Presenting Author:

Ina Dervishi, M.D.

Principal Investigator:

P. Hande Özdinler

Department:

Neurology, Ken and Ruth Davee Department

Keywords:

hgf, als, neurodegeneration

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B107 - Basic Science

Investigating the role of HGF on motor neuron in ALS

Hepatocyte growth factor (HGF) was first discovered as a hepatocyte mitogen and its role in angiogenesis, fibrosis, muscle regeneration, apoptosis and neurodegeneration has been studied. Recent evidence suggests that HGF has a supportive role for motor neuron survival. ALS is a progressive neurodegenerative motor neuron disease involving both the upper and lower motor neurons. Therefore, HGF treatment has been considered as a potential option for ALS disease. VM 202 is a plasmid DNA containing HGF-x7, which encodes two isoforms of HGF, and allows production of HGF in the introduced cells and neurons. We initially investigated the expression patterns of HGF-receptor (c-Met) and HGF in the neuromuscular junction, spinal cord and the motor cortex of hSOD1G93A-UeGFP mice, in which both the upper and the spinal motor neurons are genetically labeled with eGFP expression that is stable and long-lasting, allowing visualization and cellular analysis of different components of the motor-neuron circuitry. We detect HGFR (HGF receptor) at the neuromuscular junction, spinal cord and the motor cortex. Interestingly, CSMN displayed selectively high levels of HGFR expression at P80 and P120. Our initial studies suggest that astrocytes are the primary source of HGF in the spinal cord, and that spinal cord has higher levels of HGF than that of the cortex. Interestingly, especially towards end-stage, HGFR levels were increased in diseased mice. These results suggest that both upper and lower motor neurons would respond to HGF treatment. Our goal is to investigate whether constant supply of HGF would have an impact on degenerating motor neurons. Current experiments involve biweekly intramuscular injections of the VM202 plasmid into 4 different muscles in the leg of hSOD1G93A-UeGFP mice, at P60, – a time of disease onset¬, and investigate the correlation between motor function improvements and motor neuron survival with respect to disease progression. Upon completion, we will have a better understanding for the correlation between HGF treatment and improved motor neuron health and motor function, an important preclinical assessment in ALS therapies.