Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps research team reverses Friedreich's ataxia defect in cell culture

24.08.2006
Newly developed compounds activate silenced gene responsible for debilitating disease

The results of the research are being published on August 20 in an advanced, online version of the journal Nature Chemical Biology.

In the new study, the researchers tested a variety of compounds that inhibited a class of enzymes known as histone deacetylases in a cell line derived from blood cells from a Fredreich's ataxia sufferer. One of these inhibitors had the effect of reactivating the frataxin gene, which is silenced in those with the disease. The researchers then went on to improve on this molecule by synthesis of novel derivatives, identifying compounds that would reactivate the frataxin gene in blood cells taken from 13 Friedreich's ataxia patients.

In fact, one of the compounds the researchers tested produced what amounted to full reactivation of the frataxin gene in 100 percent of cells tested.

"This is marvelous," said Joel Gottesfeld, Ph.D., a professor in the Scripps Research Department of Molecular Biology and leader of the project. "I've met the parents of many children affected with the disease and some of the patients and it would be just a dream to be able to help them."

"Dr. Gottesfeld's work holds tremendous promise of real therapeutic benefit for Friedreich's ataxia patients," said Ron Bartek, president of Friedreich's Ataxia Research Alliance (FARA). "This discovery appears to be our only near-term prospect for significantly increasing transcription of the frataxin gene. FARA is pleased to have been able to support this important work."

Friedreich's Ataxia, a Debilitating Disease

About one of every 20,000 to 50,000 people in the United States has Friedreich's ataxia, which is caused by a genetic defect that prevents adequate production of the protein frataxin. In neuronal and muscle cells, frataxin is essential for proper functioning of mitochondria, the energy producers for cells. Low levels of the protein lead to degeneration of nerve tissue in the spinal cord and nerves controlling muscle movement in the arms and legs.

Specific symptoms, which typically first appear between the ages of five and 15, include trouble walking, reduced hand coordination, and slurred speech. The disease also typically leads to scoliosis, heart disease, and diabetes. Most Friedreich's ataxia sufferers are eventually confined to a wheelchair and die as early adults due to associated heart disease.

The genetic defect involves numerous extra repeats of a GAA-TTC triplet pattern in a person's DNA that prevent expression of the frataxin gene. Where normal cells contain 6 to 34 repeats, Friedreich's ataxia sufferers can have as many as 1,700. The more triplets a person's DNA contains, the earlier symptoms appear and the greater their severity. Several other diseases, including Huntington's disease and the spinocerebellar ataxias, are also linked to triplet repeats.

Only individuals who carry the Friedreich's ataxia defect on both of their paired alleles-i.e., who are homozygous for the trait-suffer from the condition. Those individuals who are heterozygous, with only one defective allele, produce about half the normal level of frataxin, but do not suffer disease symptoms. This suggests that a treatment for Friedreich's ataxia need not raise frataxin production all the way to normal levels to be effective.

Gottesfeld notes that the repeats causing Friedreich's ataxia are in a region of the gene that does not code for the protein frataxin, so reversing gene silencing may be all that is needed to treat the disease.

A New Theory

Researchers are still working to understand the reasons the triplet repeats prevent transcription of the frataxin gene, although the gene itself remains intact. Although other theories have been proposed, the new research supports an explanation known as the "histone code theory."

Histones are proteins that are the chief constituent of the nucleosomes around which DNA is wrapped in cells. The new theory suggests that histones must contain certain chemical cues, including acetyl groups, for nucleosomes to assume the formation that allows the genes they package to be expressed.

One idea suggested by the paper's authors is that the triplets cause an unusual DNA structure that attracts proteins such as histone deacetylases (HDACs), removing critical acetyl groups from the histones, packaging the histones in an inactive form called heterochromatin, and ultimately leading to silencing of the frataxin gene.

Based on this theory, Gottesfeld and his colleagues began looking for compounds that might block the HDACs with the goal of reactivating frataxin production. The researchers were able to draw from a range of commercially available products because many HDAC inhibitors have been developed as tools for molecular biology research and as potential cancer treatments.

Though Friedreich's ataxia impacts neuronal and muscle cells, these are not readily available for research. So, the group instead worked with white blood cells, or lymphyocytes, which are easily obtained from blood samples and can be prevented from dividing, making them a suitable proxy.

Experiments revealed that one HDAC inhibitor, called BML-210, did in fact reverse the heterochromatin formation in cultured lymphocytes from Friedreich's ataxia patients and increased the production of frataxin messenger RNA (mRNA), a precursor to production of the protein, although not sufficiently to bring protein production to normal.

Next, the researchers chemically modified BML-210 to produce a variety of analogs whose effects on the cells were then tested. One class of analogs produced a two to three-fold increase in frataxin transcription amounting to full reactivation of the frataxin gene in an astonishing 100 percent of cells from 13 Friedreich's ataxia sufferers.

"They never failed," said Gottesfeld. Such therapeutic reactivation of a silenced gene has only been achieved for a handful of other diseases.

Importantly, the team's HDAC inhibitors have also proven uniformly non-toxic to the lymphocytes and do not significantly affect cell growth rates. Ongoing animal studies also have not revealed any toxicity. If the results of animal testing remain positive, said Gottesfeld, the HDAC inhibitors could enter human trials as a Friedreich's ataxia treatment in as soon as 18 months' time.

"FARA is truly excited about rallying additional support," Bartek noted, "so as to move Dr. Gottesfeld's compounds through preclinical drug development and into clinical trials just as quickly as possible."

Other Friedreich's ataxia treatments under development are largely aimed at better treating symptoms of the disease, rather than grappling with the root cause of low frataxin production. Additional compounds that increase expression of frataxin protein have also been developed, but are likely too toxic for therapeutic use. Gene therapies or stem cell treatments may eventually be available to increase frataxin production, but such options are probably many years off.

"Our small molecules offer a therapeutic approach to pursue in the near term," said Gottesfeld.

Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>