Novo Nordisk A/S
In december 2009, Novo Nordisk and Combine announced a research collaboration in the field of autoimmune diseases.
Under the agreement, Novo Nordisk and Combine will work to develop a better understanding of how the immune system responds in patients with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.
The aim will be to develop novel therapies for the treatment of autoimmune diseases. The collaboration will also work on determining why certain patients do not respond to current treatments and how autoimmune diseases develop over time. It is hoped this can lead to the development of more targeted treatments, which can be used to treat particular groups of patients.
The agreement allows relevant Combine members to test Novo Nordisk pre-clinical development compounds in patient tissue samples. Such samples are routinely collected by Combine members from patients with autoimmune disease. Additionally, blood samples from patients with autoimmune diseases who are being treated with conventional therapies will be analysed for specific biomarkers to help understand why some patients respond to a particular therapy and why others do not.
The collaboration will run for an initial period of two years, and covers three projects. The collaboration can be expanded to contain more projects if needed.
P2I
P2I Care is a network initiated at Karolinska Institutet, Sweden, which is one of many components in Combine that aims at improving the care of the patients. P2I'sobjective is to improve the quality of life of chronic ill patients by developing new tools and processes that facilitate the interaction between the patient and the professional care provider. The methods and processes we develop offer care providers an enhanced decision-support basis and enable patients to participate in work to improve the care they receive, and ultimately their own health.
For more information, please click the picture below to open an information film.
Workpackage progress March 2009
WP2
An animal models platform has been established
• An animal model platform which allow investigation of genes and testing of drugs have been established
• The platform is based on genetically defined C57Bl6/J and B10.Q mouse genetic backgrounds.
• The platform is of highest quality and based on more than 40 unique mouse strains that has been transferred and thawed to achieve highest possible quality. In addition we have more than 100 additional mouse strains that can be thawed upon request.
• The animal platform allows investigation of model for common autoimmune inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.
A mouse heterogenous stock for genetic findings has been established
• A heterogenous stock has been established in the animal model platform
• An heterogenous stock is mouse cohort built of 8 defined inbred strains in which their genetic background has been mixed. It mimics the human population which we believe that once was initiated as a species through only a few individuals.
• The advantage of a mouse HS (compared to a human cohort) is that it allows control of environmental factors, it allows experimental inventions and genetic isolation of the identified genes.
The crystal structure of how an arthritogenic antibody recognize citrullinated proteins has been reported in the Journal of Experimental Medicine. This report was highlighted in the journal and also illustrated the journal cover. It was also highlighted in Nature as a critical step for understanding rheumatoid arthritis.
A monoclonal antibody ACC4) recognize a citrullinated epitope on joint cartilage protein type II collagen
WP3
In the EIRA registry are now 2800 cases and 3800 controls.
A new system for follow-up in EIRA patients has been evaluated
Published article:
Ding B, Padyukov L, Lundström E, Seielstad M, Plenge RM, Oksenberg JR, Gregersen PK, Alfredsson L, Klareskog L. Different patterns of association with anti-citrullinated protein antibody-positive and anti-citrullinated antibody-negative rheumatoid arthritis in the extenced major histocompatibiligy complex region. Arthritis Rheum. 2009 Jan;60(1):30-8. Epub 2008 Dec 30
Articles accepted for publication:
Liao KP, Gunnarsson M, Källberg H, Ding B, Plenge RM, Padyukov L, Karlson EW, Klareskog L, Askling J, Alfredsson L. A specific association exists between type 1 diabetes and anti-CCP positive rheumatoid arthritis. Arthritis Rheum, in press
Lundström E, Källberg H, Smolnikova M, Ding B, Rönnelid L, Alfredsson L, Klareskog L, Padyukov L. Opposing effects of HLA-DRB1*13 alleles on the risk of developing ACPA-positive and ACPA-negative Rheumatoid Arthritis. Arthritis Rheum, in press.
