Development of a novel therapeutic for osteoporosis

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

Osteoporosis, which affects a large proportion of the elderly population, frequently results in bone fractures due to uncontrolled bone loss; 1 in 2 women and 1 in 5 men over the age of 50 will experience an osteoporosis-related fracture during their lifetime. This severely impacts on quality of life and 20-30% of hip fractures lead to death within 12 months. There is currently no ideal treatment for osteoporosis due to side effects and problems associated with their long-term use, e.g. atypical fractures of the hip and immune suppression resulting in infections. Poor compliance (due to these side effects and under diagnosis) is a significant problem and consequently treatment rates are less than 20% throughout the world. Most importantly osteoporosis is a long-term condition that requires long-term therapy, i.e. up to several decades. Therefore, there is a growing clinical need for the development of new therapies to provide additional treatment options to allow better management of this common, debilitating and potentially fatal condition.

We have identified a molecule that is a potent inhibitor of bone loss, which we propose to develop as a novel treatment for osteoporosis. This drug candidate is derived from a human protein that has a role in the normal regulation of bone turnover. We anticipate that this protein will have limited undesirable side effects (unlike existing therapies), thus enabling its long-term use (and improving compliance).

This project will build on our preliminary data and is aimed at establishing an optimal treatment protocol in an approved experimental model of post-menopausal osteoporosis; initial safety testing will also be carried out. This preclinical evaluation will inform and facilitate future studies, including trials in humans, and help us obtain a commercial partner with whom to co-develop our technology.

Technical Summary

Osteoporosis, which affects a large proportion of the elderly population, frequently results in fragility fractures due to uncontrolled bone loss; 1 in 2 women and 1 in 5 men over the age of 50 will experience an osteoporosis-related fracture during their lifetime. This severely impacts on quality of life and 20-30% of hip fractures lead to death within 12 months. There is currently no ideal treatment for osteoporosis (i.e. due to side effects and problems associated with long-term use, e.g. atypical fractures of the femur and immune suppression) and poor compliance is a significant problem; consequently, treatment rates are less than 20% throughout the world. Most importantly osteoporosis is a long-term condition that requires long-term therapy, i.e. in order to effectively manage the multi-decade "osteoporotic career" of sufferers. Therefore, there is a growing clinical need for the development of new therapies to provide additional treatment options to allow better management of this common, debilitating and potentially fatal disease.

We have identified a biologic that is a potent inhibitor of bone loss in vivo, which we propose to develop as a novel treatment for osteoporosis. This drug candidate is derived from a human protein that has a role in the endogenous regulation of bone turnover/remodelling. We anticipate that this recombinant protein domain will have limited undesirable off-target effects (unlike existing therapies), thus enabling its long-term use.

This development plan will build on our preliminary efficacy data in order to establish an optimal treatment regime in an FDA-approved model of post-menopausal osteoporosis; initial pharmacokinetic and toxicological testing will also be carried out. This preclinical evaluation will inform and facilitate future studies, including trials in humans, and help us obtain a commercial partner with whom to co-develop our technology.

Planned Impact

The aim of this DPFS proposal is to continue the pre-clinical development of our drug candidate with the ultimate goal of generating a novel treatment for osteoporosis. Thus, if successful, this work will benefit osteoporosis patients, healthcare providers and the pharmaceutical industry (e.g. in the UK, Europe, Japan and USA). We anticipate our drug will have a similar efficacy to existing treatments but without the side effects that lead to poor compliance and that limit their long-term use; this should result in good uptake and its use as a prolonged treatment. This would help to increase the treatment rates of osteoporosis, leading to improved quality of life and a reduction in mortalities.

Thus, this work has the potential to provide significant socioeconomic impact (e.g. reducing the burden on the healthcare system and carers (as a result of osteoporotic fractures) and have a beneficial environmental impact (a lower number of hospital visits, both in terms of less patient travel and reduced hospital activity); currently women over 45 years spend more days in hospital due to osteoporosis than diabetes, heart attack or breast cancer, and hip fractures alone account for >20% of orthopaedic bed occupancy in the UK.

In the shorter term, the outcomes of this work will improve our understanding of the regulation of the bone remodelling process, which will be of benefit to other investigators working in this field. This might ultimately lead to the development of other treatments for bone disease. We know that our drug candidate acts by inhibiting bone-resorbing osteoclasts and this activity could form the basis of therapies for conditions or diseases associated with bone loss, e.g. bone metastases, osteoarthritis and Paget's disease.

