Associate Professor Geoffrey Krissansen is one of the first recipients of the inaugural HRC Explorer Grants. Although just 6 months have passed since the grant recipients were announced, Dr Krissansen and his colleagues at the University of Auckland are excited about the prospects of their new drug delivery platform designed to combat certain incurable genetic disorders.
Dr Krissansen’s research team have developed a novel drug delivery platform based on a cell-penetrating peptide called Xentry, which is derived from the hepatitis B virus. Xentry can be used to deliver drugs directly to layers of cells called epithelia. These cells line organs and glands such as the skin, and respiratory and gastrointestinal tracts.
Funds from the Explorer Grant are helping the team test whether Xentry-based technologies could potentially combat two particularly cruel incurable diseases arising from single gene defects: cystic fibrosis, which affects epithelia in the lungs, and hereditary diffuse gastric cancer (HDGC), which affects epithelia in the stomach.
Both cystic fibrosis and HDGC are associated with high morbidity and lead to premature death.
The Xentry drug delivery platform, which is patented by the University of Auckland, is being employed to replace mutated proteins encoded by single genes with the normal proteins.
Dr Krissansen says that part of what makes Xentry so special is its extremely small size and unique structure.
“Large molecules don’t get across the plasma membrane of cells, which is a big problem for the pharmaceutical industry. If you can’t get inside the cell, then you can’t reach many potential drug targets,” says Dr Krissansen.
“Xentry is a tiny peptide. Its functional core is only four amino acids long, whereas most other cell-penetrating peptides are made up of between 10 and 20 amino acids. It’s also a new class of cell-penetrating peptide that can make its way across the cell membranes of virtually any cells – except, unlike all other cell-penetrating peptides, circulating blood cells. This is a distinct advantage because it means the peptide doesn’t get diluted by blood cells following intravenous delivery.”
The team’s studies in mice have shown that Xentry is taken up very strongly into epithelial cells lining the stomach, bowel and lung.
In the case of cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupt its function, which leads to mucus build up in the lungs. Dr Krissansen and his team plan to replace the mutated CFTR protein with a normal protein by using Xentry to deliver therapeutic cargoes by an intravenous route.
“It’s believed that you would only need to restore 10 per cent of the CFTR protein’s activity back to normal to treat someone with cystic fibrosis,” says Dr Krissansen.
HDGC is a whole different scenario though, says Dr Krissansen. Whereas with cystic fibrosis you inherit a copy of the defective gene from both your mother and father, with HDGC you only need to inherit a defective E-cadherin gene from either your mother or your father. Even though you still have a ‘good’ copy of the gene, this can be deactivated to become ‘bad’ – and does so in about 80 per cent of cases.
Dr Krissansen’s research team is seeking to use the Xentry peptide to deliver a good copy of the E-cadherin gene to HDGC patients. This poses a real challenge because all of the epithelial cells in HDGC patients’ stomachs have a copy of the bad gene. This means they need to restore the epithelial cell function of as many cells as possible. The more cells they can repair, the lower the risk of cancer.
To date, Dr Krissansen’s team have a cell line from both a cystic fibrosis patient and a HDGC patient, and are testing whether they can restore the expression of the CFTR and E-cadherin genes in these cells. Once they’ve finished the cellular studies, they plan to move onto animal studies, hopefully towards the middle of 2014.
“We know Xentry can deliver large cargoes into the cell. We’re now trying to improve its release from the cell’s endosomes into the cytoplasm.”
Dr Krissansen says they are trying to see how far they can push the technology.
“It’s still only early days, but I personally believe cell-penetrating peptide technology will eventually transform medical practice.”