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Author Topic: Promising update on siRNA gene therapy  (Read 10835 times)

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Offline J220

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Promising update on siRNA gene therapy
« on: September 30, 2007, 08:28:58 AM »
From http://www.sciencedaily.com/releases/2007/09/070926172235.htm .A definite step in the right direction, as researchers have demosntrated that the use of siRNA (small interfering), as opposed to shRNA (small hairpin) RNA interference works to silence specific genes, without causing death of the mouse models as the latter did.

Full text:

Promising Genetic Therapy Uses RNA Interference

Science Daily — Researchers from MIT, Alnylam Pharmaceuticals and other institutions have demonstrated the safety of a promising type of genetic therapy that could lead to treatments for a wide range of diseases such as cancer.

The work, which will be published in the Sept. 27 issue of Nature, describes a new approach to conducting the therapy. A paper in Nature last year reported that another commonly used approach caused fatalities in mice.

The research focuses on RNA interference, or RNAi, a key part of the body's genetic machinery. RNAi works by using short strands of RNA to block the expression of specific genes.

"RNAi has huge potential as a therapeutic agent," said Daniel Anderson, a research associate at MIT's Center for Cancer Research and one of the authors of the new paper.

However, a paper published in Nature last year by a different team showed that large doses of one type of RNA used for RNAi, short hairpin RNA, disrupted another key RNA pathway, the microRNA pathway, and caused the mice in the study to die. That result worried some RNAi researchers, said Anderson.

"That first paper demonstrated that short hairpin RNA could lead to mouse fatality," he said. "Researchers were concerned that a second type of RNA, small interfering RNA (siRNA), would induce the same toxicity."

In the current study, the researchers demonstrated that siRNA did not have the same toxic effects as large doses of shRNA because it does not interfere with the microRNA pathway. Further, they achieved 80 percent silencing of target genes in mice and hamster liver cells.

"Using chemically synthesized siRNA, you can deliver sufficient siRNA to achieve therapeutically valuable gene silencing, without interfering with the cell's endogenous microRNA," said David Bumcrot, a director of research at Alnylam (an MIT startup) and one of the authors of the paper.

The research team used a new RNA delivery system developed at MIT, the details of which will be published in another upcoming paper, to perform the RNA interference.

In many RNAi studies, including the one that the MIT/Alnylam team was following up on, researchers use retroviruses to deliver genes that code for short hairpin RNA, which is a precursor to siRNA. Once the gene is incorporated into the cell's DNA, short hairpin RNA is synthesized and transported from the cell nucleus to the cytoplasm for further processing.

The earlier study showed that large amounts of short hairpin RNA blocked the cell's ability to export microRNA, which uses the same export pathway. Without normally functioning microRNA, the mice died. Low doses of short hairpin RNA were not toxic, but the dosage is difficult to control because once the shRNA gene is incorporated into the DNA of the host cells, it is expressed for long periods of time, said Bumcrot.

In the current MIT/Alnylam study, siRNA was delivered directly to the cell cytoplasm, so it did not compete with the export of microRNA.

"We wanted to demonstrate that if you go downstream of that (export) step in the pathway, you don't get interference with the microRNA pathway," said Bumcrot. "With synthetic siRNAs, we deliver a defined dose and we know how long the effect lasts. If toxicity issues arise, dosing can be stopped at any time. It's much easier to control and, therefore, safer."

Other MIT authors on the paper are Institute Professor Robert Langer and Michael Goldberg, a graduate student in chemistry. Researchers from the University of Texas Southwestern Medical Center and the Swiss Federal Institute of Technology are also authors on the paper.

The work at MIT was funded by the National Institutes of Health.


Note: This story has been adapted from material provided by Massachusetts Institute of Technology.

"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David


Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #2 on: October 18, 2007, 04:03:16 PM »
What I find so facinating about these animations is that for decades I always thought, yes there is dna, yes there is the double helix, yes there is genes and chromosomes etc, but what determines when and if they turn on and off, to express or not express to unwrap or stay bound up, these animations above and the speech explain all that, the siRNA, iRNA, microRNA, and RNAi and the other molecules that tend to them, with fun names like slicer and dicer, all do the work of the train yard workers in deciding what dna is active or not.  And the breakthroughs in this are happening weekly and treatments will come from this and are already coming in form of gene therapy and knowledge.  Perhaps a silencer RNA could be created.

Even if you are not a scientist take a look at the animations above.


