Navigation Links
For Stanford scientists, RNAi gene therapy takes two steps forward, one step back

Three years ago Mark Kay, MD, PhD, published the first results showing that a hot new biological phenomenon called RNA interference was an effective gene-therapy technique in mice. That finding kicked off an RNAi gene therapy research flurry amongst both academic and industry research groups.

Now, with three human RNAi gene therapy trials under way, Kay's initial excitement is proving to be on target. However, reaching this point hasn't been without challenges. In the latest twist, Kay, professor of genetics and of pediatrics at the Stanford University School of Medicine, and postdoctoral fellow Dirk Grimm, PhD, report an unexpected side effect of another type of RNAi gene therapy not on trial - mice in that study suffered liver toxicity from the treatment and some died. Despite that initial result, to be published in the May 25 issue of Nature, Kay and Grimm went on to find a way that shows promise in resolving this side effect.

"Just like any other new drug, it is just going to mean that we need to proceed cautiously," Kay said.

In traditional gene therapy the inserted DNA produces a gene to replace one that carries a mutation. In hemophilia, for example, the inserted gene makes a protein that is missing in the blood of people with the disease. RNAi gene therapy has the opposite effect. The inserted DNA produces a molecule called an shRNA, which turns off an overactive gene.

With key genes shut off, viruses such as hepatitis B, hepatitis C or HIV are unable to multiply and cause disease. However, some reports had suggested that RNAi gene therapy might induce an immune reaction or switch off the wrong gene or genes.

As these concerns faded, things began looking up for RNAi with three RNAi therapies now in human trials - two for macular degeneration and one for a type of pneumonia. However, these studies involve simply infusing the RNAi molecules into the eye or lung. The RNAi effects in these therapies aren't permanent. Instea d, patients may need to receive repeat doses of the RNAi.

If RNAi is going to be viable as a therapy for organ-wide diseases such as hepatitis B or C, it will have to stick around. Kay and Grimm felt they needed to show that the shRNA molecule made by the therapeutic gene would continue to be safe if it existed in high levels in a tissue over long periods of time.

Instead of proving the safety of RNAi gene therapy, the pair found that persistent, high levels of the shRNA made the mice sick, and in some cases the mice even died.

The problem, it seems, is that in the process of shutting down the viral genes, therapeutic shRNA molecules also hijack the cell's normal RNAi machinery. With that machinery otherwise engaged, it's not available to carry out its normal role in the cell.

"One benefit of RNAi gene therapy is that it uses the body's own machinery, making it an effective approach," Kay said. "However, the detriment of RNAi gene therapy turns out to be that it uses the body's own machinery."

Nonetheless, Grimm and Kay bypassed the toxic effects by producing the therapeutic shRNA molecule at lower levels. They were able to prevent the human hepatitis B virus from replicating in mouse liver for more than half a year after a single therapy using this technique. Kay and Grimm said they have more work to do to learn the best way of making shRNA at levels high enough to be effective as gene therapy but low enough to avoid toxicity in humans.

Kay said that cancer and viral diseases such as AIDS or hepatitis B and C are likely targets for future RNAi therapies. In order to get to these trials, Kay said he and Grimm would need to work out what caused the toxic effects in mice and further develop strategies for circumventing that reaction. He expects that trials already under way will help him and others figure out the best way to bring RNAi gene therapy safely to humans.


Source:Stanford University Medical Center

Related biology news :

1. Same mutation aided evolution in many fish species, Stanford study finds
2. First real-time view of developing neurons reveals surprises, say Stanford researchers
3. Stem cells from brain transformed to produce insulin at Stanford
4. Stanford gut check shows diversity of intestinal ecosystem
5. Young Blood Revives Aging Muscles, Stanford Researchers Find
6. Stem cell training program to make its Stanford debut
7. Gene therapy for muscular dystrophy fixes frail muscle cells in animal model, Stanford study finds
8. Sooner is better with cochlear implants, Stanford scientist shows
9. Learning to love bacteria: Stanford scientist highlights bugs benefits
10. For one Stanford doctor, the beat goes on during open-heart surgery
11. Stanford study of owls finds link in brain between sight and sound
Post Your Comments:

(Date:5/9/2016)... 2016 Elevay is currently known ... freedom for high net worth professionals seeking travel for ... connected world, there is still no substitute for a ... sealing your deal with a firm handshake. This is ... advantage of citizenship via investment programs like those offered ...
(Date:4/26/2016)... Research and Markets has announced ... 2016-2020"  report to their offering.  , ,     (Logo: ... analysts forecast the global multimodal biometrics market to ... period 2016-2020.  Multimodal biometrics is being ... the healthcare, BFSI, transportation, automotive, and government for ...
(Date:4/13/2016)... , April 13, 2016  IMPOWER physicians supporting ... are setting a new clinical standard in telehealth thanks ... By leveraging the higi platform, IMPOWER patients can routinely ... pulse and body mass index, and, when they opt ... and convenient visit to a local retail location at ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... DIEGO , June 27, 2016  Sequenom, Inc. ... committed to enabling healthier lives through the development of ... Court of the United States ... courts that the claims of Sequenom,s U.S. Patent No. ... patent eligibility criteria established by the Supreme Court,s Mayo ...
(Date:6/27/2016)... ... June 27, 2016 , ... ... medical technologies, services and solutions to the healthcare market. The company's primary focus ... distribution, manufacturing, sales and marketing strategies that are necessary to help companies efficiently ...
(Date:6/27/2016)... 27, 2016   Ginkgo Bioworks , a leading ... was today awarded as one of the World ... world,s most innovative companies. Ginkgo Bioworks is engineering ... real world in the nutrition, health and consumer ... with customers including Fortune 500 companies to design ...
(Date:6/24/2016)... , ... June 24, 2016 , ... While the majority ... as the Cary 5000 and the 6000i models are higher end machines that use ... height of the spectrophotometer’s light beam from the bottom of the cuvette holder. ...
Breaking Biology Technology: