clinical trials 
IP Reference WO2013079696 
Protection Patent application published
Year Protection Granted 2013
Licensed Yes
Impact Clinical trial
 
Title GSK 
Description A new antagonist for AMD, starting clinical trials end of 2011 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact Oral treatment could transform AMD therapy 
 
Title Neuroprotecctants for AMD/DR 
Description Initiated new drug development programs with GSK and Roche to find neuroprotectants for AMD/DR 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact in development 
 
Title Roche clinical trial for AMD 
Description New Ab for AMD 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact ONgoing 
URL http://clinicaltrials.gov/show/NCT01941082
 
Description Harvard Translational Medicine Steering group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Provided advisory assistance to increase interaction with Pharma, and described the novel model and its utilities for accelerating drug development and pharma interaction

Recommendation to hire an INdustry alliance liason
Year(s) Of Engagement Activity 2012,2013
 
Description Lasker IDDF meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Health professionals
Results and Impact 50 experts in diabetic retinpathy drafted new guidance on areas of focus for future research

We included srong statements on neuroprotection
Year(s) Of Engagement Activity 2011,2012
 
Description Lecture to primary student at Lochinver School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact 75 Pupils attended a lecture on "Careers in Drug Development Research"

Follow up contact from student directly to guide
Year(s) Of Engagement Activity 2013
 
Description Presentation to medical doctors and pharmaceutical company employees 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Health professionals
Results and Impact 100s of medical doctors and pharma employees were informed about the complications of anti-VEGF therapy for neuron survival

Entire filed shifting away from VEGF conept to look for new approaches
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Presentation to public audiences as part of an RNIB, and RNID event, and as part of NHS events 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Numerous attendees (100's) to educational events talking about advances in healthcare and research

Increased helathcare provider and patient awareness
Year(s) Of Engagement Activity 2008,2009,2010