In this next Devices & Diagnostics TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Frédéric Lange highlights his Devices & Diagnostics TIN (co-lead by the UCL Institute of Healthcare Engineering’s Translational & Industry Delivery Group) Pilot Data Fund awarded project, “Understanding the role of brain oxygenation and metabolism in the pathophysiology and prognosis of relapses and progression in multiple sclerosis”.

Please give an overview of your research and the project that has been funded by the TIN Pilot Data Fund.

I am a biomedical engineer/physicist with a focus in biophotonics. Since I started my PhD, I’ve been working on using near infrared light to monitor the human brain physiology. Indeed, light in that range can probe deep tissues like the brain, giving us access to very useful information on tissue oxygenation or metabolism. If you are interested in that subject, I recommend consulting our public engagement website, https://metabolight.org, that explains the basics of the physics and engineering of what we do, and how we use our systems in the clinic.

The title of my TIN Pilot Data project is “Understanding the role of brain oxygenation and metabolism in the pathophysiology and prognosis of relapses and progression in multiple sclerosis”. In this project, I will use an optical instrument that I developed with some colleagues, to collect information on brain’s oxygenation and energy levels in people with multiple sclerosis (pwMS).

What is the motivation behind your project/therapeutic?

MS is the most common cause of non-traumatic disability in young adults, affecting 131,720 people in the UK. UCLH alone treats more than 5000 people with MS. Despite advances in treatments, at 17 years post-diagnosis, 11% of patients cannot walk unaided, and 18% enter a progressive form of the disease. Identifying additional mechanisms of disease progression and which patients are most likely to benefit from additional treatments therefore represents a huge unmet need.

All current MS treatments target neuroinflammation, yet substantial pre-clinical and clinical data suggests a causal role of hypoxia. We hypothesise that our instrument will allow us to identify those pwMS with the greatest such deficits, hence allowing:

• Enrichment of future clinical trials testing interventions aimed at reversing these processes.
• The monitoring the patient’s response to such treatment.

Why did you want to apply to the Devices & Diagnostics TIN Pilot Data Fund?

The Devices & Diagnostics TIN Pilot Data Fund was a great opportunity for me as it was perfectly fitting the stage of my current research. Indeed, I was just finishing the developmental phase of the instrument that I wanted to build, and I was transitioning to its use in the clinic. With my clinical colleague, we could start to use the instrument on patients, but we realized that a few changes were needed in order to facilitate its use in a clinical environment, so we needed to make some adjustments. However, it can be difficult to find funds at this stage of a project, as it is not an engineering project anymore, but at the same time, it is not a clinical project yet. We needed some preliminary data on patients in order to be able to apply to a more clinically focused grant. So, this kind of fund is perfect to close the gap between an engineering and clinical project.

Moreover, from a more personal point of view, this fund was a good opportunity to apply to my first independent grant, which I hope will be the first step towards my independent career.

Learn more about TIN opportunities for researchers

What do you hope to achieve in the 6 months duration of your project and what are the next steps from now?

With this project, I will be able to upgrade my existing optical instrument, so it is easier to use in the clinical environment and more robust. The fund will be used to buy the essential components needed to make these upgrades. I am currently purchasing the equipment needed. The upgrade process will occupy the first half of the project, between the hardware and the software work, and the recalibration of the system. Then, in the second half of the project, we will aim to scan as many pwMS as possible, so we can have a good set of preliminary data. This will certainly prove challenging in these trouble times, but I am confident that we will be acquire some very useful data.

About Dr Frédéric Lange

Dr Frédéric Lange received his Ph.D. degree in biomedical optics from the University of Lyon and INSA de LYON in France in 2016. Since then, he has been a Research Associate with the Biomedical Optics Research Laboratory, which is part of the Department of Medical Physics and Biomedical Engineering at UCL.

His main research interests are in the development of diffuse optics instrumentation and methodologies for biomedical applications, especially for brain monitoring.

Written by Linda von Nerée, NIHR Blood and Transplant Research Unit in Stem Cells and Immunotherapies at UCL.

How many pairs of jeans do you have in your wardrobe? How many genes are in your body? What are genes anyway and do you know how they can help to treat an illness?!

All is explained in this brand-new animation from us at the NIHR Blood and Transplant Research Unit in Stem Cells and Immunotherapies at University College London (UCL BTRU). Well, except how many jeans you own, that stays your secret.

Gene therapy helps to treat some inherited diseases passed on from parent to child that don’t have a treatment or cure yet. Many different gene therapies are currently in development all over the world for many inherited diseases such as those that affect the ability of our blood’s immune system to fight off infections that make us ill.

The animation shows, Alexis and Freddie, two members of the Young Persons’ Advisory Group (YPAG) at Great Ormond Street Hospital for Children asking questions to understand what gene therapy is about. All members of the group were involved in shaping the animation and they regularly work with doctors, nurses and scientists helping to improve health care research for children. When possible, the group meets near the Zayed Centre for Research into Rare Disease in Children, where scientists look for new and better ways to treat uncommon diseases in children.

Why this Gene Therapy animation?

‘I spent most of my career as a researcher developing gene therapies for children who have an immune system that doesn’t function properly. The immune system of these children can’t protect them from infections and become life-threatening. A lot is said on the news about gene editing, less how it can help to treat inherited diseases.