Publications

10 25 50
 
Description Arthritis Research UK Translational Business Case
Amount £250,000 (GBP)
Funding ID 21946 
Organisation Versus Arthritis 
Start 01/2018 
End 12/2019
 
Description Doctoral Training Programme
Amount £100,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2013 
End 03/2017
 
Description MRC Confidence in Concept Award
Amount £71,471 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 09/2018 
End 05/2019
 
Description MRC Proximity to Discovery (P2D) Relationship Incubator Award
Amount
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 02/2019
 
Description Renewal of Wellcome Trust Centre for Cell-Matrix Research
Amount £4,975,692 (GBP)
Funding ID 203128/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2016 
End 11/2021
 
Description Research and Development Innovation Fund
Amount £444,907 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 12/2014 
End 12/2016
 
Description University of Manchester MRC Confidence in Concept Scheme
Amount £53,982 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2015 
End 06/2016
 
Description Wellcome Trust iTPA Projects for Translation (P4T) award
Amount £32,838 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 09/2019
 
Title Use of TSG-6 for osteoarthritis 
Description A patent has been filed that includes the use of TSG-6 (Link_TSG6) for the treatment of osteoarthritis; this was filed on 9/9/14 (14/481841) as a continuation in part to our US patent (Method of treating bone disorders using TSG-6), which was granted on 30/6/15 (US 9066908 B2). The continuation in part was published on 26/02/2015. The patent is due to grant in 2018. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? No  
Impact We are in discussions with pharmaceutical companies regarding this technology. 
URL http://umip.com/wp-content/uploads/2015/02/TSG-6-for-Osteoarthritis.pdf
 
Description Assessing the anti-resorptive effects of TSG-6. 
Organisation University of Liverpool
Department Department of Musculoskeletal Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided the samples for bone analysis and were involved in data collection/analysis.
Collaborator Contribution Provided advice and assistance with bone analysis.
Impact None as yet.
Start Year 2013
 
Description Collaborationn with Seikagaku 
Organisation Seikagaku Corporation
Country Japan 
Sector Private 
PI Contribution We supplied protein and expertise to allow studies on the potential of our biological drug (Link_TSG6) for the treatment of osteoarthritis to be carried out by Seikagaku Corporation, Japan.
Collaborator Contribution Seikagaku Corporation (Japan) assessed the potential of our protein-based biological for the treatment of osteoarthritis. New discussions are ongoing about the use of Link_TSG6 for treating ocular symptoms associated with Sjogren's syndrome.
Impact No outputs as yet.
Start Year 2016
 
Description Investigation of anti-resorptive properties of TSG-6 
Organisation University of Liverpool
Department Institute of Ageing and Chronic Disease
Country United Kingdom 
Sector Academic/University 
PI Contribution We have conducted in vivo efficacy studies with our TSG-6-based biological and the bones (from the treated/untreated mice) have been analyzed using facilities in the collaborator's lab.
Collaborator Contribution The collaborator has made his facilities available to us to allow us to conduct analyses on bones from TSG-6-treated (and untreated) mice; the collaborator has also helped us with analysis of the data and has advised on various aspects of the study.
Impact 1 paper is in preparation. Abstract at 3rd Joint Meeting of Bone Research Society and British Society for Matrix Biology, Edinburgh, UK (2015). Abstract at Get Connected 5: Chrono-Matrix, Manchester, UK (2015). Abstract at BSMB Spring Meeting (2016). Abstract at Gordon Research Conference on Proteoglycans (2016). Abstract at International Cartilage Repair Society World Congress (2016).
Start Year 2014
 
Title Continuation in part filed (to granted US patent) 
Description A continuation in part was filed in US on 9/9/14 (14/481841: Method of treating bone disorders using TSG-6) and published on 26/02/2015. This covers the use of Link_TSG6 for the treatment of osteoarthritis. The claims have been allowed so the patent will now proceed to grant in 2018. 
IP Reference US9878003 
Protection Patent application published
Year Protection Granted
Licensed No
Impact None to date; but discussions with pharmaceutical companies are in progress.
 
