Abstract Details

Title Effect of complement C3 inhibition with pegcetacoplan in an iPSC-derived ALS neuromuscular junction model of neuroinflammation

Topic General Neurology

Presentation(s) P13 - Poster Session 13 (8:00 AM-9:00 AM)

Poster/Presentation
Number 12-004

Objective Evaluate the effect of C3 inhibition with pegcetacoplan on neuromuscular junction (NMJ) number and function in a human iPSC-derived ALS NMJ model of neuroinflammation.

Background

The complement cascade is a critical component of the immune system; its activation has been implicated in ALS. Complement (C3) breakdown products are reported to be deposited on ALS NMJs. However, the therapeutic potential of complement system modulation in ALS using clinically relevant human cell-based models is unknown.

Design/Methods ALS NMJ systems were established by plating human iPSC-derived motoneurons (TDP-43 [G298S] or healthy wild-type [WT] donors), skeletal myoblasts, Schwann cells, and microglia. NMJ systems were combined with activated M1 macrophages in a microfluidic co-culture system at a 1:25 ratio (vs. skeletal myoblasts). To determine the effect of C3 inhibition on NMJs, human complement intact serum (hCS; 0.05%) with or without the C3 inhibitor pegcetacoplan (50 µg/mL or 100 µg/mL) was applied for 3 hours before testing. NMJ fidelity was calculated by assessing the ratio of myotube contractions under indirect stimulation to the number of stimuli at a given frequency. Fatigue index (FI) was generated from the area under the curve when muscle contraction demonstrated complete or partial tetanus at 2 Hz.

Results

In this interim analysis of an ALS TDP-43 NMJ system, hCS treatment reduced NMJ numbers to 17.9% of the no dose (ND) control, and increased NMJ FI by 12.2%. NMJ numbers were 79.4% and 75.6% of the ND control in the 50 µg/mL and 100 µg/mL of pegcetacoplan, respectively. Compared to hCS, FI was 9.7% and 46.6% lower in the of 50 µg/mL and 100 µg/mL of pegcetacoplan, respectively.

Conclusions In this interim analysis, inhibiting C3 in an inflammatory environment may improve NMJ survival and function in clinically relevant ALS models.

Authors/Disclosures
Yan Li, PhD (Apellis Pharmaceuticals, Inc) PRESENTER	Dr. Li has received personal compensation for serving as an employee of Apellis Pharmaceuticals, Inc.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Leticia Lenkiu	No disclosure on file
Heather Cannon-Patron (Hesperos, Inc.)	Heather Cannon-Patron has received personal compensation for serving as an employee of Hesperos Inc.. Heather Cannon-Patron has stock in Hesperos Inc..
	No disclosure on file
	No disclosure on file
James Hickman (Hesperos, Inc.)	James Hickman has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Hesperos, Inc.. James Hickman has stock in Hesperos, Inc.. The institution of James Hickman has received research support from Hesperos, Inc.. James Hickman has received intellectual property interests from a discovery or technology relating to health care. James Hickman has a non-compensated relationship as a Chief Scientist with Hesperos, Inc. that is relevant to AAN interests or activities.
	No disclosure on file

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