Alexis and Freddie helped us to brilliantly explain just this in our animation. We hope it finds much interest and explains a ground-breaking future treatment for some inherited conditions.’ – Adrian Thrasher, Professor in Paediatric Immunology and Research Lead at the NIHR Blood and Transplant Research Unit in Stem Cells and Immunotherapies at University College London (UCL)

What was it like to work on the Gene Therapy animation?

It is a new and innovative way to treat some inherited diseases, which surprised me because I thought there were a few other remedies and cures already out there. I really like the animation, and I’m so glad it has turned out this well, (especially the hair), I am so grateful to have had an opportunity to be a part of this! – Alexis, member of the Young Persons’ Advisory Group (YPAG) at Great Ormond Street Hospital for Children

 I enjoyed being part of the animation because I have never done anything like that before. Because of the lockdown I went in my bedroom and recorded my voice on a phone which was strange, but I think the finished animation is good.’ – Freddie, YPAG member at Great Ormond Street Hospital for Children

‘It was a huge pleasure to work with Alexis, Freddie and YPAG as a group of inspiring young people involved in improving health through research. Their ideas and invaluable input made the animation so much better and very different from the first draft we presented back to them at a meeting in summer 2018.’ – Linda von Nerée, Patient and Public Involvement Lead at NIHR Blood and Transplant Research Unit in Stem Cells and Immunotherapies at UCL

‘It is such a privilege to work in the gene therapy field and see research in action. I had a great time attending the YPAG group and hearing from its members. Alexis and Freddie have done a great job!’ Katie Snell, Lead Gene Therapy Research Nurse at UCL Great Ormond Street Institute of Child Health

Did you know?

Researchers estimate that we have between 20,000 and 25,000 genes in our body. We have two copies of each gene, one from each parent.

Learn more in the full animation:

‘Gene Therapy explained: Changing our bodies’ recipe to treat disease’

Let us know what you think and if you like it. Please share widely with your friends and family!

About the authors

• Alexis – I joined YPAG when I was 8 years old and I have been a member for 5 years! Including the voices of young people is important because we are the next up and coming generation, and in a few years we will be the ones filling these roles so I think it’s important we have a say in how our future is going to be like.
• Freddie – I am 12 years old and I joined YPAG when I was 9. I really enjoy YPAG because I learn something new every time and get to be involved in interesting things like this animation.
• Linda – In my role, I bring together patients, members of the public, researchers, doctors and nurses to learn from each other and design research in the best possible way for those to benefit from it. Working with YPAG is a huge pleasure!

About the Young Persons’ Advisory Group (YPAG)

We are a group of young people working with doctors, nurses and researchers to add our views and opinions to the development of new treatments for children. We are part of GenerationR, a network of young people improving health through research.

More at: https://www.gosh.nhs.uk/research-and-innovation/nihr-gosh-brc/patient-and-public-involvement

About the NIHR Blood and Transplant Research Unit in Stem Cells and Immunotherapies at University College London

The NIHR Blood and Transplant Research Unit (BTRU) in Stem Cell and Immunotherapies at University College London (UCL) is an academic partnership with NHS Blood and Transplant funded by the National Institute for Health Research (NIHR). It focusses on improving stem cell transplants (transfer of stem cells, which lead to new blood cells in the recipient) and the use of novel therapies, including CAR-T and gene therapy, both to treat inherited genetic disorders and to repair or strengthen the immune system’s ability to fight infection or disease. For more information, please visit https://www.ucl.ac.uk/cancer/research/centres-and-networks/nihr-blood-and-transplant-research-unit-stem-cells-and-immunotherapies or follow @BTRUinStemCells on twitter.

Contact for any questions or inquires: Linda von Nerée, Patient and Public Involvement Lead at NIHR Blood and Transplant Research Unit in Stem Cells and Immunotherapies at University College London, email: l.vonneree@ucl.ac.uk

In the next Small Molecules TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks (TINs), Benedikt Hölbling highlights his Small Molecules TIN Pilot Data Fund awarded project, “Enhancing Stathmin-2 protein levels in familial and sporadic ALS/FTD”.

What is the title of your project and what does it involve?

The title of my project is “Enhancing Stathmin-2 protein levels in familial and sporadic ALS/FTD”: Cellular loss of the protein Stathmin-2 is a common hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), two devastating neurodegenerative diseases. We aim to identify ways to modulate Stathmin-2 protein levels in cells to improve neuronal health. For this aim, we developed a high throughput screen to identify small molecules that could be used as novel therapeutics for ALS/FTD treatment.

What is the motivation behind your project/therapeutic?

ALS and FTD are fatal neurodegenerative diseases with no effective treatment available yet.
ALS, also commonly known as motor neuron disease, occurs when specialized motor neurons in the brain and spinal cord perish. Every year approximately 1700 people in the UK are newly diagnosed with this disease, with a mortality rate of 50% within the first 2 years.

Approximately 16,000 patients in the UK live with FTD. This rare form of dementia causes symptoms such as changes to personality and/or difficulties with language.

The majority of therapeutics under development would require regular, invasive lumbar punctures to administer or focus on specific disease-causing genes. However, most ALS cases are sporadic (90%) without familial history of the disease. Further, the genetic causes are very diverse. A common characteristic that is shared among most familial and sporadic cases is the loss of cellular Stathmin-2 protein levels. It was shown that overexpression of Stathmin-2 improves neuronal health in cell cultures (Klim et al., 2019 and Melamed et al., 2019). Therefore, finding modulators of Stathmin-2 expression may enable treatment of a large number of patients with various ALS and FTD disease backgrounds rather than targeting specific disease-causing genes. In addition, an oral delivery of small molecules is non-invasive and easy to administer.

