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Effect of complement C3 inhibition with pegcetacoplan in an iPSC-derived ALS neuromuscular junction model of neuroinflammation (P13-4.004)

2023; Lippincott Williams & Wilkins; Volume: 100; Issue: 17_supplement_2 Linguagem: Inglês

10.1212/wnl.0000000000203916

1526-