Offline milker

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Re: Promising update on siRNA gene therapy
« Reply #3 on: October 18, 2007, 06:21:22 PM »
If you are interested in how this works, you may be interested by this book:

Molecular Biology of the Cell by Bruce Alberts

http://www.amazon.com/Molecular-Biology-Fourth-Bruce-Alberts/dp/0815332181/ref=pd_bbs_2/102-8243986-2936124?ie=UTF8&s=books&qid=1192745492&sr=8-2

It also comes with a CD with good animations & electron microscope pictures that help understanding the processes. This is a complex book, and it helps if you have biochemistry basics. However, as one of the reviewers says:

"It is a beautiful book, both from an aesthetic viewpoint and because of its content. The book reads more like a story than a textbook, but the information gain when reading it is considerable, with less entropy than what might be expected from such a deep subject with myriads of terms that must be understood before moving on to others. The author's approach to the book is well-organized, with many accompanying diagrams that illustrate the complicated processes and structures that can occur in the molecular realm. In addition, helpful summaries are put at several places in the book. There are no exercises in this book but there is a workbook that one can purchase separately."

Milker.
mid-dec: stupid ass
mid-jan: seroconversion
mid-feb: poz
mar 07: cd4 432 (35%) vl 54000
may 07: cd4 399 (28%) vl 27760
jul 07: cd4 403 (26%) vl 99241
oct 07: cd4 353 (24%) vl 29993
jan 08: cd4 332 (26%) vl 33308
mar 08: cd4 392 (23%) vl 75548
jun 08: cd4 325 (27%) vl 45880
oct 08: cd4 197 (20%) vl 154000 <== aids diagnosis
nov 2 08 start Atripla
nov 30 08: cd4 478 (23%) vl 1880 !!!!!!!!!!!!!!!!!!!!!!!!!!
feb 19 09: cd4 398 (24%) vl 430 getting there!
apr 23 09: cd4 604 (29%) vl 50 woohoo :D :D
jul 30 09: cd4 512 (29%) vl undetectable :D :D
may 27 10: cd4 655 (32%) vl undetectable :D :D

Now accepting applications from blowjob ninjas™

Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #4 on: November 25, 2007, 02:59:37 AM »
milker is there any new news on this   short interfering RNA

siRNA

and the other new RNA discoveries?

can you do a search on papers

or some of the other science guys

can you go to your sources and see if you find anything


Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #5 on: August 07, 2008, 01:27:57 PM »
http://www.sciencenews.org/view/generic/id/34998/title/Making_T_cells_tougher_against_HIV

http://www.eurekalert.org/pub_releases/2008-08/hms-rhs080408.php

http://www.eurekalert.org/pub_releases/2008-08/cp-hw080108.php

"Both prophylactic and therapeutic regimens proved successful," said Kumar. "Apparently, the siRNAs kept HIV from entering most T cells and kept it from replicating when it managed to slip inside."

Kumar and Shankar caution that labs need to confirm the findings in other animals, tweak the dosage, and tinker with the siRNA delivery vehicle before attempting clinical trials. In addition, the molecules degrade with time, so periodic shots may be necessary to maintain cellular immunity, precluding large-scale vaccination.

"I'm not saying we've developed tomorrow's therapy, but this is a major step forward," says Shankar. "We've used a small animal model for HIV and proven that RNAi works in that model."

John Rossi, a pioneer in RNA-based therapeutics who was not part of the study, hopes labs will use the new animal model to compare the side effects of potential and existing therapeutic regimens.

"The number one problem with the current antiretroviral drug regimens is toxicity," says Rossi, a professor at the Beckman Research Institute of the City of Hope. He wonders if siRNAs will eventually enable doctors to lower the doses of existing drugs in patients. Perhaps siRNAs will one day supplement or replace harsh antiretrovirals.

"Overall, I see this work as an exciting proof of principle," says Rossi. "This is a strategy that can be developed for clinical applications in humans."

###

This research is supported by the National Institutes of Health, the Korea Ministry of Education and Science Technology, and the Center for AIDS Research at Harvard.

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #6 on: August 07, 2008, 05:39:35 PM »
Nice Newsweek article based on the Nobel Prize winning technology.  Step by step by step by step by step....  Some day some of this gene based technology is going to play out in a big way.

http://www.newsweek.com/id/151217 
Beware Romanians bearing strange gifts

Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #7 on: August 08, 2008, 01:23:14 AM »
Professor Premlata Shankar of Texas Tech University, who carried out the work when she was at Harvard Medical School in Boston, said: "RNA interference has great potential as an antiviral treatment... We think it has real promise, but there is a lot more to be done."

The results are the first to demonstrate the success of RNA interference in animals. Priti Kumar, of Harvard Medical School, said: "No one has demonstrated before that HIV infection can be stopped in vivo, not just in cell lines, but in animals. It implies it might work in humans." Further animal studies, however, are needed before the approach can be used on humans in clinical trials. The discovery of RNA interference won a Nobel prize in 2006.
www.sciencedaily.com


http://www.sciam.com/article.cfm?id=researchers-silence-hiv-in-human-like-mice-rnai

The researchers used RNAi to block three genes: two found in the virus itself and one found in mouse T cells—the primary immune system cells infected by the virus. The T cell gene codes for a protein that HIV uses to get into and infect a cell. The team hitched the RNA segments to an antibody—a protein that specifically seeks out and attaches to T cells—to deliver their cargo.

In mice already infected with HIV, the amount of virus in the blood dropped significantly two and a half weeks after treatment. "We saw that the viral load was low in these animals [after treatment]," says Shankar. "It means maybe you're blocking transmission into other cells."

In animals that researchers treated with RNAi, the virus never seemed to take hold.

Because the RNA segments degrade over time, Shankar explains, this treatment would have to be done repeatedly. She suggests that it may one day be used as a supplement to anti-HIV drugs that are on the market that may help to lessen the amount of drugs—and side effects—patients have to put up with.

John Rossi, a molecular biologist at the Beckman Research Institute in Duarte, Calif., who was not involved in the research, noted that from his own work, using RNAi to treat T cells may allow patients to significantly reduce the dosage of the anti-HIV drugs—up to 100-fold. He agreed with Shankar that the RNAi method would not lead to a stand-alone treatment "The virus goes beyond T cells," he says, noting that it attacks several other types of immune cells. "It might be that the antibody is not going to get at these other cells, so it might not work without other antiretrovirals."

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #8 on: August 08, 2008, 08:05:39 PM »
One last article on this approach which expands a bit on the previous.

Note to sceptics: this has nothing to do with Dachshunds!

http://www.webmd.com/hiv-aids/news/20080808/gene-silencing-may-stop-aids-virus
Beware Romanians bearing strange gifts

Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #9 on: August 10, 2008, 03:54:01 AM »
http://www.topnews.in/health/new-gene-technique-stops-hiv-its-tracks-23889

The research team led by Prof. Premlata Shankar found that through new technique based on silencing genes HIV can be stopped in its tracks.

The positive point of this technique is that it doesn’t use toxic anti-viral drugs to fight HIV.

The study researchers discovered that through RNA interference, HIV infection can be suppressed. During RNA interference, where genes are artificially silenced by making use of a natural molecular switch in the cell, can slow down the duplication of HIV in human blood cells.

The researchers have conducted these experimentations on rodents.

“For the first time, we have used RNA interference to dramatically suppress HIV infection in an organism. RNAi has great potential as an antiviral treatment... We think it has real promise, but there is a lot more to be done,'' Prof. Premlata said.

In the lab experiments, the study researchers mixed the silenced RNAs with the antibody carriers and injected the mixture into the veins of the animals.

The researchers also said that further research has to be done on this subject.

Researchers have previously shown that siRNA aimed at HIV can shut down the AIDS virus in the test tube. It can also target the T cells HIV loves to infect, shutting the window through which HIV enters.

Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #10 on: August 19, 2008, 06:23:42 PM »

another peptide, and interesting genetic discovery will be announced at gallo's conference in September - the rate of discovery is EXPONENTIAL in science as the human genes reveal secrets
the link to entire article is worth a read -- perhaps this should have a new post because not perfectly related to siRNA


Viral Genetics, Inc. Unveils Potential Mechanism of Action in HIV/AIDS Research, Accepted to Present Findings at Prestigious IHV Meeting
Team Welcomes Attendees to Poster Session to Discuss Findings, Which Could Lead to Inexpensive, Effective HIV Therapy, and May Be Applicable to Autoimmune Diseases

Last update: 2:02 p.m. EDT Aug. 19, 2008
AZUSA, Calif., Aug 19, 2008 (BUSINESS WIRE) -- Viral Genetics, Inc. (Other OTC:VRAL), a biotechnology company that discovers and develops immune-based therapies, today unveiled a new theory regarding a potential mechanism of action, which could advance HIV/AIDS research and the development of an inexpensive, effective therapy for HIV. The study team says some of the study findings may also be applicable to autoimmune disease. Viral Genetics has been accepted by the Institute of Human Virology (IHV) to unveil and discuss its new model and findings at IHV's 11th Annual International Meeting in an interactive poster session. The prestigious conference, founded by Dr. Robert C. Gallo, who co-discovered HIV as the cause of AIDS and developed the first HIV blood test, will take place September 11-13th in Baltimore, Maryland. For more information on the conference, visit www.ihv.org  http://www.marketwatch.com/news/story/viral-genetics-inc-unveils-potential/story.aspx?guid={1E990E99-A89F-4DF4-B329-C6D805BFE087}&dist=hppr 

