Is targeting vascular remodelling by filarial parasites a viable anti-morbidity solution?

Filariasis is caused by a group of thread-like parasitic worms, known as filariae. Filariasis affects the 'bottom billion' of society; 150 million people in some of the world's poorest nations are infected and 1.3 billion are at risk of infection. Lymphatic dwelling filariae cause lymphatic filariasis (LF), which, in its most severe form, manifests as disfigurement of the limbs or genitals, known as elephantiasis. People with elephantiasis suffer from loss of mobility affecting daily activities and often experience social stigmatisation and psychological problems. The WHO classifies LF as the second leading cause of global disability. The related skin dwelling filariae, Onchocerca volvulus, causes the disease river blindness following chronic infection of the eye. An estimated 800,000 people suffer visual impairment as a result of onchocerciasis, mainly in sub-saharan Africa.
Transmission of filariasis can be blocked by annual treatments to endemic communities. Unfortunately, these drugs do not cure infected individuals nor do they stop the progression of elephantiasis. This means that if LF elimination is achieved, a generation of people will be left with a gradually worsening disability (~40 million individuals). Current drugs are very also limited (only a single drug is available for onchocerciasis) and are vulnerable to the development of resistance after their protracted use. The current onchocerciasis treatment does not appear to help reverse the early visual impairment of river blindness. Therefore, new approaches to tackling filarial morbidity are required to alleviate the suffering and improve the daily life of filariasis disease sufferers, their families and communities.
Toward this aim, a full understanding of how filarial parasites cause disease and how a proportion of infected individuals avoid developing pathology is required. A deeper understanding of filarial disease processes will facilitate the identification of disease pathways that can be potentially targeted by either current drugs or new improved experimental treatments.
This proposal will examine the role of blood and lymphatic remodeling in the pathogenesis of filariasis. In filarial pathology patients, markers of angiogenesis (growth of blood vessels) are increased in the circulation. In onchocerciasis, loss of visual acuity is associated with leaky blood vessels and in a mouse model of river blindness, blood dilation and growth of new vessels occurs during filarial inflammation. However, it is not known how blood remodeling events are induced, how important they are in driving development of disease or whether they offer suitable 'druggable' anti-morbidity targets. Our laboratory has recently identified that direct inflammation by filarial worms causes both the upregulation of a group of important pro-angiogenic molecules, the vascular endothelial growth factors (VEGFs), stimulates remodeling of blood vessels and causes vascular leak. By providing a modified VEGF growth factor signal that can only activate lymphatic but not blood vessels, we have evidence that this improves the pathological ramifications of filarial inflammation.
In this proposal I will investigate the importance of VEGF-specific blood activation in filarial disease processes using murine pre-clinical pathology models of LF and river blindness. I will assess a putative host immunological mechanism of lymphatic repair that is induced naturally during LF infection and the pro-lymphangiogenic responses that this process is associated with. I will then test the therapeutic value of targeting blood remodeling, including the VEGF pathway and lymphatic regenerative processes in ameliorating LF or river blindness pathologies. I will test both registered drugs that could be translated into therapies in the immediate future as well as next generation 'biologic' interventions that could become more cost-affordable as biologics continue to be incorporated into mainstream medicine.

This proposal seeks to address cellular and molecular mechanisms of the filarial pathologies lymphoedema and ocular kerititis. The project is focussed on the role of blood and lymphatic endothelial remodelling events (including neovascularisation; NV, angiogenesis, dilation, contusion and fibrosis), the molecular processes that initiate or prevent remodelling during filarial inflammation and the pathological ramifications of their occurrence. A second major aim of the proposal will be to test whether these putative pathogenic processes can be successfully targeted by registered small molecule drugs, novel small molecule drugs or novel biologic therapeutics.
The proposal will utilise preclinical murine models of dermal, lymphatic and ocular filarial pathogenesis to examine these hypothesised disease pathways. Canonical pro-angiogenic (VEGFR2) or pro-lymphangiogenic (VEGFR3) pathways will be manipulated using a combination of specific murine reagents including antagonistic or neutralising antibodies, Fc-fusion receptors (Traps), agonistic Fc-fusions or transgenics over-expressing agonists. Mouse lines with specific fluorescent protein gene knock-ins into lymphatic endothelium will be exploited in addition to standard immuno-staining to examine morphological changes in blood and lymphatic vasculature by confocal microscopy. Lymphatic reporter mice will also be used in a lymph node transplant model to explore a putative immune cellular mechanism of lymphatic repair by multi-photon confocal microscopy. A non-invasive, optical imaging-based technique will be applied to study effect of filarial parasitism on the development of lymphatic insufficiency and how specific cellular or biologic treatments may improve this pathology. Antiangiogenic drugs or drugs with possible antiangiogenic properties will be tested for anti-pathology efficacy. Finally a novel VEGFTrap molecule will be engineered to examine whether this offers an improvement on standard treatment for ocular NV.

