MICA: Efficacy of Saracatinib (AZD0530) in treatment of chronic otitis media in the pre-clinical mouse models Junbo and Jeff

Lead Research Organisation: MRC Mammalian Genetics Unit

Abstract

Otitis media is an important medical condition affecting the middle ear. There are a number of distinct forms of the disease and all cause ill health and have considerable health care costs. 80% of children will suffer one or more episodes of earache before the age of three and this condition is one of the most common reasons for taking child to see their GP. In most cases these painful episodes of earache resolve spontaneously. However, about 10% of children go on to have persistent ear problems and one particularly common condition is known as 'glue ear'. Although the symptoms of pain and fever go away, the child may suffer significant hearing loss. Glue ear is the most common form of childhood hearing loss. It occurs as a result of fluid accumulation in the middle ear space behind the eardrum. The fluid occupies a space that is normally air-filled in the healthy ear and this interferes with sound transmission through the three small bones that link the eardrum to the inner ear. Hearing loss manifests itself in delays in the child's language development and can result in learning and behavioral problems. Currently the only effective treatment is surgery to place a grommet in the eardrum. Grommet surgery is the most common surgical procedure performed on children. The NHS performs 30,000 grommet surgeries per year. Grommet surgery is not always effective, but there are currently no alternative beneficial medical treatments.
In this work we will use an animal model of chronic otitis media to explore new medical treatments for glue ear. Previously we have has shown that a molecular pathway involved in the response to low oxygen conditions is important in the development of disease and similar process occurs in children.
Our plan is to use existing drugs that have been developed to target these pathways and look at their ability to moderate hearing loss in our animal model. The particular drug that will be used is Saracatinib that Astra Zeneca developed to treat cancer. Cancer is very different medical condition to glue ear but both diseases share an underlying disease process associated with blood vessel growth and fluid leakiness. In the ear we hypothesize the accumulation of glue and fluid is driven by the leakiness of the blood vessels that line the middle ear space.
The use of anti-cancer drugs in children is restricted to serious life-threatening disease because of the potential for significant side effects when given as a tablet. The aim of this project is to investigate the potential of medicating the ear directly so that the drug is delivered to where it is needed to prevent hearing loss. It will be necessary to develop a formulation of drug that will release drug over periods of up to one month. The response to the treatment will be measured in hearing tests and measuring the action of the drug on the blood vessels of the ear. We will also investigate whether drug levels in the blood are sufficiently low after medicating the ear to make them safe for use.
If our work is successful it will open up new avenues of research in medical treatment of ear disease. There is a major effort to find new ways of medicating the ear and if this is achieved there will be great interest from pharmaceutical companies to discover new uses for their existing drugs, as well as developing new drugs. This has the potential to revolutionize the treatment of chronic middle ear disease and shift treatment away from surgery to medical treatments such as eardrops that could be prescribed by a GP.

Technical Summary

Middle ear effusion without the symptoms of acute infection is termed otitis media (OM) with effusion (OME). Chronic OME (COME) is the most common cause of hearing impairment in children potentially causing language delays, learning and behavioural problems [1,2]. About 2.2 million episodes of COME occur annually in the US with an annual cost estimate of $4.0 billion [3]. The prolonged ventilation of the middle ear with tympanostomy tubes, also known as grommets, remains the preferred treatment for COME [4]. Placement of tympanostomy tubes is the most common operation in the UK (30,000 procedures per annum) however children have to undergo general anesthesia and the benefits of surgery for hearing are temporary [4]. Therefore there is a clinical need to develop new medical treatments based on the molecular pathways of OM. Our work on the chronic OM mouse models Junbo and Jeff has identified chronic inflammatory hypoxia as a key mechanism of OM pathogenesis. VEGFR signaling inhibitors moderate hearing loss in the Junbo model [5]. Children with OME have elevated VEGF protein in their ear fluids implicating its clinical relevance [6]. Src signaling plays a key role in regulation of vascular endothelium permeability induced by VEGF [7]. We hypothesize that increased vascular permeability in blood vessels of the inflamed middle ear mucosa is a key pathophysiological mechanism that generates fluid and inflammatory cell accumulation. Our objective is to explore Src kinase as a novel target for treatment of chronic OM by testing AZD0530 in our mouse models.
1.Davidson J et al (1989) Int J Ped Otorhinolaryngol 17:239-266
2.Kubba H et al (2000) Clin Otolaryngol Allied Sci 25:181-194
3.Rosenfeld RM et al (2004) Otolaryngol Head Neck Surg 130:S95-S118
4.Lous J et al (2005) Cochrane Database Syst Rev CD001801
5.Cheeseman MT et al (2011) PLoS Genetics 7:e1002336.
6.Sekiyama K et al (2011) Auris Nasus Larynx. 3:319-24
7.Hu G et al (2008) Chem Biol Interact 171:177-189

