ALS drug-discovery research is proceeding on many fronts at the ALS Therapy Development Institute (ALS TDI), an MDA-supported laboratory in Cambridge, Mass., whose mission is to rapidly develop therapeutics for ALS.
ALS TDI scientists updated the ALS community on their efforts during a Web-based seminar on Dec. 10.
Chief Scientific Officer Steve Perrin, and Director of Therapeutic Investigations John McCarty, summarized lab activities and answered submitted questions.
Below are highlights of the seminar, which can be accessed in its entirety through the ALS TDI Web site.
Perrin described the Institute’s testing of a “short hairpin” molecule that targets the genetic instructions for the SOD1 protein. SOD1, when abnormally formed, is a cause of human ALS in a small percentage of cases and forms the basis of the mouse model of the disease most commonly used by researchers.
Perrin said the hairpin construct, when packaged inside an adenoviral delivery vehicle and injected into the muscles of test animals, was not toxic and entered the spinal cord very well.
Researchers at the Institute are now testing the efficacy of the hairpin molecule against SOD1 genetic instructions in mice with mutated SOD1 genes.
Initial observations are that the SOD1-targeting hairpin extended survival of male ALS mice by about 14 days but didn’t help female mice. Perrin said the investigators are considering fine-tuning the strategy and the dosing regimen to see if they can improve the effect in both genders.
The 32-person research group is also investigating delivery vehicles made from adeno-associated viruses (AAVs), which don’t provoke the immune system as much as adenoviruses do. So far, they’ve found type 2 AAV, although it’s well tolerated in mice, doesn’t enter the nervous system robustly from muscle tissue.
The Institute has a collaboration with Asklepios BioPharmaceutical, an MDA-supported biotech company located in Chapel Hill, N.C., to develop new AAV strains designed to enter the spinal cord.
New mouse model
Perrin also described how ALS TDI scientists will soon begin researching, in depth, a mouse that has an ALS-like disease because of a mutation in the gene for the dynein protein, rather than the SOD1 gene. This mouse model, called the LOA (“legs at odd angles”) mouse, has defective transport of molecules through nerve-cell fibers and shows ALS-like symptoms.
Perrin said the Institute has profiled some 250 human blood samples in search of ALS-specific biological indicators (biomarkers). Initial candidates have been identified, and the project will continue.
John McCarty said there is “currently no substantial preclinical data and no significant anecdotal data” supporting the use of Iplex (a combination of insulin-like growth factor 1 and binding protein 3) in ALS. The drug, made by Insmed of Richmond, Va., has recently become available to ALS patients outside Italy, but it’s estimated to cost about $100,000 a year, and each patient’s request for it must be approved by a review board.
McCarty reported that Institute scientists have seen no effect of lithium on body weight, neurological function scores or survival in mice with mutated SOD1 genes. The drug is being tested in an MDA-supported clinical trial, following a February 2008 publication saying it slowed disease progression in ALS patients in Italy.
ALS mice treated with the antioxidant apocynin, which was reported to be beneficial in a preclinical ALS study last year, fared no better than untreated mice when rigorously tested at the ALS TDI. The Institute will not pursue further apocynin testing, McCarty said.
McCarty noted that drugs reported, even anecdotally, to be beneficial in ALS, are being tested in the laboratory at ALS TDI.
Perrin noted that “if you really want to have better shots on goal, move drugs toward the clinic, you have to understand the disease mechanism better. We have the tools in place, the data in place, to get drugs hitting a disease mechanism, targeting disease biology, and that will be better than in the past.”
MDA has made a three-year, $18 million commitment to ALS TDI through MDA’s Augie’s Quest initiative.