Biotechnology Club

Can RNAi help us create healthy people and a healthy economy?

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Is it true? Can RNAi really cure genetic diseases?

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RNAi can treat infectious diseases.
Is this the end of pandemics?

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Can RNAi help eradicate difficult cancer?

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Cancer, HIV/AIDS, killer pandemic flu, blindness, Parkinsons, Alzheimers and Huntingtons get knocked down; there is a new class of weapons for the war on disease. This new type of medication is called RNA interference (RNAi) and it can be used to stop gene expression. It can stop gene expression when your own genes go bad or it can stop virus from expressing genes that are needed to be infectious. Even though RNAi is limited to controlling diseases that are caused by the expression of “bad” genes, we were far more limited before. RNAi when approved for prescription medication will reshape how we tackle genetic and infectious diseases. The first RNAi treatment may be on the market this year [1]. Potentially all virus infections and autosomal dominant genetic disorders could be treated by RNAi [8].

For an excellent video on RNAi and how it works go to PBS at:
http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html

For more information on RNAi use the links at the bottom of this page.

Can RNAi help us create healthy people and a healthy economy?

RNAi may yield:

- More productive, illness-free workdays for employees
- Independent and active lives for elderly Americans
- A higher quality of life for children

For RNAi it is about efficiency in medication design and treatment. RNAi with the proper delivery systems can be quickly designed to treat diseases [6].

Traditionally, the risk that a promising new treatment will not work out is large.

- High investment costs, one of the largest research industries
- Significant time and money is spent
- 12-15 yrs and an average of $800 million to develop
- One of every five dollars in revenue is re-invested into R&D
- On average only 5 out of 10,000 compounds make it to clinical trials
- Only one of those five is used for patients
- Only three of ten medications make revenues that exceed the cost of R&D
- Years of scientific education
- State-of-the-art research tools
- 12-15 years worth of research and development
The time companies have to recoup investments are shrinking due to branded and generic competition. Still, there is tremendous value in the pills. [2]

In any system resources are limited; reducing time and cost through efficiency in the design and implementation helps [4] RNAi move forward as a new tool for improvements in pharmaceutical design and will potentially provide independent and active lives for elderly Americans, a higher quality of life for children and more productive, illness-free workdays for employees [2].

Is it true?
Can RNAi really cure genetic diseases?

The most common cause of blindness is from macular degeneration (MD) and it is the first on the list to be treated with RNAi. There are two main reasons that MD was chosen for early trials with RNAi. First, eyes as an organ are easily accessible. The medication can be injected into the eyes right at the target. Second, in MD blindness is caused by a single, well known, gene VEGF (Vascular Endothelial Growth Factor) being over expressed. This gene is over producing protein that causes excess blood vessel growth at the back of the eyes. The blood vessels begin to leak, pooling blood clouds and may with time entirely block vision. In 2004 the first clinical trails ever were performed using RNAi to knock down genetic expression in vivo in humans. (Having injections in your eyes doesn’t sound pleasant but it is a good alternative to blindness.) The vision of all patients treated stabilized and 25% had significant improvement in vision. Early detection and treatment by RNAi should stop blindness from developing. MD has previously been untreatable. It is expected this treatment will be released this year as the first RNAi treatment ever. [1]

The promising results of RNAi on MD have not given scientists any reason to think they should stop at MD; diseases that are in tissues that are more difficult to access and are caused by more complicated pathways like neurological disorders are being tested with RNAi. The neurological disease Parkinsons is traditionally treated by treating the symptoms. Now, RNAi may be able to stop the genes that cause the damage thereby stopping the progression of the disease, not just the symptoms [5]. RNAi can give us hope for Parkinsons and other neurodegenerative disorders like Alzheimers, and Huntingtons [8]. Systems designed to stabilize the RNAi and target it to the diseased tissue will make these more complex diseases treatable [6]. There are approximately 2000 known autosomal dominant genetic disorders [7]; these could potentially be treated with RNAi [8].

RNAi can treat infectious diseases.
Is this the end of pandemics?

Infectious diseases such as HIV, Malaria, or even pandemic killer flues (H1N1, H5N1), may be treated by the use of RNAi therapy.

Now, Judy Lieberman, Harvard Medical School professor of pediatrics at Children’s Hospital Boston and the Immune Disease Institute has designed and tested on mice an ointment using RNAi to stop Herpes from being able to infect. The ointment could be applied as long as a week before sexual intercourse or within a couple of hours afterward steps are being taken to begin human clinical trials [9]. The same technology could be directed to stop HIV infections.