Viral Genetics has and continues to use TNP-1, a mixture of peptides derived from thymic histones, to research HIV/AIDS. When used in six international human clinical trials, including a double blind placebo controlled study in South Africa, results indicated that 25-35% of the HIV-infected population exhibited significantly reduced viral load and clinical improvement. During in vitro research, the study group found that individual peptides in the TNP mixture can bind to antigen-presenting cells and may be able to redirect the immune response. The long-term goal of the study is to obtain an IND for testing the newly identified and synthesized peptides or "targeted peptides" that can appropriately redirect the immune response to HIV.
"Our findings suggest that, with the proper predictions, we can synthesize targeted peptides to treat people with different types of MHC alleles providing potentially an inexpensive, biologically active therapy for HIV," added Newell.
The Immune Response to HIV: Friend or Foe?
"While the results in human clinical trials are promising, the challenge has been identifying the mechanism and the active component of the mixtures," said Newell. Targeted Peptides as a Therapeutic Strategy for HIV
Viral Genetics' working hypothesis is that treatment with custom-designed and predicted "targeted peptides," which will bind to the surface of the right white cells (antigen presenting cells) could, in turn, activate specific Tregs (a special category of T cells widely reported to dampen chronic inflammation). Dampening inflammation may be required to decrease the number of activated CD4 T cells that can become virally infected. The hypothesis is supported by recent findings showing that there is a correlation between the presence and numbers of Tregs and the length of time between initial infection with HIV and full-blown AIDS  .
"We are very excited after many years of research to finally have discovered what appears to be the promising mechanism of action that could optimize our treatment to its fullest potential. This also opens the door to a paradigm shift in thinking around HIV/AIDS therapies," said Monica Ord, SVP of corp. development and communications for Viral Genetics.

Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #11 on: August 26, 2008, 03:27:39 PM »
sounds to me like this is a very very big step in the right direction
http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html
watch this to learn about siRNA -- pbs special

Nature Reviews Immunology 8, 657 (September 2008
--expert in RNA-based therapeutics,
--Both prophylactic and therapeutic regimens proved successful.
--humanized mice, in which the mouse immune system is replaced with human immune cells,
--holy Grail' for research
--silence the expression of three genes specifically in T cells,
--deliver small interfering RNAs (siRNAs
--could be developed into a viable therapy.

http://www.nature.com/nri/journal/v8/n9/full/nri2411.html

Research Highlight

Nature Reviews Immunology 8, 657 (September 2008) | doi:10.1038/nri2411

In the news: Interfering with HIV

Olive Leavy

Developing an effective treatment for HIV infection is the 'Holy Grail' for many researchers. New evidence reported in Cell (7 August 2008) now shows that HIV infection can be dramatically suppressed in a mouse model using RNA interference.

The authors developed a new method to deliver small interfering RNAs (siRNAs) to silence the expression of three genes specifically in T cells, thereby limiting HIV infection. According to the lead author of the study, Premlata Shankar, "No one has demonstrated before that HIV infection can be stopped in vivo, not just in cell lines, but in animals." (The Independent, 8 August 2008).

The method involves linking the siRNAs to an antibody that is specific for T-cell-expressed CD7. The siRNA–antibody complex is rapidly internalized after binding to CD7, thereby delivering the siRNAs directly into T cells.

One of the siRNAs targets the surface receptor used by HIV to enter T cells (CCR5), whereas the other two siRNAs suppress viral genes. These siRNAs were delivered to humanized mice, in which the mouse immune system is replaced with human immune cells, allowing them to be used as a model of HIV infection.

"Both prophylactic and therapeutic regimens proved successful. Apparently, the siRNAs kept HIV from entering most T cells, and kept it from replicating when it managed to slip inside," says Shankar (Nature News, 7 August 2008).

John Rossi, an expert in RNA-based therapeutics, sees this study as "a nice proof of principle that ... could be developed into a viable therapy." (ScienceNews, 7 August 2008). However, more research is needed to "confirm the findings in other animals, tweak the dosage, and tinker with the siRNA delivery vehicle" before progressing to clinical trials, says Shankar (Biocompare, 8 August 2008).
----------------------------------------------------------

here are more links on
siRNA

#
Small interfering RNA - Wikipedia, the free encyclopedia
Most notably, siRNA is involved in the RNA interference (RNAi) pathway, ... When a mammalian cell encounters a double-stranded RNA such as an siRNA, ...
en.wikipedia.org/wiki/SiRNA - 71k - Cached - Similar pages The scientific community considers RNA interference the breakthrough biological discovery of the decade with the potential to change how diseases are treated. Sirna Therapeutics is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.
#
Sirna - RNAi Therapies - Revolutionary Science, Revolutionary ...
Develop treatments based on RNAi technology for asthma, diabetes, hepatitis C, macular degeneration and Huntington's Disease. Includes product pipeline ...
www.sirna.com
------------------------------------------------------------


