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 Amy Richardson highlights her Cell and Gene Therapy Therapeutic Innovation Network (TIN) Pilot Data Fund awarded project based on testing a novel gene therapy for epilepsy.  (more…)

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.

Join the Small Molecules TIN on Teams (UCL-Only) to be part of UCL’s multidisciplinary CGT community with direct access to expertise 

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 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 Matthew Wilcox highlights his Devices and Diagnostics Therapeutic Innovation Network (TIN) Pilot Data Fund awarded project, BANTER (Blood biomarker Assessment of Nerve Trauma and Early Reinnervation). 

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

BANTER (Blood biomarker Assessment of Nerve Trauma and Early Reinnervation), involves the development of a blood test which hopes to improve nerve injury identification. This study will use the SIMOA^TM Neurofilament Light (NfL) chain assay which has been tried and tested in capturing changes associated with a number of diseases of the brain and/or spinal cord such as Alzheimer’s disease and Traumatic Brain Injury. For the first time, this project will repurpose this technology to determine whether it is possible to detect the presence and severity of nerve injury using a well-established animal model. This will involve a collaboration between the UCL Centre for Nerve Engineering and UK Dementia Research Institute Fluid Biomarker Laboratory.

What is the motivation behind your project/therapeutic?

Nerve injuries often lead to permanent loss of movement and pain leading to significant quality of life impairments for patients. It currently takes too long for nerve injuries to be identified and referred for assessment by clinicians with special expertise in this area who may be able to offer surgery to improve outcome. In many cases, this means many patients suffer worse outcomes than had earlier referral been made. A major reason for this is because swift identification of nerve injuries depends on patients being able to access facilities with expensive imaging and tests which measure the electrical properties of nerves (such as MRI scans and Electromyography). Even if patients are able to access this technology, clinicians often find them difficult to interpret.

This project addresses this issue by developing a cheaper, readily available and objective test which may be able to predict the presence and severity of a nerve injury from a small blood sample.

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

A challenging step in transitioning from an early career researcher to an independent investigator is turning research ideas into compelling grant proposals. The TIN Pilot Data Fund provided an invaluable opportunity to develop a research idea right the way from planning and costing the experiment through to pitching to academics and industry representatives. This funding will provide the data necessary to design larger studies and help establish my research identity.

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

Throughout the application process, support was provided through the ACCELERATE training workshops which focused on developing communication and presentation skills. This experience has helped me to understand how to develop convincing pitches to different members of the academic and industry community; a skill that will be essential in my next career steps towards a surgeon-scientist.

Learn more about the translational training offered through ACCELERATE 

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

We will reach the first milestone of our project in 6 months. The success criteria of this will be to show the validity of the SIMOA^TM Neurofilament Light (NfL) chain assay in identifying the presence and severity of nerve injury in a controlled animal model. Alongside this laboratory-based research, I will be working closely with clinical colleagues at the Royal National Orthopaedic Hospital to design a corresponding study in nerve injured patients.

What are your next steps from now?

I hope to move into full time clinical training as a Foundation Doctor from August 2022 with the long term view of becoming a reconstructive surgeon-scientist. I am excited by the challenges I will encounter within the clinical arena along the way and look forward to addressing some of these by continuing to work closely with the diverse research community that UCL offers.

Join the Devices & Diagnostics TIN on Teams (UCL-Only) to be part of UCL’s multidisciplinary D&D community with direct access to expertise 

About Dr Matthew Wilcox

Dr. Matthew Wilcox is a Research Fellow at the UCL School of Pharmacy and a final year UCL medical student. In 2020, Matt was awarded a PhD in Translational Neuroscience which benefited from a collaboration between the Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital (a national referral centre for nerve injury) and the UCL Centre for Nerve Engineering.

