siRNA therapy in dominant skin and eye disorders

Lead Research Organisation: University of Dundee
Department Name: Molecular Medicine

Abstract

Incurable genetic diseases represent a major cost to the NHS, requiring specialist care costing billions per annum. RNA interference is a new Nobel prize winning technology that is suitable for treatment of a large number of genetic disorders but a major hurdle to applying this clinically is the the problem of delivery of these therapy molecules, that are slightly larger than conventional drugs, into the target tissues and organs. This programme grant focuses on a group of painful, debilitating genetic skin diseases and a related corneal eye disease, where the target tissues are very small and very accessible. The programme brings together leading researchers who uncovered the genes causing these disorders, with experts in developing new methods to deliver molecules into skin or cornea. State-of-the-art model systems will be developed to validate delivery of these new formulations into the skin and the cornea, setting the scene for taking this new therapy method into the clinic.

Technical Summary

Despite the progress in identification of genes causing human disease, development of therapies tailored to these genetic defects has been disappointingly slow. RNAi represents a promising new means of silencing genes or mutant alleles, particularly in dominant conditions, however, a major hurdle is delivery of these agents in vivo. The palm/sole epidermis and the ocular surface epithelium are two very accessible target tissues of limited size, with obvious advantages for development of RNAi therapy. Here, we will perform identification and lead optimisation of gene-specific and mutation-specific siRNA inhibitors for keratin disorders of palmoplantar epidermis and of cornea. We will systematically compare the efficacy, specificity and stability of alternative methods of gene-specific and allele-specific silencing including morpholino oligonucleotides, locked nucleic acids (LNA) and peptide nucleic acids (PNA), relative to optimised lead siRNA inhibitors. We will develop a novel multi-target reporter gene mouse where a bioluminescence signal is targeted to footpad epidermis as a preclinical model for epidermal keratin disorders. This will be complemented by a phenotypic model of footpad hyperkeratosis. We will develop an analogous multi-target bioluminescent reporter gene mouse and a phenotypic corneal dystrophy mouse as preclinical models of a corneal keratin disorder. We will develop and optimise non-invasive methods for siRNA delivery into the skin and into the corneal epithelium, using the appropriate animal models generated. Using two different, complementary target tissues increases the chances of successful translation of this technology into human application. Solving the siRNA delivery problem opens up this technology for treatment of a wide range of incurable genetic diseases that collectively amount to a massive healthcare burden.

Publications

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Abbas M (2015) PCQoL: A Quality of Life Assessment Measure for Pachyonychia Congenita. in Journal of cutaneous medicine and surgery

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Bolling MC (2014) Plectin mutations underlie epidermolysis bullosa simplex in 8% of patients. in The Journal of investigative dermatology

 
Description European Dermatology Forum
Geographic Reach Europe 
Policy Influence Type Citation in other policy documents
 
Description Clinical Fellowship
Amount £82,258 (GBP)
Organisation Dystrophic Epidermolysis Bullosa Research Association (DEBRA) 
Sector Charity/Non Profit
Country Austria
Start 10/2015 
End 10/2016
 
Description Industrial collaboration
Amount £200,000 (GBP)
Organisation Wave Life Sciences 
Sector Private
Country Unknown
Start 09/2015 
End 08/2017
 
Description Marie Curie Fellowship
Amount € 299,558 (EUR)
Organisation European Commission 
Department Horizon 2020
Sector Public
Country European Union (EU)
Start 04/2014 
End 03/2016
 
Description New Investigator Award
Amount £548,800 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2014 
End 06/2017
 
Description Project Grant
Amount £169,773 (GBP)
Funding ID 1450/1 
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Project Grant
Amount £111,995 (GBP)
Organisation Pachyonychia Conenita Project (PC Project) 
Sector Charity/Non Profit
Country United States
Start 10/2013 
End 09/2015
 
Description Project Grant
Amount £126,206 (GBP)
Organisation Pachyonychia Conenita Project (PC Project) 
Sector Charity/Non Profit
Country United States
Start 10/2011 
End 09/2013
 