Title TSG-6 patent granted in Europe and Japan 
Description Use of TSG-6 for treating osteoporosis. 
IP Reference EP2001499 
Protection Patent granted
Year Protection Granted 2013
Licensed No
Impact This discovery underpins the ongoing development of TSG-6 as a novel therapeutic for osteoporosis, which is currently being funded by a collaboration with GSK.
 
Description Art-science collaboration on ageing 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This is an ongoing collaboration between a local artist (see http://sallygilford.com/) and researchers at the Wellcome Trust Centre for Cell-Matrix Research. The artist is using images from our research into age-related diseases (including age-related macular degeneration and osteoarthritis) as the basis for art works using screen printing. The aim of this collaboration is to encourage awareness by the general public in the research we are doing by holding exhibitions, activities and workshops in and around Manchester. To date there has been:
A family screen printing workshop at the Manchester Museum as part of our annual Body Experience (21/3/15)
A work in progress exhibition, entitled Immortality, at Islington Mill, Salford (9-12/4/2015)
Premiere of Video at Celebrating Art/Science Engagement Event at Nowgen Centre, Manchester (13/5/15); video available on YouTube (see URL below).
Exhibition, entitled Immortality II, at The Wonder Inn, Manchester (26/11/15-6/12/15).
The Portico Print Fair, The Portico Library, Manchester (5/10/15).
Wellcome Trust Public Engagement Exhibition, Centre for Cell Matrix Research, Manchester (26/7/16).
Science Uncovered Manchester, European Researcher's Night, Manchester Museum, Manchester (25/9/16).
Ocula Bionica, Manchester Museum (20/10/16).
Primary School Masterclass, The Whitworth Art Gallery, Manchester (26/10/16).
Manchester Science Festival, The Whitworth Art Gallery, Manchester (18/11/16).
Primary School Masterclasses, The Whitworth Art Gallery, Manchester (2-6/10/17).
Who's That Girl, Salford Museum & Art Gallery, Manchester (from 29/11/18).


Attendees at the 'work in progress' exhibition at Islington Mill expressed their interest and excitement regarding the research work that the exhibition was based on; see short film in URL below.
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL https://www.youtube.com/watch?v=FQUVhkX_Mq0
 
Description Final year undergraduate 'education' project on healthy ageing at community hospital and care home in Manchester. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact The final year undergraduate carried out a project to evaluate the barriers and facilitators of physical activity in older adults (over 65 years of age). This included outreach to 63 outpatients/visitors at Withington Community Hospital and 26 residents at the North Manchester branch of Great Places House Group (that provides extra care housing) aimed at educating older adults about the benefits of engaging in regular exercise and mentally stimulating activities.

Many of the participates realised that they did not take part in sufficient physical/mental exercise.
Year(s) Of Engagement Activity 2013,2014
 
Description Invited speaker at lay reviewer training day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Guest/invited speaker at Arthritis Research UK's Lay Reviewer Training Day, Chesterfield, 22 April, 2016.
Talk title: Translating a discovery towards the clinic; development of a novel therapeutic for osteoarthritis
Year(s) Of Engagement Activity 2016
 
Description Manchester schools outreach/widening participation 
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 Year-10 students, individually or in small groups, took part in lab shadowing events in our lab as part of work experience weeks at the University of Manchester; i.e. to give the students insights into scientific research. The visits in 2014/2015 were associated with the University of Manchester's Widening Participation Scheme.



Positive feedback from the students regarding their lab-based experience; this is pat of an on-going outreach programme that is proving effective at attracting underprivileged students to apply for University.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL http://www.ls.manchester.ac.uk/schoolsandcommunity/schooleventhighlights/workexperience/
 
Description Press release for DPFS grant. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact A press release was covered in the Manchester Evening News

None as yet.
Year(s) Of Engagement Activity 2013
URL http://www.manchestereveningnews.co.uk/business/innovation/university-manchester-800k-rd-boost-33188...
 
Description Workshops for Manchester schools on inflammation. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Final year undergraduate 'Education' project aimed at GCSE and A level students; workshops on inflammation and inflammatory disease were delivered as part of a Manchester Museum Activity Day for Schools and revision activities on these topics were delivered to GCSE students at a Manchester school. Positive feedback from students and their teachers and interest was stimulated in studying science degrees at university.

Positive feedback to project supervisor on the value of the school visit and the quality/impact of the content delivered.
Year(s) Of Engagement Activity 2014