The World Health Organization estimates that each year 300 to 500 million cases of malaria occur and more than 1 million people die of malaria. Five targets are identified in the host parasite that cause malaria, all of which resulted in significant reductions in infection in vitro when silenced with RNAi. One of these key targets, PKCzeta was selected for evaluation in vivo. RNAi against PKCzeta was delivered in mice by the use of liposomes and observed loss of PKCzeta function in vivo which led to decreased infection rates by approximately 80%. [10]

When the next killer flu pandemic breaks RNAi may stop it from spreading. In the early part of the 20^th century the pandemic bird flu, H5N1, caused millions of human deaths and no one knows if the swine flu, H1N1, may mutate into a highly leathal form or when H5N1 will return.  RNAi design can be done very quickly and specifically for any of the mutant strains that may threaten us. Computer algorithms have been designed so that you can simply enter the sequence of the targeted gene and you receive a list of RNAi designs for that gene. While still on the computer you can place an order for the actual RNA which could begin being synthesized immediately. If systems are designed in advance for stable delivery of RNAi into the patient, then the RNAi knock down could be individualized quickly for any mutant form the next pandemic virus might take.

Can RNAi help eradicate difficult cancer?

Cancer such as skin cancer can be completely treated by surgery. But there are some cancers such as lung cancer [12], ovarian cancer [3] and brain cancer which do not have lifelong treatments [11]. Treatments such as radiation, chemotherapy and other drugs available have severe side effects and they often do not work. From all the data available, it is clear that RNAi has great potential for the treatment of evasive cancers with less or no side effect compared to traditional treatments in part do to the appropriate delivery systems [6] of RNAi to silence the over expressed genes.

One of the latest reports (April 03, 2009) from the Alnylam pharmaceutical informed that it has started the phase I clinical trial of RNAi for the treatment of liver cancer [8]. Annually, more than 1 million people are diagnosed with liver cancer and this cancer has a minimal survival rate. From the successful pre-clinical trial in mice model, they generated RNAi to target two genes: Kinesin spindle protein (KSP) and VEGF (Vascular Endothelial Growth Factor) which are found to cause tumor proliferation and growth respectively [8]. Scientists are confident that ALN-VSP (RNAi) will pass the clinical phase I in human successfully.

RNAi Summary and Links

There are hundreds of paper and articles regarding the effectiveness of RNAi treatment of diseases both in vitro and in vivo. The information that we provided is just a small portion of those papers. The areas being worked on are improvement on stability, safe delivery, reduction of off-target and non specific effect. RNAi is a new treatment for infectious, genetic, and cancerous diseases. It is estimated that some RNAi treatments in the pipeline will be available by 2012 [8].

Links to references:

1. Nova scienceNOW RNAi PBS
www.pbs.org/wgbh/nova/sciencenow/3210/02.html

2. What goes into the cost of prescription drugs
www.phrma.org/files/Cost_of_Prescription_Drugs.pdf

3. RNA interference can suppress ovarian tumor growth
http://web.mit.edu/newsoffice/2009/ovarian-cancer-0209.html

4. The Effect of Managed Care on Hospital Cost Efficiency: Estimating Efficiency from Frontier Model with Panel Data.
http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102272124.html

5. RNA interference meets brain disease : Article : Nature
Gene Therapy – RNA knockdown as a potential terapeutic strategy
http://www.nature.com/nrn/journal/v5/n1/full/nrn1318.html

6. Alnylam and Collaborators at MIT Publish Research on the  Discovery of Lipidoids, a Novel Class of Lipid-Based Molecules for the Delivery of RNAi Therapeutics
http://www.drugs.com/clinical_trials/alnylam-collaborators-mit-publish-research-discovery-lipidoids-novel-class-lipid-based-molecules-4099.html

7. Classes of genetic disease >> Diseases associated with single-gene Mendelian inheritance >> Autosomal dominant inheritance
http://www.britannica.com/EBchecked/topic/228874/human-genetic-disease/242824/Autosomal-dominant-inheritance

8. Alnylam Pharmaceuticals RNAi Project Pipline

http://www.alnylam.com/Programs-and-Pipeline/index.php

http://www.alnylam.com/Programs-and-Pipeline/Product-Platform.php

http://phx.corporate-ir.net/phoenix.zhtml?c=148005&p=irol-newsArticle2&ID=986093&highlight=

9. Harvard Makes Topical RNAi Treatment That Can Effectively Stop the Transmission of Herpes
http://nextbigfuture.com/2009/01/harvard-makes-topical-rnai-treatment.html

10. IMM, Cenix, and Alnylam Discover New Targets in Malaria Infection with RNAi Technology
http://www.drugs.com/clinical_trials/imm-cenix-alnylam-discover-new-targets-malaria-infection-rnai-technology-6183.html

11. NCBI National Center for Biotechnology Information
http://www.ncbi.nlm.nih.gov/pubmed/15927361

12. Study on new lung cancer therapy by RNAi targeting molecular charactersitics of cancer cells
http://sciencelinks.jp/j-east/article/200510/000020051005A0212292.php