Matt works within an interdisciplinary team focused on providing novel insights into the cellular and molecular basis of human nerve regeneration, developing improved imaging-based outcome measures of nerve regeneration and diagnostic tools for nerve injury. Together, this is informing the development of clinical trials which hope to test the efficacy of regenerative therapies for nerve injury and disease.

In this Regenerative Medicine TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Charlie Arber highlights his Regenerative Medicine TIN Pilot Data Fund awarded project, involving the potential of stem cells in Alzheimer’s. 

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

The Regenerative Medicine TIN have supported my project titled “Cell therapy in Alzheimer’s disease”. This is a project to understand the potential of stem cell derived astrocytes in repairing the brain in the dementia. Astrocytes are brain support cells, capable of cleaning the brain and even replacing some of the cells that degenerate in disease.

The project will answer three questions:

1. Can human astrocytes interact with mouse brain slice cultures?
2. Can astrocytes change the inflammatory state of the brain?
3. Can astrocytes sense and respond to amyloid (the main pathology in Alzheimer’s disease)?

What is the motivation behind your project/therapeutic?

There remain no therapies to slow, reverse or prevent dementia. In 100 years, how will we treat dementia? Possibly by replacing the cells that have degenerated? Like Luke Skywalker’s hand? This project is a first step to understand the value of astrocytes in cell replacement therapy in Alzheimer’s disease.

Can you highlight any challenges have you experienced as an early career researcher in the regenerative medicine/translational research space?

I am a basic scientist. I think understanding the importance of basic biology in translational science is under-appreciated. All basic scientists should have translational goals. This is the major impact of our work.

I have found keeping an eye on the larger picture and the long term goals a challenging aspect to my career. Small pilot grants such as the initiatives from the TINs have an invaluable role in supporting this type of research.

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

It is often hard to generate the pilot data that is required to apply for large grants and fellowships. I applied to the Regenerative Medicine TIN Pilot Data Scheme to learn a new technique (organotypic slice culturing) that has enabled me to generate new data which will be central to my fellowship applications and my career progression.

Join the Regenerative Medicine TIN to be the first to hear about similar opportunities 

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

I found the application process straight forward. Before the dragon’s den style interview, we had interview/pitch training from a professional coach, provided through ACCELERATE. I received some really useful feedback, especially in conveying a message in just two slides and 5 minutes.

Learn more about the training offered through ACCELERATE Success

Since the project began, I have had useful experience in budgeting for a small grant and deadline management due to the short, 6 month nature of these projects (as well as COVID-related setbacks!).

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

Having had this opportunity and support from the Regenerative Medicine TIN, I have generated some interesting and exciting pilot data. I am now looking forward to building on these findings as a major thread of my research career. I really look forward to driving this research question forward.

About Dr Charlie Arber

Charlie Arber is a stem cell biologist. He has worked with human stem cells for 15 years, understanding the best ways to make brain cells in a dish and using stem cells from patients to investigate the earliest causes of dementia.

Charlie is a senior research fellow in the department of neurodegenerative disease at the Institute of Neurology. His current research focus is looking at the role of brain inflammation in early onset Alzheimer’s disease.

In this Regenerative Medicine TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Hassan Rashidi highlights his Regenerative Medicine TIN Pilot Data Fund awarded project, involving human stem cell-derived 3D hepatospheres (3D Heps) for liver diseases.

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

The project’s title is “Dissecting the cross-talk between parenchymal and non-parenchymal derivatives within human pluripotent stem cell-derived 3D hepatospheres (3D Heps) using spatial transcriptomics”.

Previously, I developed a novel xeno-free protocol to generate 3D liver organoids suitable for clinical applications. I also formulated a new culture medium to stabilise the phenotype and function of 3D Heps for over a year in culture. In this project, I will use spatial transcriptomics to dissect the crosstalk between various populations of cells within the 3D Heps.

What is the motivation behind your project/therapeutic?