http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html
see this video!!!   A PURPLE FLOWER MAY BE THE accidental breakthru that leads to the SOLUTION TO HIV -  FIGURES THE COLOR IS PURPLE -- does the universe have a sense of humor, isnt a teletubby gay purple?? lol
watch this video
http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html

siRNA all started in 1990 with a white and purple petunia plant - they were trying to make one white and it turned purple
and they discovered a new genetic switch   http://www.sirna.com/science_technology/timeline.html

1990   Over-expressing transgenes leads to "co-suppression" in plants Napoli C, Lemieux C, Jorgensen R. Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous gene in trans.

they got noble prize in 2006
http://nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html

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

I WROTE all about this stuff many months ago on my posts, search for siRNA or RNAi on this forum

 :) ;) :D ;D >:( :( :o 8) ??? :P :-[ :-X :-\ :-* :'(

of course it will take 3, 5 years to ten years to get to clinical trials in humans


Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #12 on: August 26, 2008, 03:31:08 PM »
they are already treating people with siRNA for Macular Degeneration

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #13 on: August 26, 2008, 06:34:17 PM »
The PBS video from "Nova" back in 2005, is pretty cool and does a good job at explaining to a layperson (in a somewhat cartoonish way) how RNAi works.  It's not long, about 15 minutes, and is well worth watching assuming you have any interest in learning how this approach works.  If you do choose to take a look, my suggestion is to right click and expand it up to full screen as this was far better on my computer. 

RNAi holds a lot of promise for the treatment of a variety of diseases by most accounts.  However, having said that, the challenges that lie ahead in applying the technology to HIV, Cancer, Hepatitis, etc., are quite large and seem to center around coming up with efficient and targeted non toxic delivery systems for the technology.  Research on a variety of approaches continues but it's not there yet.  Many experts are extremely optimistic about solving the delivery system puzzle, some less so.  Nevertheless it's an exciting technology that did win the Nobel Prize and has garnered hundreds of millions of dollars of investment over the past few years by companies large and small.  We'll see.
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Offline newt

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Re: Promising update on siRNA gene therapy
« Reply #14 on: August 26, 2008, 06:43:35 PM »
Anyone who sets hope in gene therapy or immune-based therapy reports needs to break out the deckchair and case or two of scotch for the wait cos this is such very difficult science and the HIV virus a wily fucker.  Gene therapy for Parkinsons or the like in my lifetime, yes, HIV, pass the whisky.

News reports is not science, its PR

- matt (44) the newt
"The object is to be a well patient, not a good patient"

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #15 on: August 26, 2008, 06:53:52 PM »
Your hard to please side is showing itself again, newt  :D

Not to be argumentative, but what I've cited in this thread are articles in WebMD and Newsweek plus the PBS "Nova" clip.  These hardly qualify as "press releases", particularly the Nova clip.  Look, I'm not a scientist and I'm guessing you're not either.  So what do we know, right?  And I'm not faulting your skepticism either; I think it's pretty much a pragmatic approach.  That said, you obviously paint anything of this sort with a pretty broad brush and my belief is in this case it's quite possible you're missing the boat a bit.  If you're interested in some sources of non "press release" information on this subject send me a PM (as not to clutter up the thread) and I'll be happy to comply.
Beware Romanians bearing strange gifts

Offline newt

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Re: Promising update on siRNA gene therapy
« Reply #16 on: August 26, 2008, 07:09:13 PM »
In my book peer review journal or conference proceedings plus Q and A from the audience = science, the rest = PR, WebMD included. Some science reporting is notably good, but even the BBC mainly lifts company/university press releases.

I have read much of the RNA original material, and, as a non-scientist who can read science, I say, in terms of HIV, deckchair please.

Non-toxic is a big claim, and the question to ask is non-toxic and effective for how many people? This is to date not answered properly. It is a pertinent question with ARVs and remains so with alternative treatments. Even in conditions where gene technology is more promising than HIV the % of people who may be helped is a fraction of all people who could.

All I am saying is these two areas, gene therapy and immune based science are so very difficult, I think the deckchair and whisky more helpful in the medium-long term, and certainly the short.

- matt
"The object is to be a well patient, not a good patient"

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #17 on: August 26, 2008, 07:20:07 PM »
Good points and good post.