Description Project Grant
Amount £81,000 (GBP)
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2016
 
Description Project Grant
Amount £38,500 (GBP)
Organisation Dystrophic Epidermolysis Bullosa Research Association (DEBRA) 
Sector Charity/Non Profit
Country Austria
Start 08/2015 
End 07/2016
 
Description Wellcome Trust Strategic Award
Amount £5,869,875 (GBP)
Funding ID 098439/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2012 
End 07/2017
 
Title K12 humanized knock-in mouse 
Description Knock-in mouse expressing human KRT12 gene carrying a dominant-negative mutation under control of the murine Krt12 gene. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Manuscript at advanced stage, submission planned Q4 of 2014. 
 
Title K12-luciferase knock-in mouse 
Description Expresses luciferase reporter gene under the control of the murine Krt12 gene. Carries multiple human therapy target sequences. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Manuscript at advanced stage, for submission Q4 of 2014. 
 
Title K9 humanized knock-in mouse 
Description Knock-in mouse carrying a dominant-negative mutation in the human KRT9 gene. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Publication planned 2015. 
 
Title K9 knockout mouse 
Description Knockout mouse for the palm/sole specific keratin gene Krt9 encoding the K9 protein. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Paper published in 2013 (on-line) and 2014 (print): Fu DJ, Thomson C, Lunny DP, Dopping-Hepenstal PJ, McGrath JA, Smith FJD, McLean WHI and Leslie Pedrioli DM (2014) Keratin 9 is Required for the Structural Integrity and Terminal Differentiation of Palmoplantar Epidermis. J Invest Dermatol 134:754-763 [Epub ahead of print Aug 20, 2013] (PubMed ID: 23962810) 
 
Title K9-luciferase reporter gene mouse 
Description Knock-in mouse expressing luciferase under the control of the murine Krt9 gene. Carries multiple therapy target sequences. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Publication planned 2015. 
 
Description ISIS Pharmaceuticals 
Organisation Isis Pharmaceuticals
Country United States 
Sector Private 
PI Contribution We are developing assay systems to test therapeutic antisense oligonucleotides for silencing the mouse and human KRT6A gene. ISIS will subsequently develop antisense molecules to test in our systems and hopefully progress these towards clinical application in the future.
Collaborator Contribution None as yet but we anticipate that we will receive antisense molecules developed by ISIS in 2015 to test in our model systems under development.
Impact None as yet.
Start Year 2014
 
Description Roslin 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Developing systems for ex vivo culture of skin.
Collaborator Contribution Provision of discarded pig skin following ova harvesting.
Impact This collaboration is helping us optimise an ex vivo skin culture system. No final outcome yet.
Start Year 2015
 
Description WaVe 
Organisation WaVe Biosciences
Country United States 
Sector Private 
PI Contribution We established an informal collaboration with WaVe Biosciences in 2014 to test their proprietary "stereopure" antisense oligonucleotides using in vitro and in vivo model systems we have available.
Collaborator Contribution None as yet but we anticipate obtaining "stereopure" oligonucleotides for testing in 2015.
Impact None as yet.
Start Year 2014
 
Description Arts-Science Public Lecture 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A talk was given by an artist who uses skin disease as subject matter, to increase awareness of skin conditions. This was followed by a lay talk on skin disease research, followed by a panel discussion with both the artist and scientist, sharing and exchanging their specific views on this field and looking for ways in which each others perspectives would stimulate further art and science work in skin. This was followed by a lively question and answer session with the general public audience. Our work on the cornea was also briefly presented.

