Abstract Details

Title Reduced Spinal Motor Neuron Expression of Insulin-like Growth Factor-2 and Insulin-like Growth Factor Binding Protein 5 in Spinal Muscular Atrophy Type 1

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S46 - Neuromuscular and Clinical Neurophysiology (EMG): Motor Neuron/Charcot Marie Tooth (4:42 PM-4:54 PM)

Poster/Presentation
Number 007

Background Insulin-like Growth Factors (IGFs) are known motor neuron survival factors which are secreted from many tissues and can be the basis of therapeutic strategies to protect vulnerable motor neurons from degeneration in SMA and ALS. While IGF-1 and its inducer somatotrophin have been investigated in ALS and SMA clinical trials respectively without success, IGF-2 has not been tested. Little is known about IGF-2 in SMA but one study shows that IGF-2 increases survival and neurite outgrowth of motor neurons derived from SMA and ALS patients. IGF-2 binds to IGF-1R, IGF2R and insulin receptors. IGF binding proteins may enhance, inhibit, or act independent of IGF signaling.

Objective Evaluate expression of IGF-2, its receptors and binding proteins in SMA Type 1 patient spinal motor neurons

Design/Methods

We compared differential mRNA expression of IGF2, IGR1, IGFR2, INSR, IGFBPL1, IGFBP5 in purified motor neuron cultures derived from iPSCs generated from SMA Type 1 patient skin fibroblasts versus wild type motor neurons derived from iPSCs generated from normal neonatal foreskin fibroblasts from 4 biological replicates. P value <0.01 was considered statistically significant.

Results IGF2 was downregulated by 5-fold (p=0.0001), IGFBPL1 upregulated by 2-fold (p=0.0001), and IGFBP5 downregulated by 1.5-fold (p=0.0003) in SMA motor neurons compared to wild type motor neurons. There was no significant difference between mRNA expression of all the IGF receptors.

Conclusions

Downregulation of neurotrophic factor IGF-2 and upregulation of IGFBP1, which sequesters and reduces local IGF-2, suggests that IGF-2 has a role in SMA motor neuron vulnerability. IGFBP5 can mediate neuronal survival independent of IGFs. We are performing clinical studies to evaluate the significance of these pathways in SMA patients and therapeutic implications in SMA and other motor neuron diseases. These have potential to confer additional neurotrophic support to SMA patients who are living longer due to recent advances in SMA therapeutics.

Authors/Disclosures
Crystal J. Yeo, MD, PhD (Partners/Brigham and Women's Hospital/Massachusetts General Hospital) PRESENTER	Dr. Yeo has nothing to disclose.
	No disclosure on file
Basil T. Darras, MD (Children'S Hosp Boston Harvard Med School)	The institution of Dr. Darras has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Darras has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus. The institution of Dr. Darras has received research support from National Institutes of Health/National Institute of Neurological Disorders and Stroke,. The institution of Dr. Darras has received research support from Slaney Family Fund for SMA. The institution of Dr. Darras has received research support from Spinal Muscular Atrophy Foundation. The institution of Dr. Darras has received research support from CureSMA. The institution of Dr. Darras has received research support from Working on Walking Fund . The institution of Dr. Darras has received research support from CHERISH, CS2/CS12 . The institution of Dr. Darras has received research support from Biogen for CS11. The institution of Dr. Darras has received research support from AveXis. The institution of Dr. Darras has received research support from Sarepta Pharmaceuticals. The institution of Dr. Darras has received research support from PTC Therapeutics. The institution of Dr. Darras has received research support from Roche. The institution of Dr. Darras has received research support from Santhera. The institution of Dr. Darras has received research support from Scholar Rock. The institution of Dr. Darras has received research support from Fibrogen. The institution of Dr. Darras has received research support from Summit. Dr. Darras has received publishing royalties from a publication relating to health care. Dr. Darras has received publishing royalties from a publication relating to health care.

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