Research - Cholesterol lowering drug offers hope in treating hepatitis C (4 news stories)

March BBC News
Scientists say they have taken a major step towards a new generation of drugs for many conditions, including cancer. Writing in Nature, a Danish team said they had "silenced" key genetic material in cells called RNA, thought to play an important role in disease.

Working on monkeys, they cut the animals' cholesterol levels by silencing strands of micro-RNA in liver cells controlling its metabolism. Previous tests had only been carried out in a test-tube, or on rodents. The study holds out hope for the treatment of liver diseases.

The team from the Copenhagen-based drug firm Santaris Pharma are aiming to use their findings to develop a treatment for Hepatitis C rather than high cholesterol, for which there are already a number of effective treatments.
But they say the technique could ultimately be employed to treat a range of conditions, including certain types of cancer, cardiac diseases and metabolic problems like diabetes.

The treatment is based on the idea of silencing certain types of RNA, which scientists have increasingly come to understand as the main regulator of what goes on in a cell.

Types of RNA have been identified which have been associated with disease. There is evidence to suggest, for example, that levels of one form of RNA are extremely elevated in lymphomas, and that they are not just a symptom but a driver of the disease. Silencing them could therefore prove an effective treatment, if not a cure.

The experiment featured in Nature shows for the first time that it is possible to employ this silencing technique in non-human primates. African green monkeys were injected with a drug aimed at silencing microRNA-122, which is known to have a role in the production of cholesterol. After three doses over five days, their cholesterol levels were lowered by 30% - an effect which lasted for three weeks.

"What's more, there appeared to be no associated signs of toxicity to the liver or kidneys," said Joacim Elmen, part of the Santaris Pharma team.

However, the side-effects of silencing RNA remain unknown. While the team hope to use their findings to develop a treatment for Hepatitis C, which is also regulated by microRNA-122, it is unclear what the implications of permanently lowering both "good" and "bad" cholesterol at the same time would be. This would in any event be one of the known side-effects. There may be others which are not yet apparent, including the risk of developing liver cancer, admits Dr Keith McCullagh, the head of Santaris Pharma. "We are going to have to take it slowly, but it is nonetheless a possibility that we could have something on the market within five years," he said.

Dr Mike Gait, of the MRC Laboratory of Molecular Biology in Cambridge said: "This exciting paper is the first to show activity in monkeys of an important new class of designed molecule that can interfere with an essential RNA that controls specific genes in the liver.
"There are great prospects for future drug development both for liver diseases and other disease types, and Europe has the potential to match the USA in this area."

27 March Reuters London Ben Hirschler

A new class of drug that fine tunes the action of genes has been shown to cut cholesterol in monkeys and may fight a range of ills, including hepatitis C and perhaps cancer, scientists said on Wednesday.

The compound, from Danish biotech firm Santaris Pharma, works by blocking or "silencing" microRNAs -- tiny strands of RNA, or ribonucleic acid, that help turn genes into proteins.

The ground-breaking study is the first demonstration of microRNA silencing in primates and an early endorsement of the technique. Phase I safety trials are now planned in humans.

Unlike other drugs in the hotly pursued RNA interference field, the new designer molecule, known as Locked Nucleic Acid (LNA), can be given as a simple injection rather than having to be delivered direct to affected tissue.

"We think LNA is a one-stop shop for silencing," Santaris Chief Executive Keith McCullagh told reporters.

Scientists from Santaris and the University of Copenhagen lowered total cholesterol in African green monkeys by up to 30 percent, without ill effects, by targeting a microRNA linked to genes in the liver that are involved in cholesterol metabolism.

The results were published in the journal Nature, along with other test-tube research showing that LNA effectively blocks the production of hepatitis C virus in human liver cells.

Santaris intends to test its first LNA compounds in humans by the middle of this year but it will take at least five years before any medicine is ready for submission for approval.

While the cholesterol effect is interesting, McCullagh said the most promising opportunity actually lay in pursuing LNA as a treatment for hepatitis C, a poorly treated viral disease that can cause serious liver damage.

Further ahead, LNA could also have a role to play in other infectious diseases, as well as cancer and autoimmune disorders, since many disease-associated genes are regulated by microRNAs.

"There are great prospects for future drug development both for liver diseases and other disease types, and Europe has the potential to match the USA in this area," said Mike Gait at the MRC Laboratory of Molecular Biology in Cambridge.

27 March The Independent Steve Connor
A drug that can lower cholesterol levels and prevent the liver from being attacked by the hepatitis C virus has come a step closer following a successful trial on laboratory animals.

The drug works in an unusual way by interfering with the natural genetic mechanism in the cells of the liver that keeps cholesterol levels high and – coincidentally – allows the hepatitis virus to replicate within the organ. The study, which was carried out on African green monkeys, lowered cholesterol levels by up to 40 per cent over three months with the help of just three intra-venous injections given over five days at the start of the trial.

Each injection contained a watery solution of a short, single-stranded molecule of RNA – a close relative of DNA – which found its way to the liver and bonded with a similar type of RNA which is found within the organ's cells. This prevented the natural RNA from working normally, boosting the activity of certain genes, which lowered cholesterol and blocked the hepatitis C virus.

The study, published in Nature, was carried out by the Danish drug company Santaris. Scientists believe the findings support the idea of a new generation of drugs based on the ability to interfere with the natural functions of RNA.

Human trials of the new drug are expected to begin later this year.

March 27 The Guardian James Randerson - science correspondent
A new class of medicine that could ultimately have applications in the treatment of cancer, diabetes, multiple sclerosis and psychiatric conditions has been tested successfully in monkeys. The treatment for hepatitis C is due to begin human testing later this year and could be available to patients in five to six years.

The new drug targets a recently discovered mechanism that cells use to fine-tune the levels at which genes are expressed. Scientists have already shown that the mechanism is involved in numerous conditions including leukaemia, lymphoma, some types of heart disease and diabetes so the success of the new treatment so far will offer hope that a similar approach may be successful for other conditions.

The new drug, which has been developed by a Danish company called Santaris Pharma, works by sticking to molecules in cells called microRNAs which regulate genes.

Keith McCullagh, president and CEO of Santaris Pharma, said: "MicroRNAs are very exciting as targets for drug treatment in disease because they are known often to be perturbed up or down in disease."

"This subject area has been exploding in the last few years," said Dr Mike Gait, an expert in microRNA at the Medical Research Council's laboratory of molecular biology in Cambridge.

Gait, who was not involved in the research and has no financial interest in any company working in the area, said one question mark was whether, by affecting numerous genes, the drugs would have unwanted side-effects. "So far from what I have seen it looks quite promising," Gait said. "We won't actually know until it gets towards the clinical trial stage."