This proposal aims to:

i) elucidate basic mechanisms of vascular remodelling during lymphatic or ocular filariasis.
ii) pre-clinically assess the therapeutic value of registered antiangiogenics, re-purposing tetracyclines or novel biologics as anti-filarial morbidity drugs based around the targeting of vascular remodelling events.

Economic impact

Commercial exploitation

Lymphatic filariasis (LF) is a major form of lymphoedema (LE), which occurs throughout the world due to inheritable or secondary causes. As a measure of the prevalence of LE in developed countries, approximately 1 out of every 25 US citizens are affected (source: Lymphatic Research Foundation) whilst there is an occurrence of at least 480,000 cases in the UK (source: Lymphoedema Support Network). As with LF, no therapy has been taken to market to treat LE.
Ocular neovascularisation (NV) disorders are leading causes of blindness in industrialised countries and humanised antibody-based therapies have become the mainstay of their treatment. In the wider context, antibody-based drugs are the fastest growing sector of the pharmaceutical industry, accounting for a third of all new drug treatments.
Thus, therapies that will be developed and/or pre-clinically evaluated in this proposal for filarial NTDs have credible potential for attracting follow on commercialisation and wider exploitation for these clinical 'first world' profiles. Identifying an overlapping commercial market for next-generation filarial NTD therapies will undoubtedly improve the chances of uptake by pharmaceutical partnership, covering shortfalls not met by the non-commercial sector, especially in the case of biologic therapies that currently have a high production cost. Further, as 'third world' economies improve and health insurance grows, a market for 'new generation' therapeutics will emerge (ie in the BRIC economies)

Attracting research and development

As this proposal is testing the proof of principle for therapeutic targeting of vascular remodelling during filariasis, outputs will justify applications for onward translational medicine awards from major funding agencies and seed corn funding for first step translational development from the pharmaceutical industry with respect to novel biologic therapies and tetracycline derivatives targeting angiogenic pathways.

Further, provision of a mechanism of action of tetracycline drugs in reduction of filarial morbidity will justify immediate onward funding for optimised clinical testing of these licenced drugs in human phase II/III trials (3-5 years). Similarly, identification of anti-pathology effects of licenced small molecule antiangiogenics may facilitate their onward clinical evaluation in the near future (within 5 years).

Societal impact

Improving health and well-being / Enhancing quality of life

Via the approaches listed above, the scientific discovery and therapeutic development in this project will evaluate potential solutions for some of the most devastating NTD morbidities at the pre-clinical level. Therapeutic targets evaluated here have the potential to be translated into new therapies for the treatment of filarial NTDs, other NTDs (podoconiosis), hereditary and secondary LE disorders and ocular NV disease within a time frame of 10-20 years.

Evidence based policy-making

The WHO and The Global Programme for the Elimination of LF (GPELF) are prioritising morbidity management of elephantiasis (2010 position statement). Doxycycline-based individual treatments for morbidity have been recently raised on the agenda of a 2012 WHO strategic and technical advisory group for NTDs. Dissecting an anti-morbidity mode of action of tetracycline drugs in this proposal will be used as strong evidence, along with recent and future clinical trial data, for the adoption of doxycycline-based or other tetracycline-based anti-morbidity interventions through WHO policy directives in the near future (2-5 years).