Liver diseases are leading causes of morbidity and mortality worldwide, accounting for about 1–2 million deaths annually. To date, orthotopic liver transplantation is the only curative option for treatment of individuals with inherited liver disorders, end-stage liver disease and acute liver failure. However, donor organ shortage, allogeneic rejection and adverse effects associated with long-term immunosuppressant medication are major limitations.

Human pluripotent stem cells (hPSCs) represent an attractive alternative source of hepatocytes, courtesy of their unlimited self-renewal capacity and potential to differentiate to all cell types found in the human body. Recently I developed a novel platform to generate 3D liver organoids exhibiting metabolic functionality for over a year in culture. In addition, therapeutic benefit of 3D Heps was demonstrated in a mouse model of inherited liver disease.

In the current project, I will perform spatial transcriptomic to gain a better understanding of the 3D Heps. In return, transcriptomic data will be used to further improve the platform to generate hepatocytes with superior functionalities and at scale for clinical applications.

Can you highlight any challenges have you experienced as an early career researcher in the regenerative medicine/translational research space?

While being fortunate to secure funding from several charities including Rosetrees Trust, Children’s Liver Disease Foundation, Sparks and Great Ormond Street Hospital Charity, a major challenge is the limited number of funding for early career researchers since most funding calls only accept applications from established academics. This is more problematic when it comes to translational research as larger amount of funding is required. Lack of stability is another issue as an extended timeframe is expected for fruition of translational projects.

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

Funding calls such as the Regenerative Medicine TIN Pilot Data Fund are the ideal source of funding for the early career researchers to generate the preliminary data required for larger grant applications such as fellowships. In addition, Blue-sky thinking is encouraged in schemes like the Regenerative Medicine TIN Pilot Data Fund, making it possible to test high-risk, high-gain projects that are typically deemed to be too adventurous.

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

The process was straightforward as the application form was short with a quick announcement of shortlisted candidates. In addition, ACCELERATE training was offered following the announcement to prepare shortlisted candidates for the Dragon Den-style interview, which I benefited from immensely. I also participated in the ACCELERATE-CASMI Mentoring workshop, which was very helpful.

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

The data from spatial transcriptomics will provide crucial insight to further improve the 3D Heps platform. Within the project’s duration, I will complete RNA sequencing of the libraries generated from liver organoids at various stages of differentiation. I will use the preliminary data to apply for additional funding to improve the platform and to develop new technologies to benefit from tremendous potential of 3D Heps for in vitro and in vivo applications.

Dr Hassan Rashidi

Dr Hassan Rashidi is a Senior Research Associate at UCL Institute of Child Health. Dr Rashidi’s academic career has been driven by a strong interest in stem cell biology and the development of new technologies to harness the tremendous potential of human pluripotent stem cells for clinical and industrial applications.

His current focus is on development of in vitro and in vivo platforms to evaluate liver toxicity and treat liver disease, respectively.

In this Cell & Gene Therapy TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Marion Mercier highlights her Cell & Gene Therapy TIN Pilot Data Fund awarded project, involving the validation of novel gene therapies for epilepsy.

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

Human brain tissue is routinely excised during epilepsy surgery, and can, given the right conditions, be maintained alive in slice culture for extended periods of time. My project, entitled “Validating novel AAV gene therapies for epilepsy in human organotypic slices”, involves firstly to optimise human tissue slicing and culture protocols for the successful maintenance of this tissue, and secondly to establish efficient viral transfection methods in these human organotypic slices. The specific virus used encodes for a protein that suppresses neuronal excitability and as such is being developed as a gene therapy strategy for epilepsy. Thus, the project aims to establish a human tissue model in which to validate and screen this, and future, gene therapies for epilepsy developed within the DCEE.

Filled and stained human pyramidal cell.

What is the motivation behind your project/therapeutic?