Because I'm not a whiskey fan, I'll go with a few (dozen?) cases of Guinness.

Cheers, mate.
Beware Romanians bearing strange gifts

Offline leit

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Re: [OT] Promising update on siRNA gene therapy
« Reply #18 on: August 27, 2008, 09:14:18 AM »

Dear "newt",

I always read your posts and hold you in high esteem. So, I'd like to know what is, in your opinion, the most viable and shortest way to the solution (i.e. eradication or, at least, clinical remission) of the HIV/AIDS problem.

Thank you very much!

« Last Edit: August 27, 2008, 11:09:57 AM by leit »

Offline newt

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Re: Promising update on siRNA gene therapy
« Reply #19 on: August 27, 2008, 03:16:00 PM »
a tall question, but I will have a go at an answer, probably thereby annoying everyone.

Gimme a day or 2 to marshal my thoughts and references.

- matt (indeed "The Newt" but that's another story...) the newt
"The object is to be a well patient, not a good patient"

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #20 on: August 27, 2008, 04:20:55 PM »
probably thereby annoying everyone.



You?  The Newt?  No way!
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Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #21 on: August 27, 2008, 07:59:40 PM »
they are already delivering it to people in thier eyes!!!! one of the most sensitive places, with siRNA for Macular Degeneration

also, remember that a RNA fragment or an antibody (now commonly Rx's for a variety of conditions according to a Dr friend of mine) or a monoclonal antibody or a small molecule medicine are very very similar if they can be given in the form of an injection or a pill,  look at the incredibly complex structure and function of a Nuke, non nuke or protease inhibitor, check out the animations of what they do also

what i am saying is the steps are getting very small

it is not 1950 or 1980 or 1890 anymore

the real issue is turning the ship of state the giant ocean liner which is mfg pills and give in large quantities and change that to more complex therapies but they do that for many diseases

costs issues for mfg - and such

still remember 50 hiv people are dying per day in USA that is over 15000 per year and even with haart

so this is a very strong pull to treat them with something new if haart if failing

15000 people saved with a 2000 dollar per month siRNA treatment would mean 30 million/month  a 360 million/year for the therapy and it does not take much money to mfg a bio compound

they are already delivering it to people in thier eyes!!!! one of the most sensitive places, already
« Last Edit: August 28, 2008, 07:48:11 PM by bimazek »

Offline leit

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Re: Promising update on siRNA gene therapy
« Reply #22 on: August 28, 2008, 06:46:01 PM »

Gimme a day or 2 to marshal my thoughts and references.

Thanks, "newt". I'm looking forward to your reply!

« Last Edit: August 28, 2008, 06:55:32 PM by leit »

Offline Peter Staley

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Re: Promising update on siRNA gene therapy
« Reply #23 on: September 03, 2008, 02:48:19 PM »
News Flash...

Previous Claims of siRNA Therapeutic Effects Called into Question by Report in Human Gene Therapy
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/09-02-2008/0004877190

Offline leit

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Re: Promising update on siRNA gene therapy
« Reply #24 on: September 03, 2008, 11:28:23 PM »
Previous Claims of siRNA Therapeutic Effects Called into Question by Report in Human Gene Therapy
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/09-02-2008/0004877190

Maybe this is good news (the ability of siRNA to stimulate an innate  immune response...) disguised as bad.
What do you think?


Offline Peter Staley

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Re: Promising update on siRNA gene therapy
« Reply #25 on: September 04, 2008, 11:03:28 AM »
Frankly, I'm not expert enough to know.  (and am proud that I'm able to say that when it's the case)

Offline freewillie99

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Re: Promising update on siRNA gene therapy
« Reply #26 on: September 04, 2008, 12:38:55 PM »
Thanks for the article, Peter.  Here's a much more detailed, albeit sort of dry and technical, explanation of what the article is referring to.

http://rnaitherapeutics.blogspot.com/2008/09/rnai-therapeutics-and-innate-immunity.html

edit: btw, because this site also serves as an independent technical investment info source, there's a bonus for you!  yes, I read your bio  :)
« Last Edit: September 04, 2008, 01:16:37 PM by freewillie99 »
Beware Romanians bearing strange gifts

Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #27 on: September 19, 2008, 02:55:34 AM »
many more articles and quotes on this are in many more journals ......  all worth a read ... more good news  ....  this is the insights on the siRNA thru many interviews and papers...
This says it all,,,, this says why this may be a powerful technique for stoping hiv, because nature uses siRNA to stop viruses.  It is natures natural defense mechanism.....

