Navigation Links
Small molecules might block mutant protein production in Huntington's disease
Date:5/3/2009

DALLAS May 3, 2009 Molecules that selectively interfere with protein production can stop human cells from making the abnormal molecules that cause Huntington's disease, researchers at UT Southwestern Medical Center have found.

These man-made molecules also were effective against the abnormal protein that causes Machado-Joseph disease, a neurological condition similar to Huntington's.

The work has been done only in cultured cells, and it will take years before the effectiveness of this process can be tested in patients, the researchers cautioned.

"I wouldn't want to give Huntington's patients or gene carriers any false hope, but I am excited about where this work might go in the future," said Dr. David Corey, professor of pharmacology and biochemistry at UT Southwestern and senior author of the study, which appears online May 3 in Nature Biotechnology.

The researchers' approach relies on interfering with the steps by which genetic information in cells is "translated" from DNA to make proteins, which carry out vital biological functions.

Huntington's and Machado-Joseph are fatal inherited diseases caused by abnormal repeats of a small segment in a person's DNA, or genetic code, represented by the letters CAG. These mutations result in the body producing malfunctioning proteins that cause the diseases. The more repeats, the worse the disease, and the earlier in life it appears. A person with the disease carries one normal copy of the gene and one mutated copy in his or her cells.

In Huntington's, this CAG repeat occurs in a gene called huntingtin, and in Machado-Joseph, it occurs in a gene called ataxin-3. A person with Huntington's can have up to 100 CAG repeats. CAG repeats are involved in several other neurodegenerative diseases, including Fragile X syndrome, the most common form of mental retardation, and myotonic dystrophy.

While these genes are best known for the devastating effects of their mutated forms, their normal forms are essential for embryonic development, nerve function and other bodily processes. Any treatment that interferes with the mutant forms must leave the normal forms as unaffected as possible, Dr. Corey said.

"Attempting to intervene is very risky, but because the problem is important, it's worth doing," he said.

In the current study, the researchers created short lengths of molecules that resemble ribonucleic acid (RNA), the chemical cousin of DNA. These mimics, called PNAs and LNAs, were specifically designed to bind to CAG repeats, preventing cells from creating the abnormal proteins. The researchers also designed short lengths of RNA called small interfering RNA, or siRNA, to interfere with CAG repeats.

In cells from Huntington's patients, the PNAs, LNAs and siRNAs decreased the amount of mutant protein produced, in some cases up to 100 percent. The effect was greatest when the compounds interfered with long lengths of CAG repeats; the effectiveness varied, however, among cells taken from different patients.

Some forms of these compounds left the normal forms of huntingtin and ataxin-3 proteins undisturbed, but other compounds partly or completely blocked their formation. In some cells, some of the RNA mimics drastically cut the production of both mutant and normal proteins an undesirable effect, Dr. Corey said.

These findings indicate that further tweaking of the molecular structures of the RNA mimics will be needed to minimize the effects on normal proteins.

"It is encouraging that small chemical changes could substantially enhance selectivity," Dr. Corey said. "If we can test a handful of compounds and identify better ones, we have reason to believe that more testing will continue to produce significant improvement."

Because this study was done in cultured cells, and not in whole animals or humans, it does not indicate how much of the abnormal proteins must be blocked to treat the disease effectively, he said. "Fifty percent inhibition might be enough, but that remains to be determined," Dr. Corey said.

In future studies, the researchers plan to try these RNA mimics in whole animals, using several different mutations of the genes.

Laurie Tompkins, who oversees neurogenetics grants at the National Institutes of Health's National Institute of General Medical Sciences, said the ability to control individual genes makes this work stand out.

"By exploiting processes that occur in normal cells, Dr. Corey has come up with a clever way to do this that may well lead to new ways to combat Huntington's and other related diseases," she said.


'/>"/>

Contact: Aline McKenzie
aline.mckenzie@utsouthwestern.edu
214-648-3404
UT Southwestern Medical Center
Source:Eurekalert

Related biology news :

1. Nanoneedle is small in size, but huge in applications
2. Small RNAs can play critical roles in male infertility/contraception
3. Scientists at CSHL discover mobile small RNAs that set up leaf patterning in plants
4. Small molecules block cancer gene
5. Freezing kidney cancer: Hot treatment should be new gold standard for destroying small tumors
6. Scientists at CSHL discover mobile small RNAs that set up leaf patterning in plants
7. Vanderbilt scientists invent worlds smallest periscopes
8. Nanoparticle toxicity doesnt get wacky at the smallest sizes
9. Small male chimps use politics, rather than aggression, to lead the pack, U of Minnesota study says
10. CSHL scientists find a new class of small RNAs and define its function
11. Small changes can lead to big rewards, says ASN president
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/3/2016)... 2016 --> ... "Automated Fingerprint Identification System Market by Component (Hardware and ... & Finance, Government, Healthcare, and Transportation) and Geography - ... is expected to be worth USD 8.49 Billion by ... and 2020. The transformation and technology evolution from the ...
(Date:2/2/2016)... 2016 Checkpoint Inhibitors for Cancer – ... Are you interested in the future of cancer ... inhibitors. Visiongain,s report gives those predictions to 2026 ... level. Avoid falling behind in data or ... revenues those emerging cancer therapies can achieve. There ...
(Date:2/1/2016)... 2016  Today, the first day of American Heart ... develop a first of its kind workplace health solution ... In the first application of Watson ... ), and Welltok will create a new offering that ... analytics, delivered on Welltok,s health optimization platform. The effort ...
Breaking Biology News(10 mins):
(Date:2/9/2016)... BERG, a biopharmaceutical company uncovering health ... announced the appointment of Jason Haddock ... Haddock brings to BERG over 20 years of ... senior financial functions at pharmaceutical companies, as well ... Niven R. Narain , BERG,s ...
(Date:2/8/2016)... Feb. 8, 2016 /PRNewswire/ - BIOREM Inc. (TSXV: BRM) ("Biorem" ... ten finalists for clean technology companies in the TSX Venture ... 10 companies listed on the TSX Venture Exchange, in each ... clean technology & life sciences, diversified industries and ... given to return on investment, market cap growth, trading volume ...
(Date:2/8/2016)... 2016  CytRx Corporation (NASDAQ: CYTR ), ... oncology, today announced that it has entered into ... Technology Growth Capital, Inc. and Hercules Technology III, ... --> --> ... financing under the loan and security agreement.  The ...
(Date:2/8/2016)... -- Novan, Inc. today announced that Director Robert A. Ingram ... Novan. In addition, Robert Keegan has been appointed to ... . --> North Carolina . ... total of $32.8 million of net proceeds in a private Mezzanine ... throughout the Research Triangle area of North Carolina ...
Breaking Biology Technology: