In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at  UCL, Dr Yang Li highlights her Small Molecules Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to develop the drug for MYB-dependent cancers. 

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In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at  UCL, Dr Jenny Lange highlights her Small Molecules Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to treat genetic epilepsies. 

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In this interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdocs and non-tenured researchers at University College London (UCL), Dr Apostolos Papandreou highlights his Small Molecules Therapeutic Innovation Network (TIN) Pilot Data Fund awarded project, involving novel drug development for a genetic neurodegenerative disorder. 

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

The title of my project is ‘Development of novel autophagy inducers for the treatment of Beta-Propeller Protein-Associated Neurodegeneration (BPAN)’. It involves developing new drugs for a rare, devastating, life-limiting neurodegenerative disorder: Beta-Propeller Protein-Associated Neurodegeneration (BPAN).

In my previous work, I performed a drug screen and identified promising drugs that ‘treat’ BPAN nerve cells in the laboratory. Namely, I developed a brain model of BPAN; I converted patients’ skin cells into ‘stem cells’, which have the capacity to transform into any cell type in the body. I then manipulated these stem cells to create a specific type of brain cell (known as “dopaminergic neurons”) that are significantly affected in BPAN. I utilised this laboratory model (our “disease-in-a-dish”) to understand disease processes and confirmed that a crucial waste disposal and recycling system (termed ‘autophagy’) is defective.

I tested thousands of drugs for their capacity to treat BPAN in the dish – using both approved drugs, and others still under development. I successfully identified several promising drugs that restore autophagy in BPAN. I now want to test derivatives of the most promising of these drugs further, to identify ones with improved qualities, that can in turn be taken forward to future studies on other preclinical models and, ultimately, to a clinical trial.

What is the motivation behind your project/therapeutic?

BPAN is a recently identified genetic condition, emerging as the commonest form of a group of disorders known as childhood-onset Neurodegeneration with Brain Iron Accumulation (NBIA). Affected children initially present with delayed development, seizures and behavioural difficulties. A second devastating illness phase manifests in teenage years or early adulthood, with an irreversible decline in abilities (loss of independent walking and talking) and dementia. There is an urgent translational need to better understand BPAN and develop effective treatments for it.

At Great Ormond Street Hospital, we have established a nationally-recognised clinical service for children with BPAN, as well as a programme of important laboratory research at UCL. Since 2016, we have been working towards better understanding the processes causing BPAN in order to develop effective therapies.

I now plan to further develop novel drugs that have the capacity to ‘treat BPAN in the dish’, with the ultimate goal to translate these novel therapies into the clinic for my BPAN patients.

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

The Small Molecules TIN is an excellent platform of drug development therapeutic innovation, into which my project and research fits really well. I am an early career researcher, and the fund was addressed to people at this career stage. Moreover, I have been working within UCL over the last few years in order to develop small molecule therapies for BPAN. UCL collaborators (from the TRO Drug Discovery Group) have now created derivatives of the most promising small molecules I identified in my previous work. My plans to further test, validate and develop these molecules not only build on my previous work and hold potential for translational therapeutic benefit, but promote intra-UCL collaborations between institutes, departments, and groups. For all these reasons, I feel that the Small Molecules TIN Pilot Data Scheme will be a very suitable springboard for future therapeutic development for BPAN, and also for my development as an academic clinician with a translational focus.

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

This process has been a very enjoyable and educational experience. The application was well advertised and straightforward, and the form easy to fill in and to the point. Importantly, as part of the application process and interview preparation, I had the chance to attend the associated ACCELERATE training workshop. This interactive workshop taught me to better pitch my research ideas in a way that my audience can understand; it was also very useful in improving my PowerPoint presentation skills. Hints and tips were given throughout, and it was nice to work interactively with other people in similar career stages within UCL. Overall, I think the whole process is an excellent opportunity for early career researchers looking for translational funding opportunities.

Learn more about the translational training offered through ACCELERATE 

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

I hope to test the new drug derivatives, and identify ones that work well in ‘treating BPAN’ in the dish but are also effective in much smaller concentrations. These can then be tested in other models, as appropriate, prior to clinical trials. I also hope to better elucidate the mechanism of action of these compounds, which would be interesting in its own, but would also shed light into the pathophysiological mechanisms leading to disease in BPAN.

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What are your next steps from now?