None to date but the artist is interested to participate in future patient meetings hosted by the Dundee group, to gain more insights into skin conditions. The aim is to work together with the Dundee science group in future to continue to raise awareness of neglected skin disease through art works.
Year(s) Of Engagement Activity 2014
 
Description Consultant Geneticist on Channel 4's "Embarrassing Bodies" 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Consultant on Channel 4's "Embarrassing Bodies" in relation to an undiagnosed patient with pachyonychia congenita. Following this mass-media appearance, more than 50 new undiagnosed families with pachyonychia congenita or related conditions contacted the research group and were given genetic testing and patient support. The programme has been repeated in the UK and other nations worldwide, and each time, further undiagnosed families have come forth and been given genetic testing, contact with patient groups and other support. Many famililes contacted in this way have attended patient support meetings organised by the group.
Year(s) Of Engagement Activity 2012,2013,2014
 
Description DEBRA Annual Conference, Weybridge, UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact More than 100 patients with the inherited skin blistering disorder epidermolysis bullosa simplex (EBS) attended 1-day meetings in Weybridge, South of England, and Staffordshire, South of England, to learn about the molecular basis of their disease and hear about progress being made in therapy development.

Owing to the success of this meeting and the preceding one in Scotland, a follow-up meeting was organised to spread this information to patients in the north of England in November 2012. These EBS patient meetings will now be an annual event.
Year(s) Of Engagement Activity 2012,2015
 
Description DEBRA UK research leadership visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Visits from DEBRA UK Research Managers and lead fundraisers to laboratories, with updates on current research and future planning.
Year(s) Of Engagement Activity 2015,2016
 
Description Discovery of a new skin disease gene 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Media interviews following this discovery of a new skin disease gene and the mechanisms through which it operates
e.g. http://www.bbc.co.uk/news/uk-scotland-tayside-central-19928039
Year(s) Of Engagement Activity 2012
 
Description PC Project America Patient support meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact About 100 patients and family members affected by the skin disease pachyonychia congenita attended a 2 day workshop in North America, co-organised by members of the Dundee research group. These meetings are run every 2 years in the USA or Canada for the benefit of patients from the Americas.

Very positive feedback received from patients.
Year(s) Of Engagement Activity 2007,2009,2011,2013
 
Description PC Project European Patient Support Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact About 100 patients and family members affected by the genetic skin disease pachyonychia congenita from all over Europe attended a 2 day meeting organised by this research group. This allowed close interaction of patients, family members, clinicians and scientists. This meeting is run every 2 years by the Dundee group and was hosted in Dundee in 2006, 2008 and in Edinburgh 2010, 2012, 2014.

Very positive feedback received from the patients and other attendees.
Year(s) Of Engagement Activity 2006,2008,2010,2012,2014
 
Description PC Project European Patient Support Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact More than 100 patients and family members affected by the skin disease pachyonychia congenita attended a 2 day meeting in Edinburgh organised by the Dundee research group.

Very positive feedback received from patients and their families. This is now a biannual event, with the next date set for Oct 2014.
Year(s) Of Engagement Activity 2006,2008,2010,2012,2014
 
Description PC Project France Patient support meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact About 50 French patients and family members affected by the skin disease pachyonychia congenita attended a 2 day French language workshop organised by members of the Dundee group. This will be a biannual meeting from now on, with the next one scheduled for 2012.

Very positive feedback obtained from the families. This is to be a bi-annual event, next meeting 2016.
Year(s) Of Engagement Activity 2010,2012,2014
 
Description PC Steering Group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Steering group for international pachyonychia congenita research consortium planning clinical trials and future research.
Year(s) Of Engagement Activity 2015
 
Description Pachyonychia congenita patient support, Hefei, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact About 20 patients with pachyonychia congenita plus their attendant family members, clinicians and scientists, all from mainland China, attended the first patient support meeting for this disease in the Far East.

Positive feedbak received from Chinese patients, many of whom had never had a firm diagnosis or any real understanding of their disease. A number of patients were given genetic diagnosis as a result of this meeting and some misdiagnosed cases correctly reassigned.
Year(s) Of Engagement Activity 2008
 
Description Press release about discovery of 10 eczema genes 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release on identification of 10 new eczema genes; local and national press coverage; local radio interviews; international web coverage
www.dundee.ac.uk/research/main/news/20151020115352/1006.html
Year(s) Of Engagement Activity 2015
URL http://www.dundee.ac.uk/research/main/news/20151020115352/1006.html
 
