- Wade-Martins Group Research Group
I am a DPhil student on the 4-year BHF Studentship Scheme, jointly supervised by Dr Richard Wade-Martins and Professor Keith Channon. I obtained a First Class Msci (Honours) in Pharmacology at the University of Bristol graduating in 2012, which included a year working for GlaxoSmithKline in their heart failure department in Philadelphia.
My research is focused on novel molecular therapies for regulating the Low-Density Lipoprotein Receptor (LDLR), to lower cholesterol in patients of Familial Hypercholesterolaemia (FH). FH is a life threatening genetic disorder caused by loss of function mutations in the LDLR, where 1 in 500 people is heterozygous and one in a million is homozygous. FH patients require an aggressive lipid lowering treatment, with gene therapy showing limited success and many patients not achieving a desirable plasma LDL-cholesterol level on statins alone. Elevated levels of plasma Low-Density Lipoprotein (LDL) cholesterol is a major risk factor in developing cardiovascular disease, as it builds up in the arterial wall and accelerates the development of atherosclerosis.
Here we are working on a gene therapy approach which could complement the loss of the LDLR gene found in FH patients with a functional WT copy of the LDLR. Previously, labs have developed various viral delivery systems to introduce the LDLR into the liver, with strong heterologous promoters then driving expression of the LDLR. Use of these vectors does not provide maintained long term expression however and the constitutively active promoters means there can be no cholesterol feedback regulation. Using expression vectors which encompass all elements required for physiological regulation of the LDLR, we are developing a gene therapy approach which may be more of a long term therapy for FH patients.
In addition to this in collaboration with Dr Angela Russell’s laboratory (Department of Chemistry, University of Oxford) our laboratory has developed a number of molecules, which are able to upregulate the LDLR which could be used in addition to statins or as a monotherapy.
Episomal Nonviral Gene Therapy Vectors Slow Progression of Atherosclerosis in a Model of Familial Hypercholesterolemia.
Kerr AG. et al, (2016), Mol Ther Nucleic Acids, 5