Epilepsy affects 1% of the global population, and 30% of patients are pharmaco-resistant, with significant associated morbidity. Several novel gene therapies for epilepsy have recently been identified and developed within the DCEE, and offer real hope for these patients. However, while results from animal models have been promising, understanding how these genetic manipulations, and the adeno-associated viral vectors (AAVs) used to deliver them, will behave in the human brain still poses a significant challenge. Furthermore, the irreversible nature of gene therapy makes transitioning from animal models to human patients particularly risky. By establishing human organotypic slices to extend the viability of excised human brain tissue, and thereby enabling transfection with AAVs (which take 2-3 weeks to express), I aim to develop a human neuronal tissue model in which to screen and validate these novel gene therapies for epilepsy and thereby help to bridge this important translational gap.

Can you highlight any challenges have you experienced as an early career researcher in the cell and gene therapy/translational research space?

Obtaining funding for your own independent ideas and research is particularly challenging as an early career researcher, and is often impossible without considerable preliminary data. This makes getting started on new projects, and gaining the independence necessary to progress on to more senior, permanent positions, especially difficult. Furthermore, as an early career researcher working at the intersect between clinical and more basic science, I have found the complex translational research pathway quite challenging to navigate.

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

I have two main objectives for the 6 months duration of the project. The first is to establish good quality human organotypic slices that are viable for up to 3 weeks, and the second is to develop effective viral transfection methods in these slices. I will be transfecting the tissue with AAV-hCaMKII-EKC-GFP, a virus that aims to increase expression of an enhanced K+ channel (EKC) in human excitatory neurons, and which has shown promise as a gene therapy strategy in animal models of epilepsy. Thus, while optimising protocols for viral transfection of human organotypic slices, I hope to also start to collect clinically-relevant data pertaining to the safety of the viral transfection and the selectivity of the expression. I am currently in the first phase of the project and have already improved the human tissue slicing protocol and started to optimise the slice culture methods.

Why did you want to apply to the Cell & Gene Therapy TIN Pilot Data Fund?

In order to start this project, all I required was two specialised pieces of equipment and a little extra funding for consumables. The Cell and Gene Therapy TIN Pilot Data Fund is ideally suited for this, and therefore provides the perfect stepping stone for getting started and obtaining quality preliminary data with which to then apply for further funding. Furthermore, it has enabled me to progress my research in a more translational direction, and to learn more about the translational pathway and all of the steps involved in getting a therapy from the lab to the clinic. This will not only be an invaluable help in establishing and advancing this current project, but also in informing my future research plans.

We are currently in the process of determining our funding availability for the Cell & Gene Therapy TIN for 2021. Please join the Cell & Gene Therapy TIN and sign up to the TIN newsletter to keep updated. 

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

The application process was rewarding and a great learning experience. I attended the ACCELERATE coaching session on pitching projects, through which I learnt a great deal about how to communicate my ideas effectively, concisely and convincingly. Receiving this training prior to the interview made the final pitching exercise exciting rather than daunting and made it an overall positive experience through which I received a lot of constructive feedback. This has given me more confidence in my ideas and capabilities and pushed me to be more competitive and ambitious in driving my research forward.

About Dr Marion Mercier

Dr Marion Mercier a postdoctoral researcher in Prof. Dimitri Kullmann’s laboratory within the UCL Institute of Neurology’s Department of Clinical and Experimental Epilepsy (DCEE). After an undergraduate degree in Psychology at Reading University and a year as a technician working on drug discovery for epilepsy, Marion moved to Bristol to do her PhD in the laboratory of Prof. Graham Collingridge where she studied glutamate transmission and synaptic plasticity in the hippocampus.

Throughout her postdoctoral work, her research interests have evolved at the intersect between basic and clinical neuroscience, focusing specifically on interneuron plasticity and synaptic function in both physiological states and pathological conditions such as epilepsy. Recently, she has begun to study human cortical function in resected human brain tissue, and is interested in establishing human neuronal models from this tissue in order to validate the gene therapy strategies for epilepsy currently being developed within the DCEE.

