Advancing knowledge of Alzheimer’s disease, towards novel therapies

Advancing knowledge of Alzheimer’s disease, towards novel therapies

Dr. Laura Aitken, a senior postdoctoral research fellow with Professor Frank Gunn-Moore’s group, is currently leading a Rosetrees-funded project that aims to identify novel drugs for Alzheimer’s disease, at the University of St Andrews. In this project Laura has been investigating the role of amyloid binding alcohol dehydrogenase, more commonly known as 17β-HSD10. She has validated its potential to act as a drug target. The hallmark, toxic protein in Alzheimer’s disease, amyloid, is a binding partner of 17β-HSD10. So, by inhibiting its activity, this could slow down or prevent the development of Alzheimer’s.

Earlier Rosetrees funding supported Professor Gunn-Moore’s team in discovering the consequences of this novel interaction, between 17β-HSD10 and amyloid. In the brain, the normal role of 17β-HSD10 is to help make energy. This process becomes dysfunctional in Alzheimer’s disease, which leads to the death of nerve cells. This takes place when glucose levels have decreased. Furthermore, they determined direct substrates of 17β-HSD10 allowing them to measure 17β-HSD10 activity in living cells. They also found specific fat (or lipid) changes in the brain that have been linked to pathogenesis of Alzheimer’s disease.

Following on from this work, Rosetrees begun funding Laura to expand the teams research into the more drug discovery aspect of Alzheimer’s disease. Here she successfully evaluated a series of potent compounds for 17β-HSD10 with a collaboration they had forged with partners in the Czech Republic. Laura also established several assays to test for cellular toxicity, and to assess the ability of the compounds to directly inhibit 17β-HSD10 in cells. This produced a pipeline of tests allowing them to subsequently rank their compounds in order of effectiveness, and lack of toxicity.

This is what Laura had to say:
“Currently, there are no disease modifying therapies for Alzheimer’s disease and the constant need to learn, improve and challenge our knowledge of the disease to achieve this has been a huge driving factor behind my research.”

In their current Rosetrees-funded research, Laura is now implementing this and testing their hit compounds in cells that are better models for Alzheimer’s disease. Using this approach, they can avoid the use of animal models. In their latest progress, they have established neuronal cell models, and began metabolomic studies to determine what energy production changes there are in these Alzheimer’s disease like cells and if this can be rescued on treatment with their compounds. They have also recently published in Molecules, showing their evaluation of a novel, different series of compounds, finding increased potency for these compounds compared to previously published data. This work with further characterisation in other Alzheimer’s disease models could become potential drugs.

Dr. Laura Aitken in TC

Laura also said:
“We really hope that our research, kindly funded by Rosetrees Trust, will lead to a major advancement in both our further understanding of Alzheimer’s disease and one day lead to a treatment for the disease.”

Written by: Dr. Rebecca Downing and Dr. Laura Aitken

A faster increase in ‘CAG’ repeats tends to give rise to early onset Huntington disease

A faster increase in ‘CAG’ repeats tends to give rise to early onset Huntington disease

Professor Darren Monckton, from the University of Glasgow, is the senior author of a study which has identified how genetic changes in the huntingtin gene contributes to Huntington disease progression. This disease is caused be an increase in the numbers of ‘CAG’ repeats in the huntingtin gene. The team have shown that the mutation expands over time, with faster growth tending towards early onset and rapid disease progression. Whereas, late onset disease was found in those who had ‘CAA’ interruptions in the CAG repeats, which slowed the rate at which CAG repeats grew.

Image from Marc Ciosi using ID 114793778 and 91801958 © Stepanenko Oksana | Dreamstime.com and ID 19477291 © Adrian Hillman | 123rf.com

The study has been published in EBioMedicine, and has been supported by a number of charities, including Rosetrees.

The findings from this research contribute to a greater understanding into the mechanisms of Huntington disease, and could have offer new potentials for the development of diagnostic testing.

Written by: Rebecca Downing

Investigating molecular targets for auditory system regeneration

Investigating molecular targets for auditory system regeneration

Professor Matthew Holley has received Rosetrees Trust funding to support a project that involved investigating molecular targets for auditory system regeneration, at Sheffield University. Dr. Tanaya Bardhan also worked on this project, as part of her PhD. They were interested in a signalling pathway influenced by a gene known as gata3, a zinc finger transcription factor which is a key regulator of auditory system development, to further understand the function of GATA3 in cochlear hair cells. For this project, the team used transgenic gata3 mice to determine the role of changing GATA3 expression levels on sensory hair cell development in the inner ear. They also wanted to find out more about specific signalling components, when GATA3 activity is altered.