Why did you want to apply to the Small Molecules TIN Pilot Data Fund?

We have developed a high-throughput screen in close collaboration with the Alzheimer´s Research UK Drug Discovery Institute at UCL. The Small Molecules TIN Pilot Data Fund will now enable us to perform two pilot screens with this model. Thereby, we will further increase the accuracy and reliability of our assay for large-scale screens in the future.

Furthermore, I applied for my personal development: There are very limited opportunities to apply for funding as an Early Career Researcher. Therefore, I was highly excited to be able to apply for the Small Molecules TIN Pilot Data Fund. From the start of this project, I could improve many of my skills in the lab and outside.

Join the Small Molecules Therapeutic Innovation Network

How did you find the process for the TIN Pilot Data Fund? What did you learn?

It was very exciting! I was never involved in a grant application before, so everything was very new to me. During the process, I attended two ACCELERATE training workshops. In the first one, I learned how to write more precise whilst not too scientific for my written application. Especially as a non-native speaker, this also will be a great help for future applications. However, the pitch was the most exciting part of the process. Explaining the innovation and importance of your project in only 2 minutes is very challenging and the ACCELERATE workshop was extremely helpful to set the right focus.

What do you hope to achieve in the 6 months duration of your project?

In the next months, we will perform two pilot screens with different small molecule libraries. Thereby, we will hopefully identify helpful tool compounds. Further, this helps us to optimize and validate our assay before utilizing larger small-molecule libraries in the future.

What are your next steps from now?

The next step is to perform two pilot screens together with the ARUK Drug Discovery Institute at UCL. Once we identify promising molecules with the screen, we will closely characterize them to determine which one of them is the most promising candidate for a novel ALS/FTD therapy.

About Benedikt Hölbling

Benedikt Hölbling works in Professor Adrian Isaac’s lab at the UK Dementia Research Institute at UCL.

He examines mechanisms of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) on the basis of stem cell models.

In the next Small Molecules TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Victor Llombart highlights his Small Molecules TIN Pilot Data Fund awarded project, “Identifying therapeutic vulnerabilities of MYC through next generation structure-function”.

What is the title of your project and what does it involve?

My project is titled “Identifying therapeutic vulnerabilities of MYC through next generation structure-function”. MYC is an important oncoprotein involved in tumour initiation and development that is difficult to target using conventional small molecule-based approaches. The main reason is that MYC conforms a structurally highly disordered protein from which is virtually impossible to obtain a crystal model unless it is forming a complex with other proteins that stabilize it. Consequently, the design of drugs based on structure models of MYC is extremely challenging. Alternatively, we have designed and generated a library of MYC mutants to identify new protein domains that are potentially “druggable”. This pooled library can be screened using our MYC-dependent cell line allowing the identification by next generation sequencing of those aminoacid residues that are crucial for MYC oncogenicity.

What is the motivation behind your project/therapeutic?

Cancer is a major public health and economic issue worldwide. In the UK, ≈1,000 new cases of cancer are diagnosed every single day and most of the current anti-cancer therapies present high toxicity, drug resistance and significant side effects.

The protein MYC is an essential global transcription factor that regulates important functions in our body such as cell growth, cell metabolism or blood vessel development. MYC is also one of the most frequently altered genes in cancer and its expression is deregulated in about 70% of all malignancies. Several studies in animal models have shown how MYC inhibition leads to a rapid tumour regression while the healthy tissue remains unaffected. This opens the way for new therapies and makes MYC one of the most appealing targets for cancer treatment. However, as I mentioned before, the design of small molecules that target MYC is challenging. Our approach overcomes these limitations allowing an unbiased functional analysis at single amino acid resolution that I believe will provide essential structure-function information. Our data will also allow the identification of critical MYC interactors that can be explored for the indirect inhibition of MYC and form the foundations of a small molecule drug screening platform.

Why did you want to apply to the Small Molecules TIN Pilot Data Fund?

As an early-stage researcher, The Small Molecules TIN Pilot Data Fund was my first opportunity to apply for a grant as the main applicant. I thought that, if successful, it would be an excellent opportunity to manage my own research funds.

Also, I felt that the preliminary results of our MYC mutants library screening were extremely promising but made us realize that an increased sequencing depth was required in order to reach single aminoacid resolution. I was convinced that our proof-of-principle experiments were suitable for applying to the Small Molecules TIN Pilot Data Fund and that the scheme would be perfect to fund the additional sequencing analyses that are needed.

How did you find the process for the TIN Pilot Data Fund? What did you learn?

The application process was very quick. After submitting my application with all the relevant details of the project, my proposal was shortlisted for a pitch with a panel of experts following a Dragons’ Den style event. This was the first opportunity I had to defend my project in such format and it was extremely challenging, mainly for the short time we were given to present our data. Before the pitch, I learned how to present complex scientific data succinctly to specialists from industry and academia with very different backgrounds. As part of the ACCELERATE program I attended a training session that helped me to deliver an impactful and convincing message. In this workshop, I also received useful advice about how to navigate through the long Q&A and how to improve my body language – which is important also in an on-line session over COVID times! My lab mates helped me too by improving my presentation and by anticipating the most probable questions – they are absolutely amazing! During the whole process, I received important feedback from different perspectives that will definitely improve the project. Overall, I consider it a very positive experience that helped me to strengthen future grant proposals.

