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Early Career Innovators: Validating AAV Gene Therapies for Epilepsy, Cell & Gene Therapy TIN

Alina Shrourou23 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 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

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.

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: AAV Delivery in Dravet Syndrome, 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 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

Juan headsh

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.

Early Career Innovators: Novel Therapies for a Rare Metabolic Disease, Cell & Gene Therapy TIN

Alina Shrourou3 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 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

Ellie Crompton headshot

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.

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.

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

Alina Shrourou19 January 2021

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

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

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

Animated children asking questions about gene therapy

Young people asking questions about gene therapy in the animation ‘Gene Therapy explained: Changing our bodies’ recipe to treat disease’. Screenshot from an animation provided by KindeaLabs.

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

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

Why this Gene Therapy animation?

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

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

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

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

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

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

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

Young Persons’ Advisory Group (YPAG) at Great Ormond Street Hospital for Children

The Young Persons’ Advisory Group (YPAG) at Great Ormond Street Hospital for Children – young people making health care research for children better

Did you know?

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

Learn more in the full animation:

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

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

About the authors

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

About the Young Persons’ Advisory Group (YPAG)

YPAG logo

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

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

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

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

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

The Development of Gene Therapy for Infantile Neuroaxonal Dystrophy

Alina Shrourou14 May 2020

Dr Ahad Rahim is an Associate Professor of Translational Neuroscience and Associate Director of Research at the UCL School of Pharmacy. Dr Rahim’s group works on the development of novel therapies for neurodegenerative diseases and recently at the end of 2019, received an MRC DPFS grant of £654,904 to develop gene therapy for infantile neuroaxonal dystrophy (INAD).

Please provide an overview of infantile neuroaxonal dystrophy (INAD) and the need to develop a new therapy.

INAD is a devastating inherited neurodegenerative condition that affects children. It’s caused by mutations in a gene called PLA2G6 that encodes for an enzyme known as Phospholipase A2, which leads to neurodegeneration in the nervous system of patients accompanied by an inflammatory response. The downstream effect of that is cognitive decline and progressive motor disorder, which leads to death in the first decade of life.

The symptoms usually present between 6 months and 3 years of age, and patients are completely dependent on family, carers and the healthcare system for the duration of their lives. This, of course, has a very significant emotional and social burden.

Palliative care is currently the only way to respond to INAD, with there being no clinical treatment available for the condition. Therefore, there’s an overwhelming need to develop a new and effective therapy for INAD.

We work closely with Professor Manju Kurian at the UCL Great Ormond Street (GOS) Institute of Child Health and she is the clinical lead for patients with this disease. She sees patients living with the condition and is invaluable to our work. Professor Kurian and I have been working together for the last 4/5 years to provide proof of concept studies supportive of gene therapy for INAD.

Why have you identified gene therapy as a good treatment potential for INAD?

The theory of gene therapy has been around for quite a while but has taken almost a generation for it to develop into something that is clinical viable. UCL now proudly has many success stories of gene therapy clinical trials leading to spinout companies.

Visit the UCL Therapeutic Innovation Networks (UCL TINs) website for more gene therapy case studies.

So overall, we have a very good track record of gene therapy at UCL.

Gene therapy is revolutionising the way that we think about treating genetic diseases and although it has taken a while to get to this point, there have been some really pioneering clinical trials in neurological diseases similar to INAD. One example is spinal muscular atrophy where gene therapy has had life-saving effects. This success story in a neurological condition with gene therapy, have led us to investigate the use of gene therapy for other neurological diseases – INAD being one of them. We know which gene is defective in INAD, so we can investigate the use of gene therapy to deliver a healthy version of that gene to compensate for the defective version. We do this in the hope that this would cure the patient.

Therefore the three overwhelming considerations that make us think that INAD is a good candidate for gene therapy are: we know what the effected gene is, there is no other option available to the patient, and gene therapy has had a good effect in another genetic neurological condition.

What is AAV-mediated gene therapy?

Adeno-associated viruses (AAV) occur naturally; we have all been infected with AAV at some point and since they are non-pathogenic, you won’t even know you have it. AAV-mediated therapy involves delivering a gene for therapeutic purposes using a modified and safe AAV virus.

Getting genes into cells is not an easy task because our cells are designed with defensive mechanisms in place to prevent exogenous DNA from coming in and corrupting its own DNA. Therefore to be able to get your therapeutic gene into the right part of the cell that you want to correct, you need a vehicle or mechanism for it to get in – that’s where we use viruses like AAV.

Viruses are at the top of the food chain in terms of being able to deliver their genetic material into a cell. In order to exploit this ability for gene therapy, we take viruses like AAV, remove the bits which are potentially harmful, toxic or we don’t need, and we replace that with therapeutic genetic material – in the instance of INAD, it’s the PLA2G6 gene. We then use the virus as a trojan horse, as it now carries our therapeutic gene and delivers it into the cell effectively.

How will you optimise AAV9-mediated gene therapy for INAD as part of this DPFS project?

In mouse models, we have been able to show that AAV-9 gene therapy is effective by rescuing the mouse from premature death and reducing the loss of neurons in the brain. However, as always, there’s room for improvement in the vector. It is important to remember that due to size differences between a mouse brain and human brain, what you do in a mouse, is very different to what you do in a human being. What we want to do is give ourselves the best chance of therapeutic effect in that much bigger brain – and that is a challenge.