They have published their findings from the project in The Journal of Physiology. They were able to show that gata3 is crucial for the survival of outer hair cells, as well as for the functional maturation of inner hair cells at the onset of hearing. In the context of work by others these results show that gata3 regulates specific, complementary aspects of development in different cells types to orchestrate the development of the auditory system. In a human condition known as Hypoparathyroidism, Deafness and Renal (HDR) anomaly syndrome, lower levels of gata3 cause severe hearing loss. In subsequent research, Professor Holley’s group has derived reporter cell lines that allow high throughput screening of drugs that can modulate gata3 and potentially compensate for gata3 deficiency. Once characterised, these lines may be of value to other conditions in which gata3 is implicated, for example some forms of cancer and allergic inflammation.

Hearing loss in a transgenic mouse in which gata3 has been deleted only from inner hair cells

Professor Holley said “Gata3 is a fascinating gene because it regulates many different processes in different tissues from the earliest stages of embryonic development through to the adult. Dissecting its function in different cell types allows us to start building a picture of how it coordinates development and how it might be targeted for therapeutic purposes in specific cells.”

Written by: Rebecca Downing and Professor Matthew Holley

Novel ways to identify HPV-driven head and neck cancers

Novel ways to identify HPV-driven head and neck cancers

Professor Ahmad Waseem is a Rosetrees Trust-funded researcher investigating the role of the Human Papilloma Viruses (HPVs) in head and neck cancers (HNSCCs). His team are based at Queen Mary University of London (QMUL), in the Centre for Oral Immunobiology and Regenerative Medicine, Blizard Institute, Whitechapel. This work originally formed the basis for Dr. Katarzyna Niemiec’s PhD, awarded in 2018 and subsequently Rosetrees Trust extended funding for a postdoctoral researcher, Dr. Deepa Avisetti, in conjunction with Queen Mary Innovation Ltd. To determine the potential patient benefit clinical collaborators involved in the project are Dr. Hannah Cottom (Barts Health NHS Trust), Mr. Zaid Sadiq (University College London Hospitals NHS Foundation Trust), Dr. Selvam Thavaraj (Kings College London), Professor Iain Hutchison (The Facial Surgery Research Foundation – Saving Faces) and Dr. Anand Lalli (QMUL). The team works closely with fellow QMUL head and neck cancer researcher Dr. Teck Teh and current PhD students Dr. Hebah Aldelahwi and Dr. Saima Usman.

Professor Ahmad Waseem and his research team

With Rosetrees Trust funding, the team are developing a novel way to identify the increasing number of HPV-driven HNSCCs, which is vital for improving cancer patient care. Their new biomarker could help identify which tumours have a better prognosis and permit patients to undergo less invasive ‘de-intensified’ treatment strategies with fewer side-effects. The team is currently validating their promising laboratory findings on patients HNSCCs tissues.

Discussing his research Professor Waseem stated “HNSCCs are the 6th most common cancers in the World and with improved awareness, close monitoring and early diagnosis, the incidence of most common cancers such as breast, lung and cervical are coming down. Worryingly the numbers of new HNSCCs are still rising in the UK and the developed World. The reason for this upward trend is most likely because of the involvement of high-risk HPVs. Fortunately these HPV-associated HNSCCs respond better to treatment with longer disease-free survival. Therefore de-intensification of treatment with fewer potential side effects whilst still producing better long-term outcomes is being proposed for HPV associated cancers. To do this we need accurate biomarkers to identify which patients can benefit most from reduced intensity treatments.”

The team have recently published a paper in Scientific Reports in which they characterised a monoclonal antibody and showed its usage in identifying adult epithelial stem cells in normal and cancer tissues. Their second paper published in BMC Cancer, provides the first evidence linking distinct molecular signatures in head and neck cancer with clinical presentations. This approach could aid clinical decision making as molecular signatures are widely used to guide treatment options offered to patients with other forms of cancer.

Written by: Rebecca Downing and Professor Ahmad Waseem