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UCL Translational Research Office Blog



Early Career Innovators: Enhancing Stathmin-2 protein in Neurodegenerative Diseases, Small Molecules TIN

By Alina Shrourou, on 5 January 2021

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

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

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

What is the motivation behind your project/therapeutic?

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

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

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

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

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

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

Join the Small Molecules Therapeutic Innovation Network

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

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

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

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

What are your next steps from now?

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

About Benedikt Hölbling

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

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

Medical Devices Regulation (MDR) 2021 – Implications for the Devices Academic Community

By Alina Shrourou, on 9 September 2020

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Development of Gene Therapy for Infantile Neuroaxonal Dystrophy

By Alina Shrourou, on 14 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.