Researchers are ‘Beating the Bushes’ at ALS TDI

by Margaret Wahl on Mon, 2007-10-01 09:16

In January, MDA announced a new strategic partnership with the ALS Therapy Development Institute in Cambridge, Mass., to identify molecular targets for drug development and to screen potential therapeutic agents for ALS treatment.

MDA, through its fast-track ALS research initiative, Augie’s Quest, pledged to give the ALS TDI at least $6 million a year for three years, to be combined with another $6 million a year from the Institute.

Augie’s Quest projects have been added to MDA’s traditional ALS research program, which is based at academic institutions throughout the world and spans the spectrum from basic ALS-related biology to clinical trials.

“It’s very important that we use all available resources in the fight against ALS,” says Sharon Hesterlee, MDA’s vice president of translational research. “Academic laboratories are very good at performing small, focused studies that help us learn about the underlying causes of the disease, whereas biotechnology companies or groups like ALS TDI use a large-scale industrial approach that depends less on developing ideas and more on trying to look at every biological change associated with the disease with no preconceived notions about the cause.”

Researchers at the ALS TDI are using a large-scale industrial approach to look for biological changes associated with ALS.

Beating all the bushes

“The analogy that I like is the different strategies you might use to find a lost child,” Hesterlee says. “An academic laboratory would interview the child’s friends and family to develop a theory about where the child might be based on his/her personality and past behavior. A biotechnology company, on the other hand, would gather everyone in the town together and march across the landscape in a line so that all possible locations would be checked. The latter approach doesn’t require any information about the lost child because the plan is to simply look everywhere.

“It’s hard to say which approach works better, but it’s very clear that the fewer resources available to you, the more clever you have to be to solve a problem. Academic laboratories usually don’t have access to industrial-scale machines that spit out data, so they have to make educated guesses about what might be causing ALS and design experiments to test their theories. If resources are available, however, you can just start beating all the bushes without having to be extremely clever at the beginning. We have always supported the academic model, but the industrial (beat the bushes) model is relatively new to ALS research. We feel that we need to apply both ideas.”

Different strategies

Recent areas of emphasis at the TDI have been counting and standardizing the number of mutated SOD1 genes in laboratory mice with a genetic type of ALS, and analyzing ALS-associated biochemical changes in the tissues of mice and humans with and without the disease.

Gene counting

Mice with a mutation in the gene for the SOD1 protein develop an ALS-like disease and have been used as models of human ALS since the mid-1990s. (SOD1 mutations can also cause human ALS.) Scientists rely on the ALS SOD1 mouse for access to disease tissue that simply would not be available from humans, such as spinal biopsies.

The most common form of the ALS mouse model has multiple copies of mutated SOD1 genes. In order for scientists to use this mouse effectively, it’s crucial that the gene copy number is consistent and stable from mouse to mouse. Lack of standardization of gene copy number may account for many of the reported discrepancies in experiments that use the ALS SOD1 mouse.

More than 400 mice have had their SOD1 genes counted at the TDI. The researchers have found a 2 percent to 5 percent error rate in the SOD1 copy number reported by the commercial mouse supplier. They use only mice with the same copy number in each of their experiments.

Making comparisons

ALS TDI researchers have taken samples of the spinal cord, brain and leg muscles of ALS-affected mice, as well as normal (“wild-type”) mice and other types of mice, and analyzed and compared them with respect to differences in gene activity (“expression”) by measuring levels of messenger RNA, the chemical made from DNA.

TDI biologists are now analyzing and comparing messenger RNA changes in tissues from ALS-affected mice at eight different time points (30, 50, 60, 80, 90, 100, 110 and 120 days of age), which correspond to presymptomatic ALS, early ALS and fully developed ALS.

TDI biologists are analyzing and comparing changes in tissues from ALS-affected mice at eight time points.

“This data set is the foundation that the Institute will utilize to understand the biological mechanisms associated with disease progression in ALS,” says Steve Perrin, TDI’s chief scientific officer. “Additional gene expression profiling and proteomics [protein level] analysis from other mouse models of neurodegeneration, as well as ALS patient samples, will help scientists at the Institute focus on the most relevant biological pathways for therapeutic development.”

Collection of blood samples from ALS patients is under way, and plans are to analyze muscle and nerve samples from patients as well.

All the tissues will be analyzed in the same manner as the mouse tissues to measure changes in messenger RNA production. Eventually, specific proteins altered in human ALS also will be catalogued.

“The specific changes in these tissues will be compared with those seen in the different animal models, allowing researchers to pinpoint the most crucial disease targets,” Perrin says.

“This project is unprecedented in scale and will, we hope, produce groundbreaking results.”

Margaret Wahl
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