Publications

10 25 50
 
Description Roslin Institute AWERB committee member
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
Impact Review of Roslin Institute Home Office PPLs before they are submitted to Home Office for Approval
 
Description Roslin Institute Small Animal Management Committee
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
Impact The committee is a steering group for Roslin Institute Small Animal facility management, looking to improve areas such as animal welfare, introduction of new reproductive technologies, gene editing, and training for researchers.
 
Description Scientific Advisory Committee PhenoImageShare
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL http://www.phenoimageshare.org/
 
Description BBSRC
Amount £440,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
 
Description Ear Nose and Throat Legacy
Amount £20,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 01/2017
 
Description Fiona and Ian Russell Seed Corn Fund for Companion Animal Research Grant Application
Amount £5,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 03/2017
 
Description Wellcome Trust - University of Edinburgh INSTITUTIONAL STRATEGIC SUPPORT FUND
Amount £150,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 01/2014 
 
Description Astra Zeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Michael Cheeseman is PI on grant in-vivo studies on a preclinical model of deafness SRC kinase is ineffective in Junbo model hearing test assessment A VEGFR inhibitor used as a positive control for SRC Kinase inhibitor is effective in one mouse model (Junbo) but not as second mouse model (Jeff), but mechanism of action is not yet established. Work is ongoing
Collaborator Contribution supply of compounds for testing intellectual input and scientific advice technical assistance
Impact Developed a good collaboration with AZ New Opportunities Matt Devalaraga Boston Jane Escott Alderley Edge
Start Year 2013
 
Description CSFR1 rodent models 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of CSFR1 rodent models
Collaborator Contribution Supply of Animals by Hume group (Clare Pridans)
Impact Paper being written
Start Year 2015
 
Description Edar signaling 
Organisation University of Lausanne
Country Switzerland 
Sector Academic/University 
PI Contribution Analysis of mouse phenotypes
Collaborator Contribution supply of antibody reagents
Impact experiments just beginning
Start Year 2015
 
Description Ear Nose and Throat seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Seminar given to Ear Nose and Throat surgery department 'What have we learnt from mouse models of Otitis Media?'.
Lauriston Building, Lauriston Place, Edinburgh (31-Oct-14)
Year(s) Of Engagement Activity 2014
 
Description National Pathology Week school visit to UoE Vet School 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 50 pupils visited the Edinburgh Vet SchoolAnnually, as part of National Pathology Week, the Centre for Comparative Pathology holds a public engagement event for school students, aged 16 and 17, (plus teachers) at the Pathology Department of the Royal (Dick) School of Veterinary Studies (ran in 2014 & 2015, planned for 2016 onwards).

The students try four different activities:

? Veterinary necropsy room: watch sheep post-mortem dissection, including examination of individual organs which they handle.
? Dissection Room: they handle pre-prepared dissected specimens, showing abnormalities e.g. goat endometrial hyperplasia, uterine leiomyoma, bovine ovarian granulosa cell tumour.
? Multiheaded microscope: under the guidance of a pathologist, they view glass slides of blood films, cytological preparations and histopathological sections showing a range of pathological abnormalities.
? Microbiological Laboratory Identification Exercise: they examine bacteria grown from a milk sample from a suspected case of bovine mastitis, performing a catalase test, a clumping factor test and a DNAse test using loops of bacteria and they examine pre-prepared sheep blood agar plates to identify the bacteria.
International Pathology Day: The Centre for Comparative Pathology ran a public engagement event for young people in November 2014.
Year(s) Of Engagement Activity 2014
 
Description Scottish Association of Histotechnology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact about 30 histology technicians from the NHS, commercial labs or University labs were given a talk on mouse histology.
the aim was to emphasise applications of histology to mouse phenotying
Year(s) Of Engagement Activity 2016