What do you hope to achieve in the 6 months duration of your project?

My plan at the end of this period is to reach an appropriate sequencing depth after the screening of our library in an adequate number of biological replicates generating a complete functional map of MYC. This will allow a robust statistical comparison and will decrease the number of false positives, ultimately reducing the costs derived from subsequent validation steps that we will carry out.

What are your next steps from now?

I will start by generating large-scale cultures of the MYC-dependent T-ALL cell line used as a model in this screening. These cells will be transfected with our MYC mutant library ensuring a proper representation of all the variants during the process and they will finally be incubated with tetracycline. During this incubation, those variants that translate to a non-functional MYC protein will drop out and will be identified by NGS and validated individually. These results will allow the identification of domains in the MYC protein that are critical for its oncogenicity. Following a mass spectrometry-based approach, we will try to identify novel MYC co-factors that are essential for its function and interact with MYC through these critical domains. We anticipate that this data will enable us to delineate in future proposals the structure of the protein-protein interaction interfaces that will ultimately inform in in silico drug design.

About Dr Victor Llombart

Dr Victor Llombart is a molecular and cellular biologist that works as a Post Doctoral Research Associate in the lab led by Dr Marc Mansour, at the Haematology Department of the UCL Cancer Institute. Dr Llombart’s main research interest is learning how proteins that are involved in key biological processes function, interact and regulate essential tasks within the cell. During his PhD at Universitat Autonoma de Barcelona he developed different proteomic approaches for the discovery of novel diagnostic biomarkers for stroke using different in-vivo and in-vitro models as well as human samples.

Later, at St George’s University of London he worked on understanding the mechanisms that regulate the trafficking and exocytosis of intraluminal vesicles in endothelial cells.

Dr Llombart joined UCL in 2018 on a CRUK-funded project aiming to identify novel domains of the oncoprotein MYC that are important in protein-protein interactions and can potentially be targeted using small molecule drugs.

In the first Small Molecules TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks (TINs), Clara Gathmann highlights her Small Molecules TIN Pilot Data Fund awarded project, “Screening a DNA encoded library on GEF-H1 for drugs targeting ocular diseases”.

What is the title of your project and what does it involve?

The title of my project is ‘’Screening a DNA encoded library on GEF-H1 for drugs targeting ocular diseases’’. GEF-H1 is a protein which our group has identified as a potential target for fibrotic and inflammatory ocular disorders. We have started to develop small molecules against GEF-H1, using computational and medicinal chemistry drug discovery techniques. However, our molecules are not very potent yet and we haven’t tried using high throughput screening.

DNA encoded libraries (DELs) contain billions of molecules in a single tube and can be screened on a protein within days. This technology is made possible by DNA tags attached to each molecule that encode their structures. As you may know, DNA can be amplified with PCR and sequenced. This enables a read-out of the structures of the most active molecules from picogram quantities in the tube. Hence, only one small tube is needed instead of thousands of 96-well plates. We decided to use the open source DEL library from WuXi and subject it to GEF-H1. With this, we hope to discover new molecules that bind GEF-H1 within a few weeks, giving a real kick to our drug discovery plans!

What is the motivation behind your project/therapeutic?

Preventable ocular disorders are still a major cause for vision loss. In addition to the high impact on human lives, sight loss is also a real economic issue for our societies. Even quite common ocular disorders like uveitis and retinopathies can cause vision loss if left untreated. Unfortunately, current treatments for inflammatory and fibrotic eye disorders either involve invasive surgeries or the heavy use of drugs like corticosteroids and anti-proliferative agents. These interventions are first of all not necessarily successful and have several side effects, including even vision loss!

As for many diseases, it all starts with a good drug target (in other words, a protein to inhibit). By finding potent GEF-H1 inhibitors, we hope first of all to produce useful clinical candidates that can prevent inflammatory and fibrotic damages done to the eye. But also importantly, we would show for the first time that GEF-H1 is a suitable protein to inhibit, paving the path for a new class of biological targets and providing a proof of concept for future drug discovery projects. I think this is truly motivating, to not only contribute to a cause such as a particular disorder, but also to a whole scientific field which might help completely unrelated disease classes.

Why did you want to apply to the Small Molecules TIN Pilot Data Fund?

DNA encoded libraries are an emerging technology that have gained a lot of attention lately. More and more data is published on the construction of such libraries, with some successful examples taken to clinical trials. However, the biggest libraries are often in-house libraries of pharmaceutical companies or offered by specialised companies to pharma giants. This means that drug discovery groups in academia don’t have easy access to these libraries for cost reasons, unless a collaboration is put in place. When we heard that WuXi launched this open source DNA encoded library for academia, it sounded like a huge opportunity to bring that technology into UCL and our department.

This technology can lead very quickly to positive results but would simply not have been possible to follow up on hits without the funds from the Small molecules TIN. The TIN pilot data fund seemed to be adapted due to the short-term character of the project and we hoped that such an unusual idea could awaken interest. In addition to this, applying for this kind of fund seemed like the perfect opportunity for me to learn about grant writing and how to fund research in general.

Learn more about the Therapeutic Innovation Networks and join a TIN

How did you find the process for the TIN Pilot Data Fund? What did you learn?

