1. The early stages of my career were spent investigating the influence of target-derived neurotrophins upon neurons of the cholinergic basal forebrain and how this altered during development, different stages of maturation and in aging. This revealed significant new information about how in these different contexts neurotrophins such as NGF, BDNT and NT-3 variably influenced neuron survival, or phenotype. This was a prelude to investigating the same issues in a mouse model of Down syndrome, revealing that the failure of retrograde transport of NGF contributed to the apparent loss of cholinergic neurons, but that these ‘phenotypically silent’ neurons could be rescued by administration of NGF.

2. The first phase of my work on the neuronal ceroid lipofuscinoses (NCLs or Batten disease) involved answering fundamental questions about how the brain is affected and the staging of pathology in these disorders. This work for the first time defined which neuron populations are affected, revealing that it is remarkably selective in the early stages of pathogenesis. The first vulnerable neuron population to be identified was GABAergic interneurons, followed by the staging of neuron loss within the thalamocortical system, which revealed the thalamus as an unexpected pathological target in these disorders. We also demonstrated the selective effects upon populations of cerebellar neurons, and have continued this work to reveal an unexpectedly severe pathology in the brainstem and spinal cord. More recently we have revealed the involvement of the peripheral, autonomic and enteric nervous systems and are investigating their contribution to disease outcome.

3. Following these discoveries we have been working to understand the selective nature of neuron loss in the NCLs and what might influence this. By comparing the relative timing and distribution of neuron loss to storage material accumulation, astrocytosis and microglial activation we have learnt fundamental lessons about the

staging of NCL pathogenesis and how it differs between disease subtypes. There appears to be no direct correlation between neuron loss and storage material accumulation. Instead there is a much closer correlation

between glial activation and neuron loss, with either astrocytosis or microglial activation consistently preceding

neuron loss, leading us to investigate the nature of neuron:glial interactions and how they may be compromised. Our work has provided evidence that glia are dysfunctional and may directly compromise neuron health, resulting in neuron loss. These studies have highlighted that while different forms of NCL share broad pathological similarities they differ fundamentally in many respects.

4. We have been using the disease landmarks gained through these neuropathological studies to test the efficacy of a variety of pre-clinical experimental therapies. Indeed, we are increasingly asked to undertake this work by a wide-network of academic and industrial collaborators around the world. As such, we have played key roles in studies of gene therapy, neural stem cell transplantation, enzyme replacement, and a variety of small molecule approaches. These include glutamate receptor antagonists, immunosuppressants, and antiinflammatory compounds, with an increasing focus on trying different combinations of experimental therapies in order to potential increase their efficacy. Most recently we identified that treating the brain and spinal cord has a powerful synergistic effect in a mouse model of Cln1 disease. This work has led to several clinical trials including that of mycophenolate mofetil in Cln3 disease, neural stem cell transplants in Cln1 and Cln2 disease, and a successful enzyme eplacement trial in Cln2 disease, which has just been approved by the FDA and EMA as the first ever treatment for CLN2 disease.

Our goal is to perform cutting-edge research to understand and treat Batten disease and other lysosomal storage disorders, while advocating for equity and representation within and beyond the lab.

This includes providing mentorship that ensures lab members are thoroughly trained to approach scientific inquiry in a methodical and hypothesis-driven manner, while simultaneously fostering the development of skills necessary to empower themselves and to accomplish their career goals.  

We also aim to foster an environment that values and rewards collaboration, sharing and teamwork, providing equal opportunity for all.

We welcome ALL races and ethnicities, ALL religions, ALL countries of origin, ALL sexual orientations, ALL genders, ALL ages and abilities