Lee, YC, Raychaudhuri S, Cui J, DeVivo I, Ding B, Alfredsson L, Padyukov L, Costenbader KH, Seilstad M, Graham RR, Klareskog L, Gregerson PK, Plenge RM, Karlson EW. Investigation of the PRL –1149 G/T Polymorphism and Rheumatoid Arthritis Susceptibility. Arthritis Rheum, in press
Rosell M, Wesley AM, Rydin K, Klareskog L, Alfredsson L. Intake of oily fish and fish oil supplements and the development of rheumatoid arthritis: results from a Swedish case-control study. Epidemiology, in press.
WP5
Data compiled in to two submitted manuscripts. Both strengthening the hypotesis that the alarmin HMGB1 possesses a pro-inflammatory activity by enhancing the effect of different DAMPs and PAMPs. For example, HMGB1 is enhancing LPS stimulation by hundredfold in cultures of PBMCs and IL-1b in cultures of synovial fibroblasts. Thereby, HMGB1 can contribute in the progression of arthritis and in flares of the disease related to infections.
A mouse model where a switch of oncogenic K-RAS in combination with GGTase defficiency leads to the development of destructive arthritis at the age of 6-8 weeks is developed. Arthritis in this model is symmetric and involves small joints of both paws resembling clinical features of human RA. Transplantation of stem cells from healthy mice reduced both inflammation and bone erosions. In contrast, transplantation of bone marrow from arthritic mice initiated joint inflammation in wild-type recepients.
In collaboration with a Danish group defining of the role of the oncogene S100A4 in the development of joint inflammation has been initiated. Preliminary data suggest that in serum and synovial fluid from patients with RA there are high levels of a soluble form of the S100A4 oncogene bound as an immune complex to IgM. To test if eliminating the expression of the S100A4 oncogene would inhibit the development of RA, we subjected S100A4-deficient mice to methylated BSA arthritis model. Mts-1 mice were protected against erosive arthritis while the severity of inflammation was similar with wild-type mice. Mts-1 mice had compromised T cell function including reduced IFN-g and TNF-a production despite an increased proportion of CD4 effector memory cells.
Published articles:
Dehlin M, Bokarewa MI, Rottapel R, Dahlberg L, Magnusson M, Foster SJ, Tarkowski A. 2008. Intra-articular Fms-like tyrosine kinase 3 ligand expression is a driving force in induction and progression of arthritis. PLoS ONE, 3(11):e3633.
Baran M, Nilsson Möllers L, Andersson S, Jonsson IM, Bjersing J, Ekvall AK, Tarkowski A, Bokarewa MI. 2008. Survivin is an essential regulator of joint inflammation interacting with urokinase signaling. J Cell Mol Med, in press.
Submitted articles:
Svensson B, Hafström I, Forslind K, Albertsson K, Tarkowski A, Bokarewa MI. 2008. Increased expression of proto-oncogene survivin predicts joint destruction in early rheumatoid arthritis. Submitted.
Fu H, Boström AE, Dahlgren C, Tarkowski, A., Bokarewa MI. 2008.
Resistin is stored in the specific granules of neutrophils becoming released upon challenge with inflammatory stimuli. J LeukBiol, revision submitted.
Lindblad S, Mydel P, Jonsson IM, Senior R, Tarkowski A, Bokarewa M.
2008. Smoking and nicotine exposure delays development of arthritis in animal model. Submitted.
WP 7
Genetics of general osteoporosis in CIA: 500 femurs from H-2q neutral arthritic CIA mice have been analysed with peripheral quantitaive computer tomography (pQCT). Another 500 femurs are prepared for pQCT analyses and will be completed in July 2009. Data will be exported to Rikard Holmdahl when all analyses are completed.
Estrogen signaling via AF-1 /AF-2 (activation function 1 and 2): AF-2 “knock-out” mice have been established. Analyses of mice at 12 weeks of age have revealed an interesting skeletal and fat phenotype in comparision to mice lacking estrogen receptor α (ER-α). The immune phenotype of these mice will be done in March 2009. Planned submission of scientific report in September 2009.
