January 31, 2007

2007 Funding: New Efforts Promise Accelerated Progress

Ten promising investigations along new avenues toward therapy for ALS are now funded for the start of the new year. The projects include investigation in veterans of genes and environmental exposures that might interact to produce ALS. Also important are new proposals to discover genes known or suspected to be at work in the disease. Each new gene added to the list of players in ALS will bring us closer to a target for therapeutic intervention.

A role for the cellular power plants called mitochondria has been strongly suspect in ALS. A renewed effort by a previously funded investigator will clarify disruption to these key sources of fuel, so important for the demanding motor neurons that must maintain cellular functions over vast distances in the human body.

Another project examines a new take on ceftriaxone, already in patient testing in ALS. It appears that ceftriaxone may be able to counter harmful metabolic products as well as work through the glutamate messaging system. These projects reflect a renewed look at how to protect the motor neuron from the disease process of ALS.

Other proposed research with direct clinical implications in ALS include investigation of compounds that resemble some of the cannabinoid molecules in marijuana to see if any might help slow the inflammation known to be at work in the disorder and a possible set of compounds that might address the abnormal deposits of the protein, copper-zinc superoxide dismutase (SOD1) mutated in some inherited forms of the disorder.

Finally, a research team has as its focus a new molecule that works on the surface of the motor neuron through a docking site for trophic factors to help resist toxic effects from ALS tissue. Extending these findings to a living mouse model might yield an outstanding clinical candidate. Another team seeks to tailor a viral vector to specifically target the motor neurons that die in the disease to deliver a gene therapy that will silence construction of mutant protein at the same time restoring production of the normal protein.

These innovative proposals represent the cutting edge of techniques that promise to rebuild the defective cell processes that might underlie not just inherited but also spontaneously arising ALS.

Funding is awarded for two starter grants, two one year grants and five multiyear projects, including an ALS Association-initiated award and a one year project funded through the TREAT ALS initiative. This round of awards supports investigators from around the world, including Australia, Belgium, Germany, and Canada, as well as the United States.

Genetics of ALS

The fruit fly is easy to use in research and has well known genetics. Callaerts and Norga plan to produce a fly with genetic changes in a protein called senataxin known to be a cause of some cases of motor neuron disease, including a slowly progressing form of ALS. As flies also have a protein called senataxin, the scientists will find out which cell processes might be changed, and which other genes might interact, to modify motor neuron disease.

Nicholson and Blair have identified a region on chromosome 7 linked to a slowly progressing form of motor neuron disease. They now seek the exact identity of the genetic change responsible. With the samples they have from families affected, they propose to find the gene mutation which will add to the list of possible molecular targets that can be the focus of therapeutic efforts.

Mitochondrial Function

Gunther will continue his examination of key defects produced by the mutant protein SOD1 using his model system in yeast. The cell’s power plants, called the mitochondria, are easily accessed in this microbe, and Gunther has capitalized on this to show changes in mitochondrial function due to the introduced mutation that he will now confirm and extend to an animal cells. If the mitochondria are  impaired because, as his findings so far show, the mitochondrial machinery is hampered (specifically, the iron-bearing heme molecule is decreased), this could open a therapeutic avenue in ALS.

Environmental Factors and Gene Interactions

The ALS Association joins the NIH and Veterans Administration in an investigation into the environmental and genetic factors that might underlie ALS. The team led by Schmidt is already gathering genetic and life history evidence from veterans with ALS and matched veterans without the disease to seek gene and environment factors that might interact to produce the disease. The study is enabled by the unique ALS Registry of 1400 veterans with ALS and might provide reasons for the increased incidence of ALS among veterans.

Axon Dynamics

A protein called stathmin is part of the place where nerve contacts muscle. Changes in the gene coding for stathmin, Davis finds, appear to damage the neuro-muscular junction in fruit flies. His team will clarify the role of the protein in the communication between nerve and muscle and look for genes in the fly that might interact with the stathmin gene in the fly with its easily manipulated genetics.

SOD1 aggregates

McLaurin and Robertson have a set of compounds that enter the brain and work against the accumulation of abnormal protein deposits. They might or might not be able to handle deposits of the relatively large protein, SOD1, responsible for some inherited cases of ALS. The team will find out by testing in mice with one of two different introduced SOD1 gene changes.

Inflammation

Compounds that mimic certain ones in the mix contained in marijuana, called cannabinoids, can modify inflammation and some show potential in mouse models of ALS. Prather’s team will identify new compounds that can act at the docking sites in nervous tissue for cannabinoids, specifically at the so- called CB2 receptor, and test if any can increase survival in the SOD1 mutant mouse, alone, and importantly, as part of combination therapies now being evaluated in clinical trials for the disease.

Glutamate

Methner and Schubert suspect that ceftriaxone, a newly identified candidate treatment for ALS, may work by more than a single means. Ceftriaxone appears to boost the ability to prevent potentially harmful glutamate messages from building up around susceptible motor neurons. But it may at the same time help another process that is protecting the cells, the movement of cystine into cells that is then used to make a protective molecule that counters the harmful molecules called free radicals and oxidizers. The new focus on the role of cystine in cells offered by this team may allow clinicians to more effectively treat ALS.

Trophic Factors

One of the helper molecules that keep motor neurons healthy is called p75 neurotrophin, and its recognition site on the surface of the cell appears to be present in larger numbers in ALS. Longo has small molecules that dock at these receptors on motor neurons, which are able to protect cells in culture dishes from toxic action of tissue taken from ALS mice. The lead candidate is able to enter the central nervous system when taken by mouth without toxicity. This project will seek to confirm and extend these findings to living ALS mice to see if they will live longer and retain motor function compared to untreated SOD1 mice.

Samulski will construct a tailor-made molecule based on a virus that has been used to deliver genes for gene therapies. The construct will be designed specifically for entry into motor neurons. It will combine the ability to target selectively the motor neurons that die in ALS and the ability to turn off the mutant gene for the protein that produces some inherited cases of ALS. Simultaneously the team will seek to restore the normal gene for the SOD1 protein. This approach, to be tested in the SOD1 mouse, might provide proof of principle for future gene and RNA therapies for the disease.