After the TIN project, promising candidate molecules will be tested in BPAN 3-D ‘mini-brains’ that I am concurrently developing in the lab, and/ or a mouse model of BPAN that I am also aiming to establish with help of international and intra-UCL collaborators. Discussions with MHRA will guide my steps to progression towards the clinic. My ultimate goal is to develop disease modifying/curative treatments for BPAN. I also aim to become an independent clinician scientist, with a particular interest in paediatric neurometabolic disorders and a bench-to-beside approach to developing novel therapeutics for my patients.

About Apostolos Papandreou

Dr Apostolos Papandreou was born in Greece in 1981. He studied medicine there, and subsequently moved to the UK in 2007. He had all his postgraduate paediatric training and then underwent paediatric neurology subspecialty training at Great Ormond Street Hospital, London (2013-2021). His PhD studies were on novel therapeutic development for rare disorders (PhD, University College London 2020).

He is now an NIHR BRC Catalyst fellow at UCL (Great Ormond Street Institute of Child Health), continuing his research in neurometabolic and neurodegenerative conditions with a focus on developing new, disease-specific treatments; he is also an honorary Paediatric Neurology Consultant at the Evelina London Children’s Hospital (Complex Motor Disorders Service).

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.

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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 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.

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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.

Motivated by an unmet medical need, you’ve identified a mechanism that may play a fundamental role in a medical condition that is currently poorly treated. You want to look at possible drug molecules that could modulate the mechanism to see how it might affect this condition – but how do you take this from an idea to a promising starting point for a new drug treatment?

Liquid handling solutions – The Tempest dispenses volumes as low as 200nl per well, with high accuracy & precision, and is available for use at the UCL TRO DDG.

In early small molecule drug discovery research, the process of going from initial idea to final pharmaceutical product is a complex, thorough, expensive process, and its success depends on your smart idea about how the disease might be treated. However, almost as important as the idea is the place from which you start. The pharmaceutical industry has invested a lot of money developing technologies to identify good starting points for drug discovery. One of the most established methods is high-throughput screening (HTS).

HTS involves testing large collections of chemicals (compound libraries) to identify molecules that bind to your target and modify the disease mechanism in the desired manner. This screening process is now largely automated and enables anywhere up to several million compounds to be screened rapidly with follow-up screening which can quickly highlight likely future issues, including off-target toxicity.

Until very recently it was normal for new insights into disease to be made by university researchers and for pharmaceutical companies to take over and do the work required to develop a treatment. However, pharmaceutical companies are increasingly working in a collaborative manner with academic institutions to identify disease mechanisms and initiate drug discovery projects.

This strategic partnership between academia and industry combines the scientific knowledge of university researchers with industry expertise to advance early drug discovery. In some cases, universities have recruited drug discovery experts to work within their institutions to initiate the drug discovery process and further enable external collaboration. The TRO Drug Discovery Group (DDG) is such a group, based at UCL School of Pharmacy.

Automated plate reading of Biochemical assays at the UCL TRO DDG – Combination of the S-lab robotic arm and the Sense plate reader allows for assay plates to be stacked up and automatically read.

By performing the wet science surrounding your drug discovery target (developing a screening assay, screening compounds) and developing a potential lead compound (synthesising and testing analogues of the hit molecules) the team is de-risking your project for industry partnering, shortening the time to testing your idea in a clinical setting.

The DDG implements an industry-standard approach to the process and provides a clear path of entrepreneurial development for UCL discoveries. By utilising the high-throughput screening capabilities available in its biology and chemistry labs, the DDG is able to build robust assays and data packages for future development.

An important component of what the team has achieved is enabled by a close working relationship with the Open Innovation team at AstraZeneca (AZ). On several occasions that has allowed screening of AZ compounds against UCL drug discovery targets and initiated new drug discovery projects.

In addition, the DDG has an extensive network of industry professionals. On occasions this has allowed linking of UCL researchers with industry experts to provide access to key technologies or further refine early drug discovery hypotheses and strategies.

The DDG offers free advice and tailored support to develop your drug discovery projects and facilitate access to funding the development pathway. Please contact us for more information or if you require help with developing your small molecule research.

Reviewed by Dr Richard Angell. 

References:

• https://www.sciencedirect.com/science/article/pii/S2352873717300653
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058157/
• https://www.technologynetworks.com/tn/articles/high-throughput-screening-accelerating-drug-discovery-efforts-288926
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269696/
• https://www.britannica.com/technology/pharmaceutical-industry/Drug-discovery-and-development
• https://www.biopharmatrend.com/post/30-pharma-rd-outsourcing-is-on-the-rise/