The state of the science in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease), current lines of research, efforts to establish a TDP43 research mouse colony, and a primer on protein-based therapies were the topics of a webcast on April 7, 2011, presented by ALS Therapy Development Institute (ALS TDI) CEO and Chief Scientific Officer Steve Perrin, and colleagues.
The webcast has been archived on ALS TDI's website and is available for viewing to all who login or register.
Perrin described the "change in dogma" in ALS research that has evolved over the past two decades. Twenty years ago, nerve cells (motor neurons) were the main focus of ALS research scientists.
Today, scientists study the complex interplay between numerous affected biological components and pathways involved in neurodegeneration – some in, and some outside of, the central nervous system. (For more on this topic, see ALS: Not Just About Motor Neurons Anymore.)
Multiple therapies aimed at a number of targets likely will be necessary, Perrin said, "alone or in combination for subgroups and individuals affected by ALS."
When it comes to searching for components and pathways that may constitute part of the ALS disease process, said ALS TDI Director of Communications and Public Affairs Rob Goldstein, we're "thinking outside the CNS [central nervous system]."
ALS TDI scientists currently are studying numerous physiological processes and targets that appear to be implicated in the disease, such as:
Experimental drugs are in various stages of development in ALS TDI's pipeline, from discovery of new leads; to formulation of experimental therapeutic agents; to preclinical testing in cell culture and in animal models.
In testing, investigators examine each drug's safety and side effects, pharmacokinetics and pharmacodynamics (what the body does to the drug, and what the drug does to the body, respectively) and any effects on disease onset or progression and survival time.
As of April 6, 2011, ALS TDI's drug development pipeline includes nine small-molecule drugs, 17 protein biologics (see below), and 45 gene therapy agents.
To read more about ALS TDI's research program, see ALS TDI Conference Summarizes ALS Research Progress.
ALS TDI Director of In Vivo Validation/Research Fernando Vieira reported that funding support from the Muscular Dystrophy Association, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration is expected to speed ALS TDI's planned characterization of the TDP43 research mouse model.
The collaborative effort was announced March 22, 2011.
The TDP43 protein, either when flawed or when produced in excessive amounts, is thought to play a role in a percentage of both familial and sporadic (noninherited) forms of ALS, as well as in other neurodegenerative disorders such as Alzheimer's disease and frontotemporal dementia.
Characterization of the TDP43 mouse — basically, a description of qualities or features specific to this particular model — will flesh out the ways in which it is affected by TDP43-mediated ALS from onset to end-stage.
The resulting set of characteristics will serve as guidelines that are expected to improve quality and efficiency in preclinical testing of new drugs that target TDP43 in mice. This in turn is expected to translate into a higher success rate for these same drugs when they move to clinical trials in humans.
Other goals include the collection of disease-associated tissue samples from the TDP43 mouse model; identification of key changes in gene activity that signify disease onset or progression; and analysis of similarities and differences between the TDP43 mouse, the more commonly used SOD1 ALS mouse model, other models of neurodegeneration, and people with ALS.
For more on the TDP43 mouse model, which carries a mutation in the gene for the TDP43 protein and was engineered by MDA-supported scientists, see New ALS Mouse.
John Lincecum, ALS TDI director of discovery biology, presented a brief primer on protein biologics, or protein-based therapeutic strategies.
Proteins potentially may serve as treatments for ALS by compensating for nonfunctional, dysfunctional or missing proteins, or by interfering with proteins that are toxic to neural cells or to cellular subcomponents such as mitochondria.
The use of proteins as therapeutic agents was originally identified 20 to 30 years ago, when scientists learned how to direct antibodies (proteins normally found in the blood that detect and destroy bacteria, viruses and other foreign invaders) as a method for treating diseases.
The idea behind antibody-based treatments is to coax the body into directing its own immune system defenses against particular tissues or other targets.
Although protein-based strategies often provide a more powerful weapon against disease, Lincecum said, they come with greater risks (side effects) and generally are more difficult to develop and deliver to intended targets.
ALS TDI's next webinar is scheduled to be webcast live May 4, 2011, at 1 p.m. ET.
Titled "ALS Advocacy: How Can I Help?" the presentation will cover a wide variety of issues important to people with ALS, their families and caregivers. Annie Kennedy, MDA’s senior vice president for advocacy, will co-host.
View the archived April 7 webcast at ALS TDI's website. (Note: You must register to view the webcast.)