Project title: Using big data and cell biology to understand carpal tunnel syndrome.

Grant Holder: Alexandra Wood

Position: MB DPhil Student

Date of award

06/06/23

Start date for research

02/10/23

Date of report

13/12/23

Grant Awarded (i.e. £10,000)

£48,000

Is this an interim, or final, report

Interim

Summary of project/progress /findings (approx 300 words)

My DPhil has three components, using big data techniques and cell biology to unpick the biological mechanisms of carpal tunnel syndrome (CTS) and which medications might be repurposed to treat the condition. The first is a genetic study, using Mendelian randomisation to identify causal relationships between risk factors that are observationally linked to CTS and the condition itself. The second is a pharmaco-epidemiology study aiming to identify whether metformin or other drugs may be repurposed to treat CTS by examining whether they reduce the risk of CTS in a cohort of diabetic patients. The third will use cell culture techniques to examine the effects of metformin and IGF-1 inhibition on fibroblasts cultured from CTS patient tenosynovium samples. This fellowship is primarily in support of the second two components.

Progress to date on each of the studies is as follows:

Mendelian Randomisation

• I have conducted an extensive literature review, identifying the exposures of interest and a suitable outcome dataset for CTS
• I have constructed a directed acyclic graph to visualise the interactions between these exposures
• I have run preliminary analyses on single exposures
• I have undergone training in Mendelian randomisation and genetics in drug discovery via two Cambridge University short courses
• I have generated a study protocol

Pharmaco-epidemiology

• I have conducted an extensive literature review
• I have undergone preliminary training in biostatistics for epidemiology via an Oxford University short course and identified two further courses in epidemiology and medical statistics, and real-world evidence using CPRD to meet further training needs
• I have completed a first draft of a study protocol

Cell biology

• I have conducted an extensive literature review
• I have completed my Good Clinical Practice and Human Tissue Act training in preparation for patient sample collection
• I have applied for an honorary contract at Oxford University Hospitals to enable tissue collection

What is the relevance/value of this research to hand surgery:

Carpal tunnel syndrome (CTS) is a condition affecting one in ten people, where compression of the median nerve in the wrist leads to hand pain, numbness, and weakness. This is commonly treated with surgery to decompress the median nerve, but up to one in four patients have incomplete recovery after surgery. In the UK over 54,000 decompression operations were carried out in 2014, at a cost of around £50 million to the NHS, and surgery rates are predicted to increase by 2030. However, up to 25% of patients either do not improve or have a recurrence of symptoms following surgery.

This research uses both big data and laboratory experiments to understand why this nerve compression occurs, aiming to provide a better insight into the biological processes that lead to CTS, and to identify drugs for repurposing that might be effective in the treatment of CTS. This will hopefully improve patient outcomes, and in addition reduce the need for surgical decompression, potentially enabling the NHS to direct resources to other operative treatments in hand surgery.

Please list presentations based on work performed in this study

None at present

Please list publications based on work performed in this study

None at present

Please state what additional research this study has/is leading to

I am aiming to identify drug targets for CTS using genetic techniques, which may lead to future research into repurposing therapeutics which already act on these pathways, such as metformin, orphan drugs which target IGF-1R, or antibody IGF-1R inhibitors. Combined with the results for the viability of metformin and other drugs from pharmaco-epidemiology this could also lead to clinical trials for the pharmacological treatment or prevention of CTS in future. I hope to pursue these future studies myself as a surgical academic following the completion of my MB DPhil and my medical degree.

Please list any further funding or grant applications (with outcome), which have resulted from the award of this grant

None at present

How has this grant award helped your career development?

Being awarded my BSSH Research Fellowship at the earliest stage of my clinical studies has enabled me to take the opportunity to intercalate during my medical degree and begin my MB DPhil. As a result, I will graduate as a doctor with the ability to produce high quality research from the beginning of my clinical practice, enabling me to pursue a strong career as a surgeon scientist.  Within my DPhil proposal, BSSH support has allowed me to fund access to the CPRD database in order to conduct a pharmaco-epidemiology study which will hopefully lead us to understand the viability of future clinical trials for carpal tunnel syndrome, as well as enabling me to perform the cell biology work to support this.

In addition, working with our research team has allowed me to collaborate with many surgeon-scientists who are clinically senior to me. The mentorship and advice I’ve been fortunate enough to receive so far from the Furniss Group has been invaluable in supporting my aspirations of becoming an academic hand surgeon, and working on this project will continue to enable me to meet and collaborate with further hand surgeons through both tenosynovial sample collections in Oxford, and future presentations of my work at relevant conferences and meetings.