Description Press release about election to The Royal Society 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press release about election to The Royal Society:
http://www.dundee.ac.uk/news/2014/professor-irwin-mclean-elected-to-royal-society.php
Several press articles and local radio coverage
Year(s) Of Engagement Activity 2014
URL http://www.dundee.ac.uk/news/2014/professor-irwin-mclean-elected-to-royal-society.php
 
Description Press release on discovery of the matted gene in atopic eczema 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Local radio interview and newspaper coverage on discovery of the matted mouse gene in atopic eczema.
Press release, 6th Nov 2013: http://www.dundee.ac.uk/pressreleases/2013/november13/eczema.htm
Year(s) Of Engagement Activity 2013
 
Description Press release regarding Buchanan Medal 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press release on Buchannan Medal of the Royal Society, local and national press coverage
http://www.dundee.ac.uk/news/2015/professor-irwin-mclean-awarded-buchanan-medal-by-royal-society.php
Year(s) Of Engagement Activity 2015
URL http://www.dundee.ac.uk/news/2015/professor-irwin-mclean-awarded-buchanan-medal-by-royal-society.php
 
Description Press release, Wellcome Trust Strategic Award to Dundee Dermatology and Genetic Medicine 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Media interviews about the Wellcome Trust's major funding boost for dermatology research at the University of Dundee
e.g. http://www.bbc.co.uk/news/uk-scotland-tayside-central-18883942
Year(s) Of Engagement Activity 2012
 
Description Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 65 people attended the public lecture.

Invited to do a follow-up lecture in 2014
Year(s) Of Engagement Activity 2013
URL http://www.cafesciencedundee.co.uk/?p=1235
 
Description Public Lecture (British Association for the Advancement of Science) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact "Are you thick skinned enough? Dermatology Discoveries in Dundee". Audience of about 60 people, all from the Tayside region general public. 60 min lecture plus 30 min discussion.
Year(s) Of Engagement Activity 2017
 
Description Public Lecture, Comber Rotary Club, County Down, Northern Ireland. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public talk hosted by a Rotary Club. "Studying inherited skin disease through thick and thin". Audience of about 30-40 Rotarians and interested public. 30 min lecture plus 15 min discussion.
Year(s) Of Engagement Activity 2017
 
Description Public Talk, South West Scotland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact By direct invitation, a 45 min presentation was given to about 100 members of the public involved in fund-raising for skin disease charities, particularly relating to the filaggrin gene in ichthyosis, common dry skin and eczema/allergy, as well as outlining our efforts to develop therapies based on this gene. Lengthy discussion followed - about 15 min formal and 2 hours informal.

Small financial donation to the lab was received from this group.
Year(s) Of Engagement Activity 2010
 
Description Scottish EBS Patient Support Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact About 100 patients and family members with the inherited skin blistering disease epidermolysis bullosa simplex (EBS) attended a 1-day meeting to learn about the molecular basis of their disease and progress being made in therapy development.

The success of this meeting led to organisation of bigger meeting in the south of England (May 2012) and north of England (Nov 2012), with help from the EB charity, DEBRA.
Year(s) Of Engagement Activity 2011
 
Description UK (North) Epidermolysis bullosa simplex patient support meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact More than 100 patients with the inherited skin blistering disorder epidermolysis bullosa simplex (EBS) attended 1-day meetings in Manchester, and in Dundee to learn about the molecular basis of their disease and hear about progress being made in therapy development.

These EBS patient meetings will now be an annual event, with 3 being held (Scotland, North of England, South of England) to cover the UK and allow patients to travel to the nearest venue.
Year(s) Of Engagement Activity 2012,2015
 
Description UK (South) Epidermolysis bullosa simplex patient support meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact About 100 patients with epidermolysis bullosa simplex (EBS) and their carers/families attended a 1 day meeting in Reading, co-organised by the Dundee group and the patient support organisation DEBRA. The purpose of this meeting was to update these individuals on the state of the art in relation to understanding the molecular basis of their disease and importantly, what therapies are in development.

None as yet.
Year(s) Of Engagement Activity 2014
 
Description Undergraduate Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Undergraduate Open Day, School of Life Sciences
Year(s) Of Engagement Activity 2015