|
Delivery systems, as well as drugs themselves, can influence gene expression,
Saghir Akhtar, University of Cardiff, warned.
He reminded conference delegates that drugs do not work by themselves
and need formulating. Much has been said about how genes influence the
response of a given drug. “We have probably forgotten about the
formulation. What does the formulation do and how critical will that
be in altering our prescribing habits,” he asked.
This is a question that Professor Akhtar has tried to answer. In laboratory
experiments his research group has shown that drug delivery systems alter
gene expression in cell culture and animal models. “They can actually
switch on or switch off gene expression. That seems fascinating to us,” he
said. He warned that these changes, which are not well understood, would
be important for gene medicines where only a single specified gene change
is sought by the clinician. “We need to take a step back and understand
why [these genetic changes are happening] and what are the consequences
to patients.”
He gave the examples of dendrimers and branched polyethyleneimines (PEIs),
formulations used to deliver gene medicines. When dendrimers are added
to cells in culture, genes are both up- and down-regulated. “In
some cases, this will lead to phenotypic changes that are quite obvious
very quickly,” he said.
One is programmed cell death, a chain of events triggered, not by a drug,
but by the delivery system.
Likewise, when branched PEIs are introduced into tumour cells in an animal
model, gene expression changes. Professor Akhtar reported that over 800
genes were upregulated and over 700 were downregulated in an array of
20,000 genes.
Laboratory results also suggested that excipients, already commonly used
in medicines prescribed today, can alter gene expression.
Professor Akhtar said that changes had been observed in a diverse range
of genes —from changes in ligands that are responsible for interacting
with cell-surface receptors and changes in the receptors themselves to
changes in signalling molecules.
What are the consequences of these gene changes on drug action and will
potential polymorphisms in the altered genes change clinical response
to drugs and their formulations? Professor Akhtar did not have the answers
to these questions but warned that pharmacists should be aware of the
influence that delivery systems can have on gene expression and drug
response.
|
The
Pharmaceutical Journal