In this Cell & Gene Therapy TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Rajeev Rai highlights his Cell & Gene Therapy TIN Pilot Data Fund awarded project, involving hematopoietic stem cell gene editing to correct platelet defects in Wiskott Aldrich Syndrome (WAS).

What does your Cell & Gene Therapy TIN project involve?

Wiskott Aldrich Syndrome (WAS) is an X-linked recessive primary immunodeficiency disease characterised with severe, persistent, and life-threatening bleeding complications. This is caused by a genetic mutation in the WAS gene, which encodes a mutated WAS protein (WASp) leading to defective functional platelets. Without definitive treatment, the prognosis for this disease remains extremely poor. This is what my TIN funded project, which is titled “Correction of platelet defects in a Wiskott Aldrich Syndrome (WAS) humanized mouse model by hematopoietic stem cell gene editing”, aims to critically address.

We seek to investigate whether our recently established targeted genome editing platform could repair the mutated WAS gene and functionally correct platelet thrombocytopenia in humanised WAS mouse model. Our final goal is to translate this approach to human Haemopoietic Stem Cells (HSCs) harvested from WAS patients, which will be corrected ex vivo and re-infused intravenously following autologous transplantation protocols.

What is the motivation behind your project/therapeutic?

HSCs transplantation remains the definitive cure for WAS. However, lack of suitable matched donor accompanied by development of graft vs host disease has caused significant morbidities and mortalities. Although autologous HSCs gene therapy provides an attractive option, the use of lentivirus is associated with unregulated transgene expression and risk of insertional oncogenesis. Hence, a paramount urgency is required to develop an alternative yet safe gene correction strategy to cure WAS and associated platelet defects permanently.

Can you highlight any challenges have you experienced as an early career researcher in the cell and gene therapy/translational research space?

With a solid background in Immunology and Biochemistry, initial move into the field of cell and gene therapy was slightly challenging during the early stage of my research career. But having great mentors and colleagues in the department from whom I have learned enormous amount of molecular genomics and bioinformatics skills have tremendously aroused my interest in this field of translational  research.

Why did you want to apply to the Cell & Gene Therapy TIN Pilot Data Fund?

My previously completed project revealed the superiority of site-specific CRISPR/Cas9 editing over traditional gene therapy approach to rescue not just immune cells but also the defective WAS platelets in vitro (Rai et al., 2020). To extend such finding, I was planning to apply for various career development fellowship and larger grants. However, I realised I had to demonstrate some proof-of-concept in vivo translational data to support my hypothesis beforehand. And this is precisely what the Cell & Gene Therapy TIN Pilot Data Fund has helped me to do, and I would like to thank the UCL Translational Research Group for providing advice and immense support throughout the application process.

We are pleased to say that some form of TIN funding for the Cell & Gene Therapy TIN will be available this year in 2021. Please sign up to our newsletter to keep up with upcoming opportunities.

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

I thoroughly enjoyed the application process from start to finish including the dragon den pitching event, in which the ACCELERATE pitch training workshop helped me to prepare.

Sign up to the current open ACCELERATE training opportunity – ACCELERATE Potential, an online, self-paced translational training programme to help you learn the basics in translational research. 

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

The wealth of data generated from this TIN funding will define for the very first time the optimum fraction of gene edited HSCs required to functionally correct WAS platelet defect in a humanised mouse model without any side effects. This would enable the project to be more attractive to major translational follow-on funding and to industry engagement.

About Dr Rajeev Rai

Dr Rajeev Rai is a research fellow in UCL GOS Institute of Child Health.

His primary research lies in the development and application of novel gene editing and gene therapy technologies for the treatment of various haematological disorders.

In this Cell & Gene Therapy TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Juan Antinao Diaz highlights his Cell & Gene Therapy TIN Pilot Data Fund awarded project, involving AAV delivery in Dravet syndrome.