In this grant, we want to modify the AAV vector by improving elements of it. This includes the optimising how the gene is expressed once it’s delivered into the cell. We’re also looking at the best way of administering this AAV9 vector via different routes of administration to give the best coverage in a larger brain.

Can you describe the results from your proof-of-concept data that demonstrates therapeutic efficacy of this approach?

Over the past 4 years we’ve been working on a mouse model that has a mutation in the PLA2G6 gene. The model has very similar symptoms, levels of neurodegeneration and inflammatory response in the brain as human INAD patients do. This is important because what we don’t want to do, is study a mouse model that is not faithful to what happens in human beings. We have been able to confirm that that is a good model to be able to test future novel therapy on.

We then designed an AAV9 vector which carried the therapeutic human PLA2G6 gene and we administered this into the PLA2G6 deficient mice. We looked to see if there was an improvement in lifespan, locomotor function, behaviour and neuropathology.

We were pleased to find a significant improvement in all of the markers of therapeutic efficacy that we were looking for which showed benefit from the AAV9 gene therapy. That’s quite promising in such an aggressive model of neurodegeneration.

It was on the basis of that preliminary data that we applied to the MRC asking for funding to be able to take this further towards the clinic. If we make the AAV9 vector better, can we administer it in a way that is more efficacious and would be most beneficial one day in human beings?

What stage are you up to with your work?

Now that we have shown proof-of-concept in our work, we want to make further improvements on survival, locomotor function and neuropathology in the mice so that we develop the very best therapy in human beings and we know that there is room for improvement in the vector to achieve this.

The two year grant will allow us to do more preclinical studies – including large animal studies which will help give us a lot of information as to how it will work one day in humans.

Can you highlight any barriers to translation you have come across?

In the gene therapy community there are certain hurdles which exist as potential bottlenecks. As gene therapy is growing very quickly and is a massively expanding field, the availability of facilities to manufacture vectors for clinical use, is relatively few in number. They aren’t many places that can take a viral vector and produce it at the quantity, quality and purity that would be suitable to go into human beings.

If you think about the amount of gene therapy activity happening around the world – it’s a huge burden on those facilities, meaning that stakeholders are having to wait an extremely long time to get the vector manufactured at an acceptable grade which they can then use to run a clinical trial.

There needs to be more of these facilities and more people trained in gene therapy technology. I would say that we as academics, need to be training more people in gene therapy technology to provide the workforce for a field that is growing so quickly.

Another consideration is the business side of gene therapy. Sometimes there are patents on certain vectors or parts of a vector. This is a commercial necessity and you may need a license to use that particular technology. This is not a problem in itself, but is something else that we have to think ahead of when working in such a rapidly expanding field.

When you write MRC DPFS applications, there are very specific questions in the application around freedom to operate which UCLB were able to help us answer, including “What is the current IP issues around this?”, and “Do you foresee any problems in the future in terms of getting access commercially to these technologies?”. These are important questions to ask because the MRC want to be sure that whatever we are developing has a commercial exit strategy. It would be tragic if we develop a promising treatment but don’t have commercially viable routes to take it forward and get it to the number of patients that need it.

How has the UCL Translational Research Office (TRO) supported you in your work?

The TRO have helped a lot in many translational projects that have come out of my lab. I’ve worked with Translational Research Manager Dr Alethea Cope right from the beginning for every one of my projects, and she has been instrumental. Alethea has recently moved on from the TRO but I am fortunate to now have support from Dr Simon Eaglestone (UCL TRO Translational Research Manager) who has managed other gene therapy projects at GOS, which are now progressing to clinical trial.

These projects are often complex in the way that they are designed and lot of things that we’re doing are the first time anyone has tried them. Within our projects, it is a common need to contract out some of the work to contract research organisations (CRO’s) external to UCL.  This process requires a lot of time invested in terms of engaging with those CROs, making them understand what work we want to do, and getting quotes from them on very specialised/tailored work. Where the TRO have been really instrumental, is connecting me with the right CROs and allowing me to have that conversation with them.

The TRO are also very up to date and knowledgeable about what’s happening in general in the gene therapy field. They often know things that we don’t and so they are able to guide us in the right direction. For example, in the manufacturing of the clinical grade gene therapy vectors, the TRO know which facilities are perhaps in the best position to help us. Those nuggets of information are critical and are invaluable in helping us to succeed.

What are the next steps for this project?

Once this grant has ended, it will allow us to have more detailed conversations with the clinical community and with regulators who will assess our work and determine whether it’s safe for potential clinical translation. The link between my lab and clinicians like Professor Kurian is really important, and it will allow us to move along a well thought-out translational pathway and get this treatment to patients who badly need it.

About Dr Ahad RahimAhad Rahim

Dr Ahad Rahim is an Associate Professor in Translational Neuroscience and leads a research team at the UCL School of Pharmacy focussed on studying lethal or debilitating neurodegenerative disorders to evaluate disease mechanisms and develop novel therapies.

His team are involved in the pre-clinical testing of therapeutic modalities including gene and stem cell therapies, exosomes and small molecule neuroprotective drugs. Diseases and conditions being studied in Dr Rahim’s laboratory include Niemann-Pick disease type C, Gaucher disease, PLA2G6-associated infantile neuroaxonal dystrophy (INAD), Batten disease (CLN2, CLN3, CLN5, CLN6 and CLN7), Parkinson’s disease, neonatal hypoxic-ischemic encephalopathy and peripheral nerve damage.