"Nature would never leave something as valuable as genetic code unprotected. One of the security measures protecting DNA in plants and animals is a mechanism that fights viruses by shutting down their genes." siRNA

http://www.genomenewsnetwork.org/articles/06_02/hiv.shtml

Nature would never leave something as valuable as genetic code unprotected. One of the security measures protecting DNA in plants and animals is a mechanism that fights viruses by shutting down their genes. In plants the phenomenon is known as gene silencing, and it has been widely used to study plant genes. It has also been used to create transgenic tomato plants that are resistant to plant viruses.

Schematic presentation of the second step of the RNAi pathway. View larger
Courtesy H. Cargill

What works in tomatoes may also work in people. A number of laboratories are investigating ways to exploit the naturally occurring defense mechanism in humans to fight HIV, the virus that causes AIDS. A new study reports success in blocking the virus in cell cultures by silencing genes in HIV and human cells.

"We were able to inhibit the production of the virus either by blocking new infections or blocking the production of new viral particles in infected cells," says Judy Lieberman, also of the Center for Blood Research. "That's pretty encouraging."

The concept of silencing genes in HIV is straightforward: Hit the virus where it counts by eliminating a protein it needs to reproduce or cause infection. The human version of gene silencing has a different name—RNA interference, or RNAi—but the mechanism is fundamentally similar to the one in plants and involves some of the same proteins.

What makes RNAi so exciting to many researchers is its potential for knocking out a protein without harming the cell. By comparison, chemotherapy invariably kills tumors by destroying cancerous cells as well as healthy cells nearby.

"This method is extremely specific," says Lieberman. "You can shut off HIV without interfering with any genes other than the ones you target." Cells are basically missing 21 nucleotides—the RNA that is degraded—and the rest of the genome is untouched.
The researchers tested the plausibility of pre-loading human cells with siRNA as a way to protect against infection. They took latently infected human cells, activated the HIV genes and were still able to block the production of new viral particles. After entering a host cell, HIV inserts itself into the genome, where it can reside without expressing its genes.

As with the drug 'cocktails' that patients take to kill HIV at different stages of its life cycle, the most effective RNAi strategy will likely include multiple targets. These could be targets that block entry into the cell and disrupt the virus life cycle inside the cell. The effects of adding siRNA to cells are transient, and finding ways to deliver siRNA to human cells—or engineer cells to express them—remains a primary challenge for the field.

Researchers at the City of Hope Cancer Center in Duarte, California, recently developed a DNA-based delivery system. As reported in Nature Biotechnology, they generated human cells that produced siRNA against the REV protein, which is important in causing human disease. The fact that one suppressor protein works in two kingdoms is strong evidence that the silencing pathways in plants and animals are related, the team concludes in Science. Furthermore, the finding suggests that animal cells have used RNAi to protect themselves from viral attacks in a similar manner as plants.

"We show that RNAi is a natural antiviral defense," says Shou-Wei Ding, who led the study. "This is a kind of secret weapon inside us that we have not noticed until now. And one reason we haven't noticed it is that viruses contain proteins that suppress the weapon."


http://www.aidsrestherapy.com/content/2/1/1
Conclusions

Both CXCR4 and CCR5 coreceptors could be simultaneously targeted for down regulation by a single combinatorial lentiviral vector incorporating respective anti-coreceptor siRNAs. Stable down regulation of both the coreceptors protects cells against infection by both X4 and R5 tropic HIV-1. Stable down regulation of cellular molecules that aid in HIV-1 infection will be an effective strategy for long range HIV gene therapy.

Conclusions

For HIV/AIDS gene therapy strategies to succeed, novel molecules need to be harnessed. In this regard, siRNAs offer great potential. Exploitation of these promising candidates to down regulate essential cellular coreceptors via the use of lentiviral vectors facilitates long term derivation of resistant T cells and macrophages which are the main targets for the virus. Our results showed for the first time that expression of both CXCR4 and CCR5 siRNAs in combination is possible by the use of lentiviral vectors. Coreceptor specific siRNAs stably transduced with the bispecific lentiviral vector showed marked resistance against both T cell tropic and monocyte tropic HIV-1 infection in cell lines and primary PBMCs. The newly developed bispecific vector shows promise for potential in vivo application.




The findings from the HIV study — published Thursday in the journal Cell — may further validate the path toward eventual treatments being followed by a number of recent area startups, including Worcester-based RXi Pharmaceuticals Inc. (Nasdaq: RXII) and Dicerna Pharmaceuticals Inc. in Cambridge.

