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Alex Langford-Smith
I am a senior postdoctoral research associate with ten years’ experience of elucidating disease mechanism and developing novel drug, protein, viral and stem cell therapies for: neurodegenerative disorders, lysosomal storage disorders, mucopolysaccharidosis, age-related macular degeneration, ageing, vascular disorders, diabetes, systemic lupus erythematosus and atherosclerosis.
Achievements
· MBiochem Molecular and Cellular Biochemistry, Oxford University
· PhD Stem Cell Gene Therapy, University of Manchester
· 10 years of successful translational research, developing therapies for rare disease and age-related disorders, with 2 now in clinical trial
· Extensive experience of leadership, driving personal and collaborative research projects resulting in publication and funding
Research Experience
In 2006 I obtained a degree in molecular and cellular biochemistry (MBiochem) at the University of Oxford, I then moved to the University of Manchester and gained research experience working on chimeric receptor T-cell immuno-therapy at the Paterson Institute before starting my PhD in haematopoietic stem cell gene therapy in 2008. In January 2012 I completed my PhD and continued working as a post doctoral research associate in the same group until the end of 2012.
From 2013 until 2015 I worked as a post doctoral research associate in the group of Professor Tony Day, in the Wellcome Trust Centre for Cell-Matrix research at the University of Manchester. I determined the effect of age, environment and genetics on the Bruch’s membrane and identified pathways involved in age-related macular degeneration (AMD) pathogenesis, utilising transcriptomics and cell models.
From 2016 to 2018 I worked as a senior post doctoral research associate in the group of Professor Yvonne Alexander and Dr Fiona Wilkinson at Manchester Metropolitan University. I utilised endothelial colony forming cells (stem/progenitor cells) to understand the epigenetic influence of diabetes and ulcers on metabolic and angiogenic functions and evaluated the effect of stress and disease (systemic lupus erythematosus) on the number, function and miRNA content of endothelial microvesicles.
From 2018 I am a senior post doctoral research associate in the laboratories of Dr Stephen White at Manchester Metropolitan University and Professor Martin Humphries in the Wellcome Trust Centre for Cell-Matrix research at the University of Manchester. The aim of my current research is to define the mechanisms of normal and pathological force sensing by endothelial cell adhesion complexes. Using this information, we will determine the consequences of targeted interventions on endothelial detachment as a potential therapeutic strategy for atherosclerosis.
Achievements
· MBiochem Molecular and Cellular Biochemistry, Oxford University
· PhD Stem Cell Gene Therapy, University of Manchester
· 10 years of successful translational research, developing therapies for rare disease and age-related disorders, with 2 now in clinical trial
· Extensive experience of leadership, driving personal and collaborative research projects resulting in publication and funding
Research Experience
In 2006 I obtained a degree in molecular and cellular biochemistry (MBiochem) at the University of Oxford, I then moved to the University of Manchester and gained research experience working on chimeric receptor T-cell immuno-therapy at the Paterson Institute before starting my PhD in haematopoietic stem cell gene therapy in 2008. In January 2012 I completed my PhD and continued working as a post doctoral research associate in the same group until the end of 2012.
From 2013 until 2015 I worked as a post doctoral research associate in the group of Professor Tony Day, in the Wellcome Trust Centre for Cell-Matrix research at the University of Manchester. I determined the effect of age, environment and genetics on the Bruch’s membrane and identified pathways involved in age-related macular degeneration (AMD) pathogenesis, utilising transcriptomics and cell models.
From 2016 to 2018 I worked as a senior post doctoral research associate in the group of Professor Yvonne Alexander and Dr Fiona Wilkinson at Manchester Metropolitan University. I utilised endothelial colony forming cells (stem/progenitor cells) to understand the epigenetic influence of diabetes and ulcers on metabolic and angiogenic functions and evaluated the effect of stress and disease (systemic lupus erythematosus) on the number, function and miRNA content of endothelial microvesicles.
From 2018 I am a senior post doctoral research associate in the laboratories of Dr Stephen White at Manchester Metropolitan University and Professor Martin Humphries in the Wellcome Trust Centre for Cell-Matrix research at the University of Manchester. The aim of my current research is to define the mechanisms of normal and pathological force sensing by endothelial cell adhesion complexes. Using this information, we will determine the consequences of targeted interventions on endothelial detachment as a potential therapeutic strategy for atherosclerosis.
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leading to deficiency of acetyl-CoA: a-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate.
To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline
inactivation of the Hgsnat gene. At 6–8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was
detected at 10 months and at 12–13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal
accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells,
fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired
mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated
tau, and amyloid-b. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: a-glucosaminide Nacetyltransferase
causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine
release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type
C manifests primarily as a neurodegenerative disease.
Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4–9 months.
Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein.
Methodology/Principal Findings
We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed.
Conclusions/Significance
Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.
leading to deficiency of acetyl-CoA: a-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate.
To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline
inactivation of the Hgsnat gene. At 6–8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was
detected at 10 months and at 12–13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal
accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells,
fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired
mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated
tau, and amyloid-b. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: a-glucosaminide Nacetyltransferase
causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine
release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type
C manifests primarily as a neurodegenerative disease.
Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4–9 months.
Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein.
Methodology/Principal Findings
We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed.
Conclusions/Significance
Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.