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

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

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

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

What is the motivation behind your project/therapeutic?

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

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

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

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

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

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

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

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

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

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

What are your next steps from now?

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

About Benedikt Hölbling

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

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