Activation of ER and GR for repair of cartilage and bone in arthritis: Experimental data prepared and manuscript drafted. Results have been communicated at scientific meetings. Submission of manuscript planned April 2009.
Protocol and ethic application for pilot clincal study using selective estrogen receptor modulator (SERM) for protection against periarticular bone loss in corticosteroid treated postmenopausal RA patients will be prepared in September 2009. Planning this clinical study will include active participation from patients representative.
WP 8
All of seven instruments selected to detect clinically important changes in fatigue among Swedish patients with SLE seem to perform similarly, but nuances in scores reflecting the question content were identified. Preferences for the Chalder Fatigue Scale and the Fatigue Severity Scale were preliminary revealed among the patients. Statistic calculations according to MCID-methodology will follow in collaboration with professor Jacques Pouchot, Université René Descartes, Paris & University of British Columbia, Vancouver and professor Matthew Liang, Harvard Medical School, Boston. (Susanne Pettersson, Elisabet Welin Henriksson)
A lower expression (p<0.01) of ERb protein expression in skeletal muscle tissue of patients with rheumatoid arthritis (RA) compared to controls was found. This is the first description of such differences and suggests that ERb may play a role in muscle weakness in RA. (Birgitta Glenmark, Håkan Westerblad)
WP9
During spring the clinical animal trial alliance will be established. This unit will offer biotech companies and groups from academia to test potential therapies in animal models available on CMM as well as MBB.
In order to be able to offer a comprehensive picture from preclinical animal models to Phase III trials there will also be possibilities for collaboration with the clinical trial alliance at the Rheumatology clinic, Karolinska University Hospital.
The clinical animal trial alliance will be up and running in May, 2009, and a webpage will be created during the spring and summer.
WP13
The first step regarding patients view on research, scientists and the patient’s own participation in research is initiated. Two research partners are involved in the project managing group and further, the planning for focus groups is settled.
A number of Combine’s work packages have now started collaboration with those members of the Swedish Rheumatism Association, who trained to become Patient Research Partners (PRP) during the past fall.
The following Work packages are involved so far:
WP 1 - A Swedish infrastructure for longitudinal patient surveillance and biobanking for chronic inflammatory diseases.
and/or
WP 12 - Implementation and dissemination in healthcare and society.
Thomas Skogh’s group at Linköping university
WP 3 - Medical informatics and bioinformatics.
and/or
WP 11 - Medical informatics. A necessary tool for the clinical research enterprise and a new business opportunity.
Lars Alfredsson’s/Lars Klareskog’s group at Karolinska Institutet.
WP 5 - Molecular pathophysiology and immunregulation in chronic inflammatory diseases.
Marie Wahren’s group at Karolinska Institutet.
WP 7 - Destruction and repair.
Hans Carlsten’s group at Göteborg university
WP 13 - Bioethics, patient rights and the plea to communicate.
Mats Hansson’s group at Uppsala university collaborate with two PRPs in Sofia Kälvemark Sporrong’s project ‘What are the patients’ conceptions on research?’
Det finns nu sju nyutbildade forskningspartners som är ivriga att komma igång och samarbeta med forskargrupper. Anmäl intresse till mig, så kommer jag att, tillsammans med projektledare Caroline Åkerhielm på Reumatikerförbundet, matcha ihop partners med forskargrupper.
Ytterligare en utbildning kommer att hållas under våren, så de som inte får någon partner nu, har ytterligare en chans före sommaren.
//Christina
Professor Christina Opava, vice coordinator of Combine and responsible for patient collaboration, was interviewed in radio channel 1 (P1) on December 16 at 12.10 pm. The program 'Vetandets värld' focuses on patient participation in research and representatives from the patient organisation Reumatikerförbundet also participated.
Listen to the program by following this link:
http://www.sr.se/cgi-bin/p1/program/amnessida.asp?programID=406&Nyheter=1&grupp=4313&artikel=2496056
Choose "vetandets värld" 16/12. The program is in Swedish.
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