The ALS Association

Gene Therapy Vector Reaches Most of Brain’s Upper Motor Neurons

February 24, 2016

Upper motor neurons can be directly and specifically targeted for gene therapy in a mouse model of ALS, according to a new study supported by The ALS Association and the Les Turner ALS Foundation. The study was published open access in the journal Gene Therapy by former ALS Association Milton Safenowitz Post-Doctoral Fellow, Javier Jara, Ph.D., out of Dr. Hande Ozdinler’s laboratory at Northwestern University Feinberg School of Medicine in Chicago.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

Upper motor neurons are one of the two types of motor neurons that die in ALS. Upper motor neurons extend from the brain into the spinal cord. When damaged, symptoms like muscle spasticity and exaggerated reflexes occur. In recent years, importance of upper motor neurons for the disease process has been more fully recognized, making them an attractive target for ALS therapy.

In the current study, Javier Jara, Ph.D., Pembe Ozdinler, Ph.D., and colleagues at Northwestern University Feinberg School of Medicine in Chicago, showed that upper motor neurons (also called corticospinal motor neurons) could be targeted with a gene therapy vector known as adeno-associated virus (AAV). AAV is the most widely used vector (carrier) due to its safety and ability to target specific tissue types. Working in a mouse model of ALS, the research team showed that direct injection of the vector into the brain’s cortex led to the transformation (i.e. introduction of the virus into cells) of about 70% of upper motor neurons, the highest percentage reported to date. Success of the technique in this model sets the stage for further research delivering therapeutic molecules using AAV in animal models, possibly leading to human trials.

“It is important to see that such a large percentage of corticospinal motor neurons can be reached by the AAV vector, as shown in this study,” said Association Chief Scientist Lucie Bruijn, Ph.D., M.B.A. “That gives us hope that targeting a therapy to these neurons using AAV has a real chance of affecting most of the motor neurons in the brain.”

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