Thomas Jefferson University

Our Research

How do motor neurons die in ALS?
The Primary Target

ALS is a disease that primarily targets the body’s motor neurons.  Within the motor neurons, many components needed for their survival become dysfunctional.

We have developed a variety of in vitro models including patients-derived induced pluripotent stem cells (iPSc) that allow us to study the dysfunctional motor neurons in ALS. IPSc originate from a simple skin biopsy from a participating ALS patient.  Scientists then reprogram the cells in a petri dish to become motor neurons, which allows us to identify patient and motor neuron specific dysfunctional elements of the cell.

What does this mean for development of new ALS therapies?

Patients with ALS will all have similar symptoms.  However, many in the research community still question if ALS is a singular disease.  It may actually be many similar diseases, with differences at the cellular level, but with the same clinical manifestations.   This could also explain why ALS has no highly effective treatment.

If this is true, an effective treatment will have to be tailored to a specific patient, or at least to an homogeneous group of ALS patients.  The use of patient-derived iPSc allows us to tailor the search of a personalized therapy.

Work done in our laboratories has identified one disease mechanism potentially relevant to a subset of patients with bulbar onset ALS.  Based on these findings, we are now researching the development of a possible biomarker-based test for bulbar ALS. 

How do glia cells work in ALS?
When bad neighbors attack

ALS researchers have known for some time that glial cells (the cells that provide support and protection for neurons in the central and peripheral nervous system) play an important role in the demise of the motor neurons.  This is how ALS progresses.

Our team has identified a new, previously unknown role for the glia cells and their transporter proteins in progression of ALS.  This transporter protein, EAAT2, is known to decrease in quantity as ALS progresses.

Our new finding showed that the little quantity remaining is also improperly located in the cells.  This triggers release of toxins from the glial cells, accelerating motor neuron death. 

What does this mean for development of new ALS therapies?

Based on our research, we and other scientists are investigating possible therapies that target the improper location of EAAT2 in ALS glial cells.  We are also working to identify the toxins that glial cells release with the goal to develop a therapy to neutralize them.  This approach could slow ALS from progressing.

How can genetics help us understand ALS? C9Orf72: Bridging the gap between ALS & FTD

One of the most promising developments in the ALS research community in the past five years has been the identification of many genes involved in familiar ALS.  This has allowed researchers, including us, to build disease models in laboratories across the country.

At Jefferson, we work primarily on three genetic models of ALS: SOD1, FUS and C9Orf72.  For each genetic form, we study the specific disease processes.

For SOD1-ALS, we found how mutations in the SOD1 gene damages the mitochondria, organelles within cells that function as the “power house.”  Without normally functioning mitochondria, cells do not generate enough energy to survive.  

For FUS-ALS, our team is working to define how mutations in this gene weaken the connection between motor neurons and muscles and we identified specific proteins located at the end of the motor neurons and near the muscles that become dysfunctional because they are “targeted” by the defected and ALS-causative FUS mutation.

Our team of researchers also discovered that one specific class of protein called arginine-rich dipeptides that are generated in patients with C9Orf72 mutation is particularly toxic to motor neurons, as well as the brain’s neurons involved in FTD.

What does this mean for development of new ALS therapies?

Our SOD1-ALS research led us to develop a therapy to protect mitochondria from the mutated SOD1 gene.  We are now testing this approach in pre-clinical trials by using mice modeling this form of ALS.

In C9Orf72 research, using patient iPSc-derived motor neurons, we are beginning to identify ways to eliminate the toxic products generated by this particular genetic mutation. 

Can we rapidly and efficiently test the effectiveness of ALS drugs?

Cell-based models are also useful to test potential anti-ALS drugs.  After adapting our cell-based models, we placed the cells into a high-throughput drug screening platform.  We can now simultaneously test the efficacy of many new ALS drugs in blocking cell death in our models.

What does this mean for development of new ALS therapies?

Based on our research, we have used these high-throughput drug screening platforms to search for drugs that (a)  target EAAT2 and restore its function; (b) drugs that restore mitochondria dysfunction and energy production in motor neurons; (c) antibodies that can neutralize the function of the toxins released by the glial cells.

How can we improve the efficacy of ALS drugs? Lessons from Rilutek®

The research community has identified promising therapeutics in the past, only to have them fail during clinical trials.  We think part of the reason they may have failed is because of hyperactive blood-brain and spinal cord barrier pumps.

Riluzole is currently the only drug FDA-approved to help slow the progression of ALS, and loses effectiveness as the disease progresses. Studies in mice reveal that little riluzole actually makes it to the brain because it is actively pumped out by two proteins on the cell membrane of the blood brain and spinal cord barrier known as P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP).

P-gp and BCRP, among other similar proteins called drug efflux transporters, normally work to protect the brain and spinal cord from external toxins.  In doing so, they also pump out drugs. This phenomenon, known as pharmacoresistance, is well-known in other diseases but surprisingly understudied in ALS.

Our team found that in ALS there is a progressive increase of P-gp and BCRP. ALS patients have higher P-gp and BCRP than controls or patients with another neurological disease.  Knowing that riluzole can bind P-gp and BCRP, we believed it lost efficacy because it was actively pumped out of the cell more effectively by P-gp and BCRP. By blocking the activity of P-gp and BCRP, the researchers believed they could improve the effects of riluzole and tested this idea in a mouse model of ALS.

Administering elacridar, an experimental pump blocker, in combination with riluzole to ALS-affected mice allowed riluzole to remain in the nervous system for longer, and in higher concentrations, than administering riluzolealone.  This prolonged survival, and slowed disease progression, improving muscle strength throughout disease.

What does this mean for development of new ALS therapies?

While our study does not guarantee the success of this regimen in human ALS patients, it nonetheless provides an important new therapeutic approach that needs to be considered when developing new drugs. 

Although riluzole is not a “blockbuster” drug, it is consistently effective in patients. Thus, ways to improve riluzole brain penetration and prolong its proven therapeutic effects should be developed for clinical use while we search for more highly effective treatments.