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

This project is called “AAV delivery of an NaV1.1 activator for the treatment of a Dravet Syndrome mouse model”. Dravet syndrome is a childhood epilepsy, caused by a mutation in one of the two copies of the SCN1A gene, which encodes the NaV1.1 ion channel. This results in a diminished expression of the protein, leading to the symptoms observed in patients. This project attempts to use a small molecule to enhance the function of the remaining NaV1.1 channels in a mouse model of Dravet Syndrome to hopefully alleviate the disease phenotype. To deliver the small molecule, we are using an Adeno-Associated viral (AAV) vector.

What is the motivation behind your project/therapeutic?

Dravet syndrome currently has limited treatment options, which struggle to control prolonged seizures and other comorbidities such as developmental delay. Patients with Dravet Syndrome unfortunately have an 15-20% mortality rate due to Sudden Unexpected Death in Epilepsy (SUDEP). In this project we aim to deliver a small molecule to enhance the function of NaV1.1 by using a AAV viral vector. As a proof-of-concept study we will aim to test this pre-clinical treatment in a mouse model of Dravet Syndrome, which also has a mutation in one of the two copies of Scn1a gene. If successful it could potentially offer an alternative treatment for Dravet Syndrome patients.

Can you highlight any challenges have you experienced as an early career researcher in the cell and gene therapy/translational research space?

I am currently in my first post-doctoral position. I would say the biggest challenge is the need to find funding for future projects. Although I was aware of this before, having to actually do it is a completely new “skill” on its own. Having no major track record has been a problem as most funding schemes require some history in the field to be eligible to apply, something that I currently do not have.

Why did you want to apply to the Cell & Gene Therapy TIN Pilot Data Fund?

This project is an exciting opportunity for me, as it is an idea I have had for some time, but could not figure out how to test it. If the results are promising, it will allow me to continue this work, applying to bigger grants, which otherwise I would have not been able to do, as these grants usually require preliminary data that for me as an ECR would have been difficult to generate without funding. The Cell and Gene Therapy TIN has given me the opportunity to kick-start this path.

Join the Cell & Gene Therapy TIN to keep up with upcoming funding opportunities. 

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

The process was simple. The application form was only a few pages long, mainly asking for details about the idea and how I was planning on executing it. I got the chance to participate in an ACCELERATE training session, which was extremely helpful when I had to present my project to the committee reviewing the applications. The suggestions I received from the coach have also been useful in other aspects, like explaining my research in terms that are easier to understand to an audience that is not familiar to the field I work in.

ACCELERATE’s online, self-paced translational training programme, ACCELERATE Potential, is now open for completion, to all. Learn more and sign-up.

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

During this time, I hope to generate preliminary data, mainly asking if the approach I proposed would be feasible as a possible treatment for Dravet Syndrome. I will test my vector in a mouse model of the disease and if the treatment modifies the symptoms, that data will become the basis on which I could apply for a bigger funding to continue this work. The timeline has been modified by COVID-19, but I am currently starting to produce the vector and hopefully I will start treating the first mice in the next few months.

About Dr Juan Antinao Diaz

Dr Juan Antinao Diaz is a Research Fellow in the Maternal and Fetal Medicine department at the UCL EGA Institute for Women’s Health.

He completed his PhD at UCL in September 2020 and continued his work in UCL as a research fellow since then.

He is currently researching the use of a gene therapy vector in Dravet Syndrome.

In this Cell & Gene Therapy TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Ellie Crompton highlights her Cell & Gene Therapy TIN Pilot Data Fund awarded project, involving new therapies for rare disease Maple Syrup Urine Disease (MSUD). 

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

My project is entitled “Development of novel therapies for Maple Syrup Urine Disease (MSUD)”. MSUD is a rare, paediatric, metabolic disease caused by mutations in three genes. When mutated, the body cannot produce a functional enzyme complex that is used to break down branched chain amino acids (BCAAs) in the liver. This leads to a build-up of these BCAAs and metabolic decompensation of the patient. In this project, we are attempting to treat the underlying disease pathology using a bioengineered novel therapy, developed at UCL, with the aim that this will lead to improved BCAA metabolism, provide neuroprotection and prolong survival.