Overall, super exciting. While making the written application, I realised how important it is to connect our (sometimes crazy) scientific ideas to real life goals. For the first time in my life, I had to define the purpose for what I am doing in such details. In some disciplines like the ones involving clinical research, it might be easier to relate to the patients, but when you are in a lab synthesising molecules, sometimes you just loose that connection. Applying for the fund made me realise that the translational aspect of research even at its early point is really important.

Then, there was the pitching, which felt a bit like preparing for a TV show! We candidates had the chance to participate to an ACCELERATE workshop on pitching, probably the most important part of the application process. My pitch before and after that session was transformed thanks to the honest comments I received. I learnt to shift completely the initial ‘science nerdy’ focus of the talk to ‘why you should fund my project’. In summary, I learnt to tell why my project is going to make a change, and how I am going to achieve my goals in time.

What do you hope to achieve in the 6 months duration of your project?

The goal for this project is mainly to generate molecules that can be useful biological tools or clinical candidates which target GEF-H1 in ocular diseases. We want to generate accurate binding data on the hit molecules to prepare them for in vivo testing. If the screen generates potent molecules that bind GEF-H1 tightly, this will enable us to irrevocably confirm that GEF-H1 inhibition is beneficial for those diseases, fast-tracking us to clinical testing.

What are your next steps from now?

In those six months, I will first prepare materials for the screen (immobilise the proteins on beads for example), to then subject the protein to the DEL screen. After the screen is done, WuXi will process our samples, amplify the DNA tags and perform a statistical analysis on these to reveal the structures of the binders. We will then order the most potent binders for resynthesis on a milligram scale and validate them using biological assays. We typically perform biophysical assays like surface plasmon resonance (SPR) and cellular assays that model for example inflammation.

About Clara Gathmann

Clara Gathmann works between the UCL Institute of Ophthalmology and the Wolfson Institute for Biomedical Research. She is working in the groups of Prof. Balda/Matter and Dr.Chan/Prof. Selwood, focussing on the discovery of small molecules as drug candidates for common ocular diseases. She started on a Moorfields Eye Charity funded project in October 2019 involving the design, synthesis and biological assessment of molecules inhibit the GEF-H1/RhoA interaction.

In the next interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Athina Dritsoula and Dr Carlotta Camilli highlight their joint Biologics TIN Pilot Data Fund awarded project focusing on the effect of LRG1 blockade in pancreatic cancer.

How did this joint project come about?

CC: Athina and I both arrived at the Institute of Ophthalmology to do our post-docs where, weirdly enough, we don’t do eye-related research but explore vessel behaviour using ex-vivo models of angiogenesis and in vivo models of solid tumours.

What is the title of your project and what does it involve?

AD: The interest of our lab is focused on the LRG1 protein, which is involved in pathological angiogenesis, but we don’t know much about its normal function. Based on our research, we believe that blocking the function of the LRG1 protein by using a specific monoclonal antibody that we have developed in the lab will be beneficial in conditions with abnormal angiogenesis like cancer. In fact, LRG1 is upregulated in pancreatic cancer, which is a type of cancer with minimal survival that remains untreated. So, Carlotta and I designed this project to study the effect of LRG1 blockade in pancreatic cancer.

What is the motivation behind your project/therapeutic?

CC: Pancreatic cancer is a leading cause of deaths from cancer that kills about half a million people worldwide each year. The current standard of care involves combination cytotoxic chemotherapy, which often fails due to the complex tumour microenvironment. So, there is a great need for developing novel therapeutic strategies that will target new molecules and pathways, and we believe that our anti-LRG1 antibody could be a great novel therapeutic candidate.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

AD: We both thought that the Biologics TIN Programme is a great opportunity to get enough funding to support a short 6-month project that would allow us to a) test our hypothesis and b) generate pilot data to design a bigger project in future if (a) proves right.

Join the Biologics TIN

What do you hope to achieve in the 6 months duration of your project?

CC: Well, we hope that we will manage to prove that our hypothesis is correct, and COVID-19 situation allowing, generate data to apply for more funding and get this project further. Our -very ambitious – aim is to get our antibody into clinical trials for pancreatic cancer in a few years’ time!

What are your next steps from now?

AD: Hope that our orders will be delivered on time and that our experiments will work as planned! We need to complete the project before a second lock down crushes.

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

AD: The 10 minutes Dragons’ Den round felt much longer than it was! Be well prepared for all types of questions, and maybe have a mock interview with your PI, if possible.

CC: Spend enough time to prepare the slide presentation. It might seem easy but it’s not, as it needs to be very concise and straight forward!

About Dr Athina Dritsoula

Dr Dritsoula studied an undergraduate degree in Molecular Biology and Genetics in Greece over a decade ago before arriving in the UK for a Master’s and PhD, and UCL has been home to Dr Dritsoula since. Although human genetics was Dr Dritsoula’s first love, Dr Dritsoula quickly found her “forte” in vascular biology – studying the biology of big human vessels during a PhD, and then smaller vessels stability and angiogenesis during post-doc.

About Dr Carlotta Camilli

After completing a Master’s in Medical Biotechnology, Dr Camilli left Italy to start a PhD at UCL focusing on the use of vascular progenitors for the development of a bioengineered muscle.

However, Dr Camilli’s broad interest in translational medicine pushed her to explore a different pathological context during post-doc, namely the tumour angiogenesis. Dr Camilli found jumping on this new field a difficult but exciting challenge!

