ALS TDI: Changes in the Works

by Amy Madsen on Tue, 2010-06-01 13:52

ALS TDI's May 2010 research update addressed changes: a new mouse model, new projects, a paradigm shift and a model for faster drug development

MDA and the nonprofit ALS TDI, of Cambridge, Mass., forged an historic partnership in January 2007 when they launched the largest drug discovery project to date in ALS. The project focuses on identifying biochemical targets in ALS and finding drugs to hit them. In January 2009 MDA renewed its partnership with ALS TDI with a grant of $2.5 million.
Article Highlights:
  • ALS TDI has added the recently developed TDP43 mouse model of ALS to its preclinical drug development program, and is working to characterize the model and devise best practices for its use.
  • The Institute has increased its emphasis on developing biological markers ("biomarkers") of ALS progression.
  • Conducting parallel studies in more than one type of research mouse represents a "paradigm shift" for ALS TDI.
  • With its drug candidate ALSTDI-00846, the Institute has shown that drug development in ALS can proceed relatively quickly and inexpensively.

In its quarterly Research Update Webcast on May 18, 2010, the ALS Therapy Development Institute (ALS TDI) informed viewers of a "paradigm shift" in TDI research. The changes include the addition of a new mouse model to the Institute's preclinical drug development program and an increased emphasis on the importance of biological indicators called "biomarkers."

 The webinar also addressed the current state of drug development in ALS, and the ways in which ALS TDI hopes to hasten the process.

 A new ALS mouse model

 ALS TDI Chief Scientific Officer Steve Perrin reported that the Institute will soon begin characterizing the recently developed TDP43 mouse model of ALS. The model, which has a mutation in the TDP43 gene, mimics aspects of neurodegeneration associated not only with ALS, but also with other neurological conditions such as Alzheimer's and Parkinson's diseases.

 Until now most nonhuman ALS research has been conducted in the SOD1 mouse, a genetic strain engineered to have mutations in the superoxide dismutase 1 gene. However, familial (inherited) SOD1-related ALS accounts for only 1 percent to 3 percent of all human cases of the disease. Applicability of the SOD1 model to ALS that results from other genetic or sporadic causes has long been a matter of fierce debate.

ALS TDI's focus on generating best practices for studies using mice is expanding. Researchers are working to fully characterize a new ALS research mouse, which has a mutation in the TDP43 gene.

The TDP43 mouse is a valuable addition to the ALS toolkit, providing researchers with another model in which to study disease onset and progression, and to test experimental treatments. (See New ALS Mouse.)

 Perrin described two TDP43 mouse model projects that ALS TDI intends to tackle as quickly as possible.  

 ALS TDI researchers will study and characterize the TDP43 mouse in an effort to best understand how to use it efficiently and rigorously in testing. Data will be collected on measurements such as the onset of paralysis and the rate of progression of the disease in these new research mice.

 "ALS TDI's [work] on the SOD1 mouse has really helped the community think about how to test and develop therapies in the SOD1 model," Perrin said. "And we want to do this in the TDP43 model as quickly as we can."

 The Institute also plans to compare measurements in the TDP43 mouse with those in the SOD1 ALS mouse model and in mice without the disease.


Biomarkers are biological indicators (such as a mutation in a gene, or the presence of a protein in blood or spinal fluid) that can be used to show the presence of a disease, the progression of a disease, the potential for a patient to respond to a specific drug therapy, or an indication of whether a therapy is working in an individual.

They are an increasingly important tool in drug development, particularly when the time comes to partner with a pharmaceutical company that can take the drug to market. Their development is an area in which ALS TDI has increased its emphasis.

 As an example, Perrin referenced some of the work TDI has done on its leading drug candidate ALSTDI-00846.

 Testing in the SOD1 mouse has shown that the immune system appears to attack the myelin sheaths insulating nerve fibers that send signals to skeletal muscles, he said. In animals treated with ALSTDI-00846, there are significantly fewer immune-system cells associated with this attack.

