분자유전학실험실 (단국대학교 분자생물학과)



 이성욱 ( 2009-12-04 13:41:21 , Hit : 4221
 RNA Silencer Shows Promise for Hepatitis C

By Martin Enserink
ScienceNOW Daily News
3 December 2009

Researchers have come up with a completely new way to thwart hepatitis C: Go after the host, not the virus. Genetically silencing a small piece of RNA in chimpanzees effectively suppresses the hepatitis C virus (HCV), a new study shows--and the virus appears unable to become resistant to the treatment. But experts caution that the approach needs to be scrutinized carefully for side effects.
New drugs against HCV are badly needed. More than 170 million people worldwide have contracted the virus, which is transmitted primarily via injection drug use and through the transfusion of blood and blood products. The virus slowly scars the liver, leading to liver failure and sometimes liver cancer.

The standard treatment, a combination of two antiviral drugs called pegylated interferon-α and ribavirin, takes 24 to 48 weeks, can cause a range of side effects, and fully eliminates the virus in only 50% to 80% of patients. Pharmaceutical companies are developing several new antiviral drugs, including so-called polymerase and protease inhibitors, but the virus can become resistant to these quite easily.

The new study builds on a discovery published in Science in 2005 by Stanford University virologist Peter Sarnow and his colleagues. The team found that HCV depends on a tiny piece of RNA that is produced by the host and involved in the regulation of hundreds of genes, many of them related to cholesterol and lipid synthesis. Exactly what the "micro-RNA" snippet, called miR-122, does for the virus is still unclear; it may boost its replication or stability, or it may somehow protect it from the immune system.

Sarnow's work led Santaris Pharma, a biotech in Hørsholm, Denmark, to develop a candidate drug that can block miR-122. The compound, called SPC3649, is a short piece of artificial DNA that blocks miR-122 in mice and in green African monkeys. But those species don't get hepatitis C.

In the new paper, published online today in Science, the researchers tested the drug in four chimpanzees, the only nonhuman animal that gets HCV. The chimps had been infected with HCV in previous studies at the Southwest Foundation for Biomedical Research in San Antonio, Texas. Two of them were injected weekly with a low dose of SPC3649 for 12 weeks, the other two with a high dose.

The high dose reduces the amount of virus in the chimps' liver by more than 99.5%, the researchers found. (With the lower dose, one of the animals had a smaller decline, whereas the other responded poorly.) Needle biopsies from their livers, taken while the animals were anaesthetized and examined under a microscope, showed that the treatment resulted in more healthy-looking tissue. Throughout the study, there were no signs of resistance; the virus didn't rebound as the weeks passed--as often happens with other drugs--and there were no genetic changes in the place where the virus binds to miR-122. Targeting a host micro-RNA may be a smarter strategy than targeting a viral protein, says Santaris's Vice President and Chief Scientific Officer Henrik Ørum, because the virus cannot modify the host the way it can its own genes.

"It's a very nice proof of principle," says virologist Ben Berkhout of the Academic Medical Center in Amsterdam; the reduction in viral load is "very robust," he adds. Stanley Lemon of the University of Texas Medical Branch in Galveston, a co-author on Sarnow's 2005 paper, agrees. But he warns that with a drug that regulates the expression of so many genes--including some cancer-related ones--there are serious concerns about side effects. None were observed in the study, but still, "if I were leading a pharmaceutical company looking where to invest my money, I might be worried about that," says Lemon.

Ørum agrees that there is a risk, but he points out that hepatitis C is a life-threatening disease and that the hope is that patients would only have to take SPC3649 for a limited time, presumably with another drug, before they clear the virus. Santaris has completed a phase I study of the drug--in which safety is tested in healthy human volunteers--but the results have not been published.

Meanwhile, it's unclear whether the same strategy can have any use in other infections, says virologist Bryan Cullen of Duke University Medical Center in Durham, North Carolina, because currently no other virus is known to be dependent on a human microRNA. "I keep hearing rumors about other papers out there," says Cullen. "But for the moment, this is a unique case."

------------------------------------------------------------------------------------

Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection
Robert E. Lanford,1,* Elisabeth S. Hildebrandt-Eriksen,2,* Andreas Petri,2,* Robert Persson,2 Morten Lindow,2 Martin E. Munk,2 Sakari Kauppinen,2,3,* Henrik Ørum2,

The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. Here, we show that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia with no evidence for viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes (IRGs), and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.

1 Department of Virology and Immunology and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA.
2 Santaris Pharma, Kogle Allé 6, DK-2970 Hørsholm, Denmark.
3 Copenhagen Institute of Technology, Aalborg University, Lautrupvang 15, DK-2750 Ballerup, Denmark.
* These authors contributed equally to this work.


To whom correspondence should be addressed. E-mail: hoe@santaris.com




--------------------------------------------------------------------------------
Received for publication 24 June 2009. Accepted for publication 30 October 2009.







927   저발현성 암 감수성 유전자 동정  정흥수 2003/08/27 4280
926   선천성 면역을 강화하는 새로운 백신 개발을 이끄는 초파리 연구  관리자 2007/03/17 4267
925   레티노이드의 항암 효과 증진 기작 확인  정흥수 2003/11/12 4267
924   암세포 성장을 정지시키는 새로운 기술  정흥수 2004/03/31 4266
923   DNA 수복의 오류가 헌팅턴병을 초래  관리자 2007/05/01 4255
922   실험실에서 만들어진 암 줄기세포  이성욱 2008/04/14 4250
921   각막 조직을 하나의 간세포로부터 재생시키는 것에 성공  관리자 2007/03/17 4244
920   당뇨와 암의 연관성  정흥수 2003/09/30 4244
919   암 세포 확산을 야기하는 단백질 변형 동정  정흥수 2004/01/11 4241
918   "올 항암제·당뇨병약 개발 주력"  송민선 2007/01/30 4240
917   세포 분화 관련 유전자 규명!  관리자 2010/04/12 4235
916   건강한 뇌세포 생존을 증진시키는 줄기세포 사멸  정흥수 2003/08/27 4234
915   화 잘 내는 사람은 따로 있다.  정수진 2006/03/22 4223
914   유전자치료의 핵심인 유전자전달체 "꿈의 의술" 유전자치료의 핵심인 유전자전달체의 국내특허출원은 내국인이 최다  정흥수 2003/08/31 4223
  RNA Silencer Shows Promise for Hepatitis C  이성욱 2009/12/04 4221
912   흡연을 하면 노년기에 실명할 가능성이 높아져  정흥수 2004/03/18 4211
911   종양 성장을 억제하는 DNA 효소  정흥수 2003/09/09 4209
910   마리화나 중독을 차단하는 식물 추출물  관리자 2007/05/31 4206
909   방사선 손상 막는 단백질 규명…원자력 의학원 이윤진씨  정흥수 2003/10/08 4206
908   ribozyme그림이다 [1]  정흥수 2003/08/26 4203

[이전 10개] [1]..[11][12][13][14][15][16][17] 18 [19][20]..[64] [다음 10개]
 

Copyright 1999-2021 Zeroboard / skin by ROBIN