What is the motivation behind your project/therapeutic?

Currently, MSUD patients are commonly treated with strict dietary management, or in some cases patients are offered a liver transplant to correct the underlying disease. Both of these approaches have major pitfalls. The low-protein diet needed to avoid build-up of BCAAs is often said to not be palatable and this leads to compliance issues in infants and children prescribed this diet. A lack of available donors also severely limits the possibility of liver transplant. By restoring metabolic function in MSUD patient cells, we have the potential to allow the body to produce the enzymes necessary to break down BCAAs and alleviate the need for sub-optimal diet management and transplant strategies. Furthermore, our therapy is unique because it will be relevant to all MSUD patients regardless of their specific genotype or phenotype. If successful and translated to the clinic, this has the potential to fulfil an unmet medical need.

Can you highlight any challenges have you experienced as an early career researcher in the cell and gene therapy/translational research space?

As a Research Fellow in my first post-doctoral position, I am beginning to navigate my way around the field in which I work. Before I started this post, I was unaware of the need to start generating ideas that could lead to fellowship applications at the very beginning of your post. The need to bring in funding of your own whilst only just starting your career can be daunting, especially when a majority of grant applications require you to have certain level of seniority to be eligible. There is some pressure that ECRs need to secure grant funding to progress their career, but this can be difficult when fresh out of a PhD, with one publication and no previous track record of successful grants.

Why did you want to apply to the Cell & Gene Therapy TIN Pilot Data Fund? How has it helped you?

The work proposed in this project is really exciting and is definitely worth exploring. I think there are some great advantages to the novel therapy approach we are researching, and without the TIN grant, this work may not have been possible. The TIN pilot fund has given me the opportunity to generate invaluable preliminary data that can support future, larger grants. There is the age-old dilemma of needing good preliminary data for large grant applications, but having no money to generate it. The TIN funding has allowed me to begin this process. I wanted to apply for this funding to kickstart my career in the cell and gene therapy field, allowing me to build my portfolio of work only a few months after finishing my PhD.

The Cell & Gene Therapy Therapeutic Innovation Network (TIN) are offering the opportunity to appear in a resource to showcase and promote the diversity/depth and breadth of expertise within the Cell & Gene Therapy space across UCL. Appearing here will raise your profile and visibility in the field of Cell & Gene Therapy, not only across UCL but with also with external academic and industrial partners leading to rewarding collaboration and funding opportunities.

UCL Researchers in the Cell and Gene Therapy field are advised to register their details to appear in the resource. To create your research profile for inclusion please click here to complete the online form.

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

Applying for the TIN Pilot Data Fund was a simple process with an application form consisting of only a couple of pages, rather than a large grant application with tens of pages. This made it feel far less intimidating. After being told I was shortlisted, the offer of a coaching session from ACCELERATE to improve the three-minute, 2-slide presentation that was requested was incredibly helpful. I learnt which elements of the project and application I should highlight, and which to prepare answers to questions, but not immediately bring up. The coach was very helpful and really useful experience for my career.

Learn more and sign up for ACCELERATE Potential, an online, self-paced translational training programme outlining key elements of Translational Research – NOW OPEN 

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

Within the 6-month duration of this project I hope to generate preliminary data that can elucidate whether a broadly applicable pan-genotype approach is more beneficial, and whether novel therapy is better than other therapies currently under development. The progress of my project has been slowed considerably due to Covid-19 and the challenges this has produced, but I am hopeful that we can generate a good package of data at the end, even if it is not entirely the same as that which was proposed.

About Dr Ellie Crompton

Dr Ellie Crompton is a Research Fellow within the Maternal and Fetal Medicine department at the EGA Institute for Women’s Health. After having completed her PhD at Royal Holloway, University of London, Ellie joined UCL in August 2020.

