Physicians' Academy for Cardiovascular Education

Animal study first step towards long-term gene therapy for homozygous FH

News - May 30, 2016

Researchers at the University of Oxford have shown that a non-viral gene vector that targets both the gene for the LDLR and the gene for the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), substantially reduces LDL-C in an animal model. After 12 weeks there was also significant slowing of atherosclerosis. The results may suggest future potential for patients with familial hypercholesterolaemia (FH) who are homozygous for mutations in the LDLR gene and are at extremely high risk of heart attacks.

The cumulative burden of etremely high LDL-C levels present since birth in homozygous FH leads to accelerated atherosclerosis. As a result, undetected individuals with homozygous FH often have their first heart attack by early adolescence, especially if the mutations that they carry result in non-functional LDL receptors.

Early detection and initiation of lipid-lowering treatment are essential for management of homozygous FH. Statins, together with lifestyle intervention, are the mainstays of treatment, usually with the addition of ezetimibe and other treatment. Lipoprotein apheresis can provide further LDL lowering, and additional new treatments are now available, such as the MTP inhibitor lomitapide, and the PCSK9 inhibitors evolocumab and alirocumab, and the antisense oligonucleotide that targets apolipoprotein B100 mipomersen in the USA. However, all of these have disadvantages and evolocumab is not indicated for homozygous FH patients with null LDL receptor activity.

The possibility of a gene therapy for FH has intrigued researchers working in the field. Previous attempts have focused on delivering a functional copy of the LDLR gene, using various viral delivery systems (single viral vectors). Lead author Alastair Kerr (Medical Sciences Division, University of Oxford) says in a press release: ‘Many attempts at gene therapy for FH have traditionally used viral delivery systems which just constitutively express the LDLR gene. However, in the ideal world we wouldn’t want to just deliver a functional copy of the LDLR gene but also restore physiological regulation of the gene.’

To address this, the researchers decided to build a combined non-viral vector, containing the human LDLR gene promoter, which drives expression of the LDLR gene, and a small non-coding RNA molecule (microRNA), which targets HMGCR. The microRNA shows that a lowering of intracellular cholesterol will further drive expression of the LDLR gene and is therefore responding in a physiological way.

This combined vector was tested in an animal model of hypercholesterolaemia. In one study (in mice lacking the LDLR gene and fed a 1% cholesterol diet), the researchers showed significant reduction in both total and LDL cholesterol after 2 and 4 weeks when compared with single vector controls. In a separate study (the same mouse model fed a 0.25% cholesterol diet) maintenance of LDLR gene expression was seen after 12 weeks, significant reduction of total and LDL cholesterol, as well as slowing of atherosclerosis.

The study is very much early days and further development of the delivery system for use in larger animals is needed. For now, these findings offer the tantalising possibility of a long-term gene therapy for homozygous FH patients.


Press release 84TH European Atherosclerosis Society Congress, May 30, 2016, Innsbruck Austria. Abstract: EAS16-057043. A novel combination non-viral vector to treat familial hypercholesterolaemia (FH). Kerr A, Tam L, Cioroch M, Hale A, Douglas G, Channon K, Wade-Martins R.