In the third interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career researchers within the UCL Therapeutic Innovation Networks, Dr Gathoni Kamuyu highlights her Biologics TIN Pilot Data Fund awarded project “Identifying monoclonal antibodies for the treatment of Acinetobacter baumannii infections” and presents some advice for future applicants.

Please provide an overview of your Biologics TIN Pilot Data Fund awarded project. 

My project, “Identifying monoclonal antibodies for the treatment of Acinetobacter baumannii infections” will use single B-cell sequencing and cloning techniques to identify monoclonal antibodies targeting A. baumannii [3]. This will involve immunising mice to generate a robust antibody response against selected proteins, obtaining antigen-specific single B cells by fluorescence-activated cell sorting and screening each individual B cell for the production of antibodies effective in controlling the bacterial infection. Once a positive antibody-secreting B cell is identified, the corresponding monoclonal antibody it secretes, can be made in large quantities by recombinant protein expression [4, 5].

What is the motivation behind your project/therapeutic?

Acinetobacter baumannii has been referred to as the perfect predator in the media [6] and is number one on a recent WHO list of antimicrobial resistant (AMR) pathogens to which alternative therapies are urgently required [7, 8].

Through many different mechanisms, A. baumannii can survive and spread rapidly within hospitals, causes approximately 6-24% of nosocomial bacteraemia and pneumonia (particularly within intensive care units) and is associated with high morbidity and mortality rates [8-10]. Current treatment options uses complex antibiotic combinations to overcome the AMR profile, and there is an increase in reports on the incidence of infections caused by pan-drug resistant A. baumannii (non‐susceptibility to all agents in all antimicrobial categories) [11].

Monoclonal antibodies (MAbs) are a viable alternative to antibiotics that avoids the problem of drug resistance [12].  A carefully selected MAb offers multiple advantages over antibiotics that include rapid development with low toxicity, have minimal effect on the human microbiome, do not drive resistance to antimicrobials and can be conjugated to additional molecules to enhance antimicrobial effects.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

The biologics TIN pilot data fund was specifically interested in funding projects by early career researchers (ECR), on biologics (including monoclonal antibodies), that were between the discovery and translational phases. This would allow the ECR to generate pilot data that could be used to apply for larger grants. My current research work had identified potential protein targets that elicited protective antibody responses against Acinetobacter baumannii making them ideal targets for monoclonal antibody development.

In addition, it was an opportunity to identify, interact and establish collaborations through the TINs, with groups within UCL that have similar research questions or have specialised research techniques.

What do you hope to achieve in the 6 months duration of your project?

I hope to have identified a subset of monoclonal antibodies targeting A. baumannii for further validation. I would also like to establish the pipeline I would use to identify monoclonal antibodies against additional antigens of interest that we would identify.

What are your next steps from now?

Hit the lab and generate data…

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

Read the application instructions carefully, keep within the word count on your application and keep your 2 min pitch, simple, straightforward and to the point.

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About Dr Gathoni Kamuyu

Dr Gathoni Kamuyu obtained a BSc. in Biochemistry (1^st Class Honours, University of Nairobi, Kenya) and MSc. in Molecular Biology of Infectious Diseases (Distinction, LSHTM,United Kingdom). Dr Kamuyu’s research career started at the KEMRI-Wellcome Trust Research Programme (Kilifi, Kenya), evaluating the link between exposure to parasitic central nervous system infections and epilepsy [1].

In 2017, Dr Kamuyu obtained a PhD from the Open University/KEMRI-Wellcome Trust programme, which focused on identifying the targets of protective antibodies against Plasmodium falciparum, one of the causative agents for Malaria [2]. During her initial post-doctoral training at University Hospital Heidelberg, Germany, Dr Kamuyu used in vivo models to evaluate a panel of P. falciparum proteins as targets of protective antibodies.

Currently, Dr Kamuyu is a Research Fellow within Prof. Jeremy Brown’s group in the Department of Respiratory Medicine, Centre for Inflammation and Tissue Repair (CITR), UCL. Her research focus includes understanding acquired immunity to Acinetobacter baumannii (A. baumannii), identifying the potential targets of protective antibodies and the mechanisms employed by A. baumannii to evade the effector functions mediated by the complement system.

References

1. Kamuyu, G., et al., Exposure to multiple parasites is associated with the prevalence of active convulsive epilepsy in sub-Saharan Africa. PLoS Negl Trop Dis, 2014. 8(5): p. e2908.

2. Kamuyu, G., et al., KILchip v1.0: A Novel Plasmodium falciparum Merozoite Protein Microarray to Facilitate Malaria Vaccine Candidate Prioritization. Front Immunol, 2018. 9: p. 2866.

3. Lu, R.M., et al., Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci, 2020. 27(1): p. 1.

4. Carbonetti, S., et al., A method for the isolation and characterization of functional murine monoclonal antibodies by single B cell cloning. J Immunol Methods, 2017. 448: p. 66-73.

5. von Boehmer, L., et al., Sequencing and cloning of antigen-specific antibodies from mouse memory B cells. Nat Protoc, 2016. 11(10): p. 1908-1923.

6. Patterson, S.S.a.T., The Perfect Predator: A Scientists’s Race to Save Her Husband from a Deadly Superbug: A Memoir.

7. (WHO), W.H.O., Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotic. 2017.

8. Tacconelli, E., et al., Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis, 2018. 18(3): p. 318-327.

9. Allegranzi, B., et al., Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet, 2011. 377(9761): p. 228-41.

10. Cerceo, E., et al., Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options. Microb Drug Resist, 2016. 22(5): p. 412-31.

