Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New Data Suggests Current Approach to Drug Discovery for Lou Gehrig’s Disease Be Re-Examined

09.05.2007
Penn Researchers Find Two Forms of the Disease Biochemically Different

> Researchers at the University of Pennsylvania School of Medicine have found an absolute biochemical distinction between the sporadic and hereditary variants of Lou Gehrig’s disease, or amyothrophic lateral sclerosis (ALS), suggesting that current approaches to drug discovery should be re-examined.

> By examining the various forms of ALS in post-mortem tissue, the researchers found that TDP-43 was the disease protein in sporadic ALS cases, but not in patients with SOD-1 mutations, all of whom have the familial form of ALS. Patients with the SOD-1 mutation account for about 1 percent of all ALS cases.

> This finding may partially account for why therapeutic strategies, shown to be effective in SOD-1 mouse models, have generally not been effective in clinical trials of sporadic ALS patients.

> The study was published this week in the Annals of Neurology.

Most research on Lou Gehrig’s disease therapeutics has been based on the assumption that its two forms (sporadic and hereditary) are similar in their underlying cause. Now, researchers at the University of Pennsylvania School of Medicine have found an absolute biochemical distinction between these two disease variants, suggesting that current approaches to drug discovery should be re-examined.

About 5 percent of all cases of Lou Gehrig’s disease, or amyothrophic lateral sclerosis (ALS), are passed from generation to generation. The most common genetic variant in this familial form is caused by a mutation in the SOD-1 gene. The researchers looked at a large set of ALS patients, including hereditary cases, both with and without the SOD-1 mutation.

The present study – published this week in the Annals of Neurology – was conducted by Penn; a group led by Ian Mackenzie from the University of British Columbia; the University of Munich; and others across the U.S. and Canada.

“Most ALS research has focused on how mutant SOD-1 proteins are toxic to nerve cells,” says senior author John Trojanowski, MD, PhD, who directs the Penn Institute on Aging. Last year, Penn investigators led by co-author Virginia Lee, PhD, who directs the Penn Center for Neurodegenerative Disease Research, identified TDP-43 as the major disease protein in sporadic (non-hereditary) forms of ALS, which are not those caused by SOD-1 gene mutations.

By examining the various forms of ALS in post-mortem tissue, the researchers found that TDP-43 was the disease protein in sporadic ALS cases, but not in patients with SOD-1 mutations, all of whom have the familial form of ALS. Patients with the SOD-1 mutation account for about 1 percent of all ALS cases.

“We argue that SOD-1 ALS does not equal sporadic ALS,” says Trojanowski. “If you pursue drug discovery focusing on SOD-1-mediated pathways of brain and spinal cord degeneration you may benefit SOD-1-bearing patients, but not the vast majority of ALS patients who have the sporadic form of this disorder with TDP-43 pathologies underlying the disease.”

“Motor neuron degeneration in TDP-43 cases may result from a different mechanism than cases with SOD-1 mutations, so this form of ALS may not be the familial counterpart of sporadic ALS,” surmises Lee.

“This may also partially account for why therapeutic strategies, shown to be effective in SOD-1 mouse models, have generally not been effective in clinical trials of sporadic ALS patients,” explains Trojanowski. “This also sounds a cautionary note in all other diseases in which you have familial and sporadic versions of the disease because it will prompt researchers to ask if mouse models for drug discovery are based on the correct mutations or disease protein.”

This research was funded by the Canadian Institutes of Health Research, the National Institute on Aging, the German Federal Ministry of Education and Research, The Wellcome Trust (United Kingdom) and the UK Medical Research Council.

Co-authors in addition to Trojanowski, Lee, and Mackenzie are Eileen H. Bigio, Paul G. Ince, Felix Geser, Manuela Neumann, Nigel J. Cairns, Linda K. Kwong, Mark S. Forman, John Ravits, Heather Stewart, Andrew Eisen, Leo McClusky, Hans A. Kretzschmar, Camelia M. Monoranu, J. Robin Highley, Janine Kirby, Teepu Siddique, and Pamela J. Shaw.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

Further reports about: Gehrig’s SOD-1 TDP-43 Trojanowski effective familial sporadic

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 >>>