Billions of dollars in financing have been flowing into the rapidly expanding RNA interence (RNAi) arena, yet its therapeutic applications are still very much in their infancy.   http://www.masshightech.com/stories/2008/08/04/weekly15-RNAi-launched-against-HIV-in-mice.html

http://www.cell.com/content/article/abstract?uid=PIIS0092867408008210


http://www.nature.com/nm/journal/v8/n7/full/nm0702-659.html

http://www.retrovirology.com/content/2/1/63



http://www.citeulike.org/user/mapplab/article/3106237
Summary Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD7-9R) for T cell-specific siRNA delivery in NOD/SCIDIL2r[gamma]-/- mice reconstituted with human lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model.



http://64.233.169.104/search?q=cache:OC9DPdVtUFMJ:web.mit.edu/mcgovern/html/News_and_Publications/pas_020603.pdf+siRNA+hiv&hl=en&ct=clnk&cd=15&gl=us
This report is a first step in demonstrating that siRNA technol-
ogy can be used as a possible therapeutic strategy to inhibit HIV-
1 replication in host cells. Several RNA-based gene therapies are
being studied to complement current antiretroviral therapies
against HIV, including ribozyme and antisense approaches
During preparation of this manuscript, a vector-based strategy to
silence an HIV-1 gene was reported
 An siRNA to the rev regula-
tory gene was reconstituted in trans by independent transcrip-
tion of sense and antisense strands of the rev siRNA (ref. 43).
Vector-based strategies that target combinations of viral genes in
addition to cellular genes may provide a significant boost to
RNA-based antiviral therapeutics



http://web.med.harvard.edu/sites/RELEASES/html/080708_shankar.html
Kumar’s siRNAs halted T cell destruction in the mice, essentially stopping the virus in its tracks.

“Both prophylactic and therapeutic regimens proved successful,” said Kumar. “Apparently, the siRNAs kept HIV from entering most T cells and kept it from replicating when it managed to slip inside.”

Kumar and Shankar caution that labs need to confirm the findings in other animals, tweak the dosage, and tinker with the siRNA delivery vehicle before attempting clinical trials. In addition, the molecules degrade with time, so periodic shots may be necessary to maintain cellular immunity, precluding large-scale vaccination.

“I’m not saying we’ve developed tomorrow’s therapy, but this is a major step forward,” says Shankar. “We’ve used a small animal model for HIV and proven that RNAi works in that model.”

John Rossi, a pioneer in RNA-based therapeutics who was not part of the study, hopes labs will use the new animal model to compare the side effects of potential and existing therapeutic regimens.

“The number one problem with the current antiretroviral drug regimens is toxicity,” says Rossi, a professor at the Beckman Research Institute of the City of Hope. He wonders if siRNAs will eventually enable doctors to lower the doses of existing drugs in patients. Perhaps siRNAs will one day supplement or replace harsh antiretrovirals.

“Overall, I see this work as an exciting proof of principle,” says Rossi. “This is a strategy that can be developed for clinical applications in humans.”

This research is supported by the National Institutes of Health, the Korea Ministry of Education and Science Technology, and the Center for AIDS Research at Harvard.


Offline bocker3

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Re: Promising update on siRNA gene therapy
« Reply #28 on: September 19, 2008, 07:46:42 AM »
What works in tomatoes may also work in people.

 ???   ???   ???

One of the biggest leaps I've seen yet.  Of course plant cells and animal cells have a number of key differences between them -- the biggest one being the presence of a Cell Wall on plant cells.

Mike
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Offline bimazek

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Re: Promising update on siRNA gene therapy
« Reply #29 on: September 19, 2008, 10:13:26 PM »
i think this part of the above post as well as reading the entire post of each and every link above shows this is very powerful in humans -- and human vegetables. :o

"  "This method is extremely specific," says Lieberman. "You can shut off HIV without interfering with any genes other than the ones you target." Cells are basically missing 21 nucleotides—the RNA that is degraded—and the rest of the genome is untouched.
The researchers tested the plausibility of pre-loading human cells with siRNA as a way to protect against infection. They took latently infected human cells, activated the HIV genes and were still able to block the production of new viral particles. After entering a host cell, HIV inserts itself into the genome, where it can reside without expressing its genes.
Researchers at the City of Hope Cancer Center in Duarte, California, recently developed a DNA-based delivery system. As reported in Nature Biotechnology, they generated human cells that produced siRNA against the REV protein, which is important in causing human disease. The fact that one suppressor protein works in two kingdoms is strong evidence that the silencing pathways in plants and animals are related, the team concludes in Science. Furthermore, the finding suggests that animal cells have used RNAi to protect themselves from viral attacks in a similar manner as plants.
"We show that RNAi is a natural antiviral defense," says Shou-Wei Ding, who led the study. "This is a kind of secret weapon inside us that we have not noticed until now. And one reason we haven't noticed it is that viruses contain proteins that suppress the weapon."  "

 


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