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By Alina Shrourou, on 7 October 2020
In the second interview as part of the new Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Anais Cassaignau highlights her Biologics TIN Pilot Data Fund awarded project “Developing an scFv binder against nascent huntingtin” and presents some advice for future applicants.
Please provide an overview of your Biologics project.
This project entitled “Developing an scFv binder against nascent huntingtin” is looking to exploit the unique features of nascent proteins, i.e. the shapes they form while they are being made. I am currently pursuing the novel disease angle that is the focus of this award.
Relative to the fully formed protein, the nascent protein is typically protected against misfolding /aggregation. We are looking to show that this entity may be a tractable therapeutic target in Huntington’s Disease.
What is the motivation behind your project/therapeutic?
I am interested in understanding how proteins fold while they are being synthesised by the ribosome, and how the ribosome itself regulates and modulates this process1. The correct folding of proteins in the cell is vital to all forms of life, and scientists are increasingly recognising that many diseases bear protein misfolding hallmarks including devastating neurodegenerative illnesses, several cancers and also diabetes.
Huntington’s is a devastating neurodegenerative disease, designated as an incurable disease with only symptomatic treatment currently available, and which often involves invasive delivery e.g. via spinal chord injections. This is despite seminal work in the field that underpins much of what we understand regarding the pathological underlying processes and in particular how the causative agent, huntingtin, forms aggregates. I hope to be part of devising new therapeutic strategies that involve targeting the mutant form of huntingtin at the earliest point of biosynthesis – an angle which has not previously been explored in this manner.
Why did you want to apply to the Biologics TIN Pilot Data Fund?
I wanted to initiate a crucially needed orthogonal extension to the research I have been undertaking; building upon the wealth of collective knowledge that the entire lab and myself have been building together over years about how proteins are made and how they fold, and applying these paradigms to develop relevant disease-related models.
What do you hope to achieve in the 6 months duration of your project?
I want to demonstrate that targeting a nascent protein is possible, through binding an antibody and scFv to a nascent huntingtin during biosynthesis and monitoring how this modulates the folding/misfolding outcomes for this protein.
What are your next steps from now?
Finessing of assays and the production of samples of the nascent huntingtin. The protein will be translationally-arrested (a “snapshot” of biosynthesis) and then we will test the interaction of our antibody and scFv to it, and see how this influences the fate of this aggregation-prone protein.
Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?
I would strongly encourage prospective applicants to reach out to the members of their respective TIN as the first step; their expertise will help you to appropriately refine your initial ideas and define the key questions in order to apply. Finally… Make a list of all the things you don’t know and read about them one by one.
Join the UCL Therapeutic Innovation Networks
Dr Cassaignau became interested in protein folding on the ribosome during her final year of BSc Biochemistry at UCL. Following this, Dr Cassaignau initiated a project within the Research department of Structural and Molecular Biology and has not left since, undertaking a Wellcome Trust-funded PhD and postdoc with John Christodoulou.
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