11. Magiorakos, A.P., et al., Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect, 2012. 18(3): p. 268-81.

12. McConnell, M.J., Where are we with monoclonal antibodies for multidrug-resistant infections? Drug Discov Today, 2019. 24(5): p. 1132-1138.

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.

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About Dr Anais Cassaignau

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.

1. How does the ribosome fold the proteome? Cassaignau, AME, et al Ann. Rev. Biochem, 2020, 89, 389-415.  https://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-062917-012226 

In the first 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 Giulia De Rossi highlights her Biologics TIN Pilot Data Fund awarded project “LRG1 antibody for diabetic macular oedema” and presents some advice for future applicants.

Please provide an overview of your Biologics project. 

There are currently 4.8 million people in the UK living with diabetes and over 300,000 of these have their sight threatened by a severe ocular complication called diabetic macular oedema (DMO), which has now become the most common cause of blindness in the working population.

Clinical studies have shown that leucine-rich alpha-2-glycoprotein 1 (LRG1) is enriched in the eyes of diabetic patients and we showed in other settings that it can drive vascular dysfunction. My hypothesis is that LRG1 is an early pathological switch in DMO and I believe that it may represent a novel/alternative pathway we could target therapeutically.

My project “LRG1 antibody for diabetic macular oedema” will test the efficacy of function-blocking antibody against LRG1 using murine models of diabetes. Specifically, I will be looking at the effects of this biologic on vascular homeostasis and permeability.

 

What is the motivation behind your project?

Currently, if you are diagnosed with DMO, you will receive monthly intra-ocular injections of VEGF-neutralizing antibodies. Unfortunately, this line of treatment has only a 50% chance of working and often responses are short-lived. As a result, despite the NHS spending £116m/annum, 2000 people go blind every year.

With diabetes reaching epidemic proportions, there is an urgent unmet need and market for developing new treatments for this devastating condition.

I believe targeting LRG1 with a function-blocking antibody has the potential not only to treat patients who are refractory to current therapies, but also to achieve earlier and therefore better outcomes in all patients.

Why did you want to apply to the Biologics TIN Pilot Data Fund?

I had an interesting set of preliminary data that I felt was suitable for applying for a pilot proof-of-concept grant.

The TIN pilot data fund was also my first opportunity to apply for and manage a grant as the lead applicant, which I hope will be a first stepping stone towards independent research and career development.

What do you hope to achieve in the 6 months duration of your project?

With the funding requested I plan to answer 3 critical questions: 1) Is LRG1 a pathological switch in DMO? 2) Is a Lrg1-deficient mouse protected from DMO? and 3) Can anti-LRG1 antibodies prevent the onset of DMO?

What are your next steps from now?

My planned experiments will support the preclinical dataset necessary to take the anti-LRG1 antibody into clinical trials, by establishing whether LRG1 is a valid target, and, together with the available supporting literature from clinical studies, will constitute the foundation for a translational grant application next year.

Do you have any top-tips for applicants currently going through the application process for the other TIN Pilot Data Funds?

Make sure you clearly describe: what the problem is, your proposed solution, why your approach is better, what you want to do next if successful (clear career and translational path).

As with every application with a limited word count, you might end up with an extremely abridged version of your initial text and some key concepts might become cryptic. Have someone from a different field review your application and tell you if they can still understand the key message you want to convey.

There is no space to describe the experiments in detail, so just explain the scientific questions you want to answer, you will have the opportunity to wear your scientist hat if you get to the Q&A stage.

Good luck future applicants!

Dr Giulia De Rossi will be discussing her Biologics TIN Pilot Data Scheme application process experience in the upcoming ACCELERATE Success event, “Grant Writing for Translational Research” on Tuesday 6th October.  This is an educational, translational training event to help UCL researchers write impactful applications by recognising the important elements of a translational research/innovation grant application and increase chances of funding success. Register here.

About Dr Giulia De Rossi

Dr Giulia De Rossi is a research fellow at the UCL Institute of Ophthalmology in the lab led by Professor Stephen Moss and Professor John Greenwood. Dr De Rossi’s training was in Biotechnology and the main focus of her PhD and post-doctoral work has been understanding the mechanisms underpinning vascular dysfunction and new blood vessel formation.

Dr De Rossi joined UCL in July 2019 to work on a Diabetes UK-funded project aimed at identifying new targets and mechanisms to treat the microvascular complications of diabetes.

Following last week’s announcement from the MHRA regarding changes to the regulation for devices to be marketed in the UK, we asked Translational Research Manager Dr Simon Eaglestone, who has represented the UCL Translational Research Office in various discussions around the new Medical Devices Regulation (MDR) for 2021, to comment on the implications this has for the devices academic community and the support available at UCL to ensure compliance and accelerate translation of medical devices to the market.

What do the new Medical Device Regulations mean for device projects in academia?
From 1 January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) will take on the responsibilities for the UK medical devices and in vitro diagnostic medical devices market that are currently undertaken through the EU system (i.e. CE mark). The new product marking will be termed UK Conformity Assessed (UKCA), with the current Medical Devices Regulations 2002 (UK MDR 2002) continuing to have effect in Great Britain after the transition period.