Her current research aims to use gene therapy and gene editing techniques in a range of paediatric diseases with the goal to develop potential new therapeutic approaches.

In this Cell & Gene Therapy TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Giulia Massaro highlights her Repurposing TIN Pilot Data Fund awarded project, involving the use of chemokines as a novel target to improve peripheral nerve regeneration.

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

I am currently working on a project entitled: ‘Developing a novel gene therapy approach for the treatment of obesity’. This preclinical study proposes to design and test a gene therapy product that could provide an effective treatment for a disease that is a growing burden in society. The study will use viral vectors to deliver therapeutic genes to mouse models of obesity.

What is the motivation behind your project/therapeutic?

A large medical need exists for novel obesity treatments as rates continue to increase to worldwide epidemic status, with demonstrated association to cardiovascular diseases, diabetes, cancer and other disabling disorders. In the absence of a specific pharmacological treatment, lifestyle modification and bariatric surgery are the standard of care. However, this requires full participation of the parents in the case of children, and failure to maintain weight loss after intervention is often reported.

The development of a long-lasting gene therapy treatment will not only have a positive economic impact on the health system, but also impact personal and social aspects of morbid obese patients particularly for children and teenagers.

Can you highlight any challenges have you experienced as an early career researcher in the cell and gene therapy/translational research space?

I think it is not always easy to find your voice as a young researcher in such a crowded space as within science. In particular in a cutting-edge field like gene therapy, where the race to the next ground-breaking innovation or commercialisation is relentless, ECRs are often left behind. Personally, I have been incredibly lucky to be mentored by Prof Rahim and Prof Waddington, who supported my research, gave me the opportunity to present our work at a range of international conferences and involved me in different collaborations.

Why did you want to apply to the Cell & Gene Therapy TIN Pilot Data Fund? How has it helped you?

The TIN Fund is a great opportunity for an ECR to build a preliminary data package that can be used in future applications for grants and fellowships. This first step in gaining independence is essential to grow further as a researcher in the academic environment, allowing you to strengthen the personal and professional skills necessary to build a future career as successful principal investigator within the University.

Learn more about the support provided through the TINs

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

It was fun! I enjoyed the ‘Dragons’ Den’ format, with both academic and industry panellists. I also attended the ACCELERATE workshop led by Simon Cane, who gave us great tips on how to present our work in the 3 minutes interview. Plus, I got the chance to meet other ECRs working in different fields and hear about their research – keep it up guys!

Future applicants will also be offered this training. Learn more – Translational training from UCL ACCELERATE

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

My plan is to develop vectors and test these in models of the disease. The COVID-19 pandemic has obviously slowed down my research, particularly affecting the availability of consumables and limiting the access to the Biological Service Unit. Nevertheless, so far I have managed to test in vitro some vector candidates, with encouraging results. I am currently producing large scale vector batches that will be used in the future in vivo studies.

Gene therapy, with its possible long-lasting effects on weight management, has to potential to offer a unified single-treatment strategy for the obese patient population, including cases due to genetic, environmental and/or behavioural factors.

About Dr Giulia Massaro

Dr Giulia Massaro is a NIHR GOSH BRC Research Fellow in Translational AAV Technology at the UCL School of Pharmacy. After her MRes in Functional Genomics at the University of Trieste and the International Centre for Genetic Engineering and Biotechnology, she joined Prof. Ahad Rahim’s Lab at UCL to complete her PhD in Gene Therapy working on rare paediatric diseases of infants. Since 2013 she has been involved in many translational gene therapy projects, collaborating with both academia and industry, focusing on rare neurological disorders with unmet medical need.

In 2020 Dr Massaro opened the GTxNeuro Viral Synthesis Facility, a state-of-the-art vector production laboratory for research-grade viral vector batches, where she provides expertise and support for new and established researchers wishing to produce customised viral vectors.