 "It's interesting that it looks as though this drug may be working in the periphery, outside the central nervous system," Perrin noted. "And that's an important biomarker  just to be able to demonstrate that the drug is affecting a particular process or pathway."

 With MDA support, ALS TDI has been collecting samples from ALS patients since 2007 and profiling tissues via a variety of different methods. Researchers have found that, out of approximately 600 blood samples taken from individuals with ALS, approximately half have biomarkers in their blood that indicate increased activity of the pathway ALSTDI-00846 is designed to knock down.

 An area in which biomarkers will be of critical importance is in the design and implementation of clinical trials. Biological readouts may help determine who can best benefit from a particular treatment and therefore should be included or excluded from a particular trial.

 Biomarkers also can function as a quick indicator of whether an experimental treatment is doing something or not, allowing researchers to speed determination of the most effective dose.

 "That's the type of information you want to present to a pharmaceutical company when you go to partner your molecule," Perrin said.    

 Paradigm shift

 The addition of the TDP43 mouse model to its drug development program, and the use of biomarkers to make comparisons between what a drug candidate does in a mouse model of ALS and what it does in a mouse without disease, mark the two parts of what Perrin called a "paradigm shift" for ALS TDI.

Perrin said that up until now the ALS TDI has not often conducted parallel studies in multiple types of mice with and without disease.

Comparing treatments in different mouse models is a critical next step, since it's vital to know the extent to which various forms of ALS overlap or don't.(See SOD1 Versus Other ALS: Apples and Oranges?.) In addition, such testing will help researchers determine whether an experimental treatment has an effect on any relevant biological pathways or processes, even if it doesn't stop or slow the progression of ALS.

 Speeding drug development

 Perrin also reported on barriers to drug development in ALS and the innovative approaches ALS TDI is taking to solve these problems.

 "In the last few years," Perrin said, "we've really made a lot of progress demonstrating that if you rigorously apply an effective strategy in preclinical drug screening, you can get to the endpoint" more quickly and less expensively than is standard today.

TDI's process starts with the discovery and understanding of the druggable pathways in the disease. “If you don't understand what's going wrong, it's almost impossible to think about what types of drugs you might want to test to move forward to the clinic," Perrin said.

The next step is to build and test the drug.

 Reducing cost, time, risk

 The way to get drugs to the clinic more quickly, Perrin said, is to "de-risk" the investment for pharmaceutical companies. This means taking on the risk and expense associated with the early stages of drug development, so pharmaceutical companies interested in taking the drug to market face less of a financial gamble.

 Perrin reported that in 2007, it took an average of eights years to bring a drug to commercialization, at a cost of approximately $800 million. And a discouraging study published in Nature Biotechnology in March 2010 showed the industry is now taking an average of 13 years to commercialize a drug at a cost of $1.8 billion.

 ALS TDI's experimental drug ALSTDI-00846, Perrin says, provides an example of how a nonprofit can dramatically increase the efficiency of this process.  

 The 00846 program has moved from the discovery of the relevant pathway in multiple tissues in ALS mice, to analyzing and building the drug, to understanding the way it works in the model and how to properly dose it, to survival efficacy studies demonstrating which doses work best in males and females, to identifying biomarkers of drug response. The entire process took approximately 24 months and $2.5 million.

 Perrin attributes the reduction in cost and time to a number of factors: funding from multiple sources; focus on a single disease; commitment of all resources to ALS drug development; and the development of a complete preclinical package that "fills in all the gaps" and makes the drug more attractive to pharmaceutical companies.

"It doesn't have to be as complicated or time consuming or expensive as the industry standard,” Perrin said, “and I think you're going to see that change over time."

Next up

The next quarterly ALS TDI research update will take place July 20 at 6 p.m. EDT.

The May 18 webcast has been archived on the Institute's website at the following link: May 18th Research Update Webcast Archive Video Link. (You must register to view the webcast.)

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