CE marking will continue to be used and recognised until 30 June 2023, with medical device manufacturers in the UK having to prepare to satisfy the new EU Medical Device Regulation 2017/745 (MDR) to be fully implemented 26 May 2021. Even with this most recent announcement of how medical devices are to enter the market in Great Britain it remains clear that to market UK medical devices in the EU, manufacturers will have to satisfy the new MDR and gain CE mark certification. Whilst the MDR is written to provide clarity of regulatory requirements of economic operators and sponsors of clinical investigations, there has been confusion and uncertainty amid the academic community regarding what the MDR actually means for those investigators working in universities and partner healthcare institutes on early stage medical device projects.

What are the most significant changes in the Medical Device Regulations?
The MDR defines new obligations for manufacturing a medical device that include revised risk classification, requirements of safety and performance, clinical evidence and vigilance reporting. Arguably, the most pertinent change to affect the academic community relates to Annex I of the MDR (the General Safety and Performance requirements) and the increased needs for technical documentation and quality management systems (QMS).

Article 10 of the MDR states what manufacturers need to put in place as a minimum QMS. The QMS encompasses a defined series of processes to ensure the appropriate documentation of the entire life cycle of a medical device (including regulatory compliance, risk management, design & manufacturing, product information, usage, safety and impact). As referenced in the MDR, ISO 13485 is the recommended (but not compulsory) international standard for QMS, whereby an organization needs to demonstrate its ability to provide medical devices and related services that consistently meet customer needs and applicable regulatory requirements.

Reflecting their charitable status, universities do not generally ‘hold’ CE mark certification or place products on the market (i.e. do not act as economic operators). Successful translation of academic device projects is usually achieved by increasing asset value within the context of academic research until such time that a strategic exit is made, either by establishing a ‘spin out’ company or brokering a licensing deal with an established device manufacturer. Either of these external parties would then take on the responsibility of managing an ISO 13485-certified QMS to support their application for CE mark certification and market authority approval for the new medical device.

What should be the impending approach to quality management systems in academia?
Universities and associated healthcare institutes undertake domestic development of non-CE marked devices, or research on modified CE marked devices or those used out of intended function (i.e. ‘CE-broken’). Whilst effectively acting as the manufacturers of these early-stage devices, the implementation and maintenance of an ISO 13485-certified QMS is resource demanding and rarely undertaken by academic centres. However, there clearly is the pressing need for a change in research culture and practice that addresses the need for appropriate technical documentation in the early life cycle of medical devices.

The incoming MDR has prompted health institutions to migrate their existing QMS infrastructure from ISO 9001- to ISO 13485-certification. Health institution exemption (HIE) from MDR may be secured for manufacturing, modifying and using custom made devices ‘on a non-industrial scale’, within the same health institution (i.e. legal entity). However this ‘in house manufacturing’ demands appropriate QMS and documentation to ensure such products meet the relevant General Safety and Performance Requirements. Significantly, health institutions will be compelled to apply for exemption under the new MDR, thereby closing a potentially overused pathway for academic medical device research via partner health institutions.

Making academic medical device translational more successful
To promote medical device development and successful translation to market with enhanced patient benefit, there is growing support in the academic community for initiatives that will improve knowledge of regulatory requirements and present investigators with both pragmatic and the least onerous solutions to satisfy regulatory compliance in early-stage device projects and facilitate commercialisation.

Whilst the academic exit strategy described earlier negates the need for implementing a fully certified QMS, there is a compelling incentive for device researchers within universities to commit time, effort and resources to implementing a proportionate QMS for each medical device project. The ability to attract external investment to support the progression of a university’s domestic device to market is greatly enhanced by the existence of a balanced QMS and documentation developed throughout the entire project lifetime toward ‘CE-readiness’.

The future for UCL
Just as the Clinical Trials Directive of 2001 enhanced the conduct of clinical trials on medicinal products for market within the European Union, the incoming MDR has presented a motivation for enhancement to the culture and way in which UCL researchers undertake and ultimately improve the likelihood of successful translation of university medical device development.

Throughout 2020, UCL’s Translational Research Office (TRO), Institute of Healthcare Engineering (IHE) and Joint Research Office (JRO) have been working closely to develop standardised tools that will support investigators in keeping and updating device project records.

Over the coming months, the Devices & Diagnostics Therapeutic Innovation Network (D&D TIN) shall be hosting community events to enable investigators to access local resources (e.g. QMS & document templates) and implement solutions for centralised management of a university department/Sponsor device project portfolio. Whilst non-compliance with the QMS would not preclude their ongoing research activity, it would likely hamper investigators ability to progress at a later stage (e.g. refusal of Sponsorship for clinical investigation).

Watch this space for the Devices & Diagnostics TIN QMS workshop, scheduled to take place before the end of the year (date TBC). In the meantime, become part of the Devices & Diagnostics community at UCL by joining the Therapeutic Innovation Networks: a platform for UCL, partner Biomedical Research Centres (BRCs) and industry partners to connect, collaborate and share best practices to translate at pace. Any workshops relating to the new MDR will be communicated to the Devices & Diagnostics TIN community through Teams and via email before being announced more publicly.

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What is the Devices & Diagnostics Therapeutic Innovation Network (TIN)?
The Devices & Diagnostics TIN is one of 6 UCL Therapeutic Innovation Networks hosted by the UCL Translational Research Office, positioned around a specific modality rather than subject area, to encourage the formation of strategic multidisciplinary alliances to close the academic/clinical/patient/industry interface.

Additionally, the TINs aim to widen participation and remove barriers to translation by providing education and funding opportunities to basic and translational researchers from Early Career Researchers to PIs.

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