UCL Research Projects

Investigating the role of balance in people living with Kennedy’s Disease

Falls are commonly reported by people with KD posing significant risks of injury and leading to activity avoidance and reduced mobility over time due to fear of falling. Despite these challenges, balance and falls remain underexplored in KD. Understanding the factors contributing to poor balance is essential for developing targeted rehabilitation interventions, enabling more effective and pragmatic treatment approaches tailored to this condition. To begin to address these questions, Dr Louie Lee is conducting two preliminary research studies exploring balance in KD, supported by funding from KDUK.

The first is investigating the frequency and circumstances of falls in people with KD. As yet, the frequency and causes of falls have not been studied specifically in this population, and neither has the provision of therapy aimed at falls prevention or management. The second study is a qualitative exploration of the lived experience of balance and falls in people living with KD. To provide appropriate rehabilitative support to persons with KD there is a need for a more in-depth understanding of how they experience the circumstances around their falls, reactions, and consequences for daily life, as well as strategies to overcome perceived adversities. Recognising obstacles and catalysts to physiotherapy and exercise in people with KD may augment the efficacy of efforts in falls prevention and can inform the design of appropriate intervention programmes.

These studies aim to build a foundation for clinical practice and future research on balance rehabilitation, offering insights that can directly inform the development of specialised support for people living with KD.

Developing a human experimental model of Kennedys Disease

In order to investigate the underlying causes of any disease, including KD, and to develop potential treatments, it is important to have reliable experimental models. Typically, scientists have relied on either cells grown in a dish (cell culture models), or on animal models (usually mice) which have been genetically modified to express the disease-causing mutation, and which develop some or all features of the human disease.

Although these models have been extremely useful and have provided much insight into the underlying pathological mechanisms of KD, it is not clear how relevant these results are to the human disease.

In recent years, there has been an important development in modelling of diseases, which involves reprogramming of human stem cells – special cells that have the ability to become ANY cell in the body. It is now possible to take skin biopsies from patients and reprogram the stem cells present in these skin samples into motor neurons, which can then be grown in a dish and examined. With support from KD-UK, Dr Helen Devine is currently generating stem cell-derived motor neurons using skin samples taken from KD patients. We will use these human stem cell-derived motor neurons from KD patients to investigate the pathways and mechanisms that are disrupted in KD, which will help provide the basis for development of novel therapeutic strategies for KD treatment. In addition, growing patient-derived motor neurons in a dish will enable us to test any potential therapy in human cells for the first time.

Investigating changes in gene expression in KD motor neurons

The underlying cause of KD is known to be a mutation in the gene that codes for the Androgen Receptor (AR). The AR protein is particularly important because it plays a role in the regulation of the expression of a large number of other genes. Mutations in the AR will therefore alter the function not only of the AR, but also of the other genes whose it expression it normally controls. It is therefore likely that much of the pathology of KD is due to changes in genes other than the AR itself.

We have been studying changes in gene expression in motor neurons induced by mutation sin the AR. Using a mouse model of KD that recapitulates the key features of KD, including motor neuron degeneration and muscle weakness, we have identified several genes and key pathways altered at an early stage of KD, both in embryonic motor neuron cells grown in a dish, as well as hindlimb muscle from mice. Our aim now is to establish the consequence of the changes in these specific pathways and how they impact on the course of disease. Additionally, we may able to manipulate these genes and pathways to alter the symptoms of disease in our model of KD.

We are also isolating spinal cord motor neurons from adult mice at different stages of the disease to determine important genes and key pathways altered at early stage of the disease and identify targets that may be triggering the onset of KD.

The results from the study of mouse motor neurons at different stages of disease will be compared to those from the patient stem cell-derived motor neurons developed by Dr Devine as part of the Project described above.

Examining the role of muscle in KD

Although widely accepted as a motor neuron disorder, it is now becoming increasingly clear that muscle may be directly affected by the disease, independent of any loss of motor neurons, and may therefore play an important and key role in initiation and progression of disease.
In order to identify what goes wrong in muscle in KD patients, we are looking at the genes and molecular pathways that may be involved in the early stages of muscle wasting in KD. We will undertake a screen of all the genes and key pathways of disease that are altered in limb muscles of KD patients. By analysing the expression of genes from muscle biopsies of KD patients, as well as muscle from mouse models of KD at different stages of disease, we aim to identify and characterise the dysfunctional pathways present in limb muscle.

Developing a biomarker of disease progression in Kennedys Disease: Muscle Imaging

The development of novel therapies for motor neuropathies requires reproducible outcome measures, which can monitor disease progression with high sensitivity to minimize the size and duration of clinical trials. Muscle ultrasound (MUS) imaging is being widely used as a safe and non-invasive diagnostic tool in neuromuscular conditions to visualise skeletal muscle and quantify tissue properties. Quantitative muscle magnetic resonance imaging (MRI) is also an excellent candidate technique due to its reproducibility and observer independence. MRI is now applied ubiquitously to characterise diseases of the central nervous system, but as yet to a much lesser extent in neurodegenerative motor neuron diseases (MND).

Currently, there are no commonly accepted imaging indicators of disease activity and progression in motor neuron diseases. The purpose of the project is to collect image sequences to identify whether MRI and ultrasound-derived muscle features are useful indicators of disease progression which can be used as outcome measures in future interventional trials to evaluate novel therapies in motor neuron disorders.

We aim to validate the use of two new methods for identifying and monitoring skeletal muscle changes, as a marker of disease progression in patients with amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). Using muscle magnetic resonance imaging (MRI) and muscle ultrasound (MUS) imaging technology as non-invasive clinical imaging techniques, we aim to perform imaging of different muscle regions (head and neck, upper and lower limbs). We aim to identify changes in muscle properties that occur as a result of neurodegenerative diseases in patients with ALS and SBMA as well as in healthy volunteers. Furthermore, we will collect detailed clinical data and repeat imaging assessments after 6 and 12 months.