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Early Career Innovators: Cell Replacement Therapy in Alzheimer’s Disease, Regenerative Medicine TIN

Alina Shrourou11 August 2021

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

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.

Early Career Innovators: Spatial Transcriptomics to Better Understand Stem Cell-derived 3D Hepatospheres (3D Heps), Regenerative Medicine TIN

Alina Shrourou5 August 2021

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.

Join the community and subscribe to the TINs newsletter to keep updated on when the next TIN funding calls open

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

Hassan Rashidi headshot

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.

Early Career Innovators: Correcting platelet defects in Wiskott Aldrich Syndrome (WAS), Cell & Gene Therapy TIN

Alina Shrourou16 June 2021

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.

Dr Rajeev Rai

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.

Early Career Innovators: Novel Gene Therapy for Obesity, Cell & Gene Therapy TIN

Alina Shrourou27 May 2021

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.

Giulia lab

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

Giulia headshot

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.

Early Career Innovators: Improving Nerve Regeneration with Chemokine Receptor Inhibitors, Repurposing TIN

Alina Shrourou5 May 2021

In this Repurposing 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 Guillem Mòdol Caballero highlights his 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?

The title of my project is “Chemokines as a novel target to improve peripheral nerve regeneration”. Treatments for nerve injuries have changed little over the last few decades and have significant limitations. The Lloyd lab, of which I am a part of, has previously identified Schwann cells, the major glial cells of the peripheral nervous system (PNS), as orchestrators of peripheral nerve regeneration. Recently, the Lloyd lab has identified a chemokine as a Schwann Cell chemotactic factor, secreted after nerve injury, that is likely to be important in directing the regeneration process. Nerve injuries are frequently associated with aberrant nerve regeneration that can lead to the formation of neuromas and neuropathic pain. Our goal is to determine whether using a chemokine receptor inhibitor, we can limit the Schwann Cell migration that leads to aberrant nerve regeneration and reduce the associated pain response.

What is the motivation behind your project/therapeutic?

The incidence of peripheral nerve injury is estimated to be between 13 and 23 per 100,000 people per year in developed countries. Currently, surgery is the conventional approach to repair nerve injuries but when there is a significant gap between nerve ends, an autologous nerve graft (autograft) is used. Although this is the current gold standard for treatment, autografts present several limitations and engineering strategies such as artificial nerve conduits have not been able to significantly improve the results. The unmet patient need include an often incomplete sensory and motor function recovery, neuroma formation or development of intractable neuropathic pain. Therefore, there is an urgent need to develop alternative approaches to treat peripheral nerve injuries and to prevent maladaptive regeneration, such as during tumour formation or neuroma development.

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

I started working in the translational research space during my PhD and I would highlight that a particular challenge is the funding limitation. Even when the therapies results are promising and are likely to be taken to the clinic, this limitation could even slow down the research. Additionally as an early career researcher, another challenge I have faced is finding collaborations with pharmaceutical companies to help develop these therapies.

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

Considering our last findings on the nerve regeneration process, we wanted to take our research towards the clinic. I thought that the Repurposing TIN Pilot Data Fund scheme would be the perfect fit to carry out this project since we wanted to use a marketed drug, and it would allow us to explore its potential as a treatment for nerve injuries associated with aberrant nerve regeneration.

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

The process for the TIN Pilot Data Fund was exciting and really fast. First, I attended the ACCELERATE training workshop and it helped me understanding not only what was required for the particular funding schemes but also the translational path. I also learnt how to be more concise with my scientific ideas when writing the application. My proposal was then shortlisted for a pitching event where we had to present our project. We received a brilliant training session that allowed me to learn how to address the pitch and connect with the audience. Overall, it was a great experience that will help me applying for future grant applications, especially for translational awards.

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

I hope to elucidate whether the treatment with the chemokine receptor inhibitor has an effect limiting the Schwann Cell migration that leads to aberrant nerve regeneration in our nerve injury model. The results obtained will allow us to improve the understanding of the nerve regeneration process. I hope this study will help us achieve more funding in the future to bring this potential therapy closer to the clinical translation. This could represent a major breakthrough in the peripheral nerve regeneration field due to the current treatment limitations.

About Dr Guillem Mòdol Caballero

Guillem Modol

Dr Guillem Mòdol Caballero is a neuroscientist that works as a Research Fellow in the Lloyd Lab, at the Laboratory for Molecular Cell Biology (LMCB) at UCL. During his PhD at Universitat Autònoma de Barcelona he evaluated the therapeutic benefits of delivering Neuregulin 1 (NRG1) to the central and the peripheral nervous systems, as a strategy to treat amyotrophic lateral sclerosis (ALS).

After finishing his doctoral studies Dr Mòdol Caballero joined the Lloyd Lab in 2019- experts in PNS biology. He is now focusing on understanding the complex multicellular interactions required for peripheral nerve regeneration and developing therapeutic modalities to take this research towards the clinic.

Early Career Innovators: Blocking LRG1 in Pancreatic Cancer, Biologics TIN

Alina Shrourou23 October 2020

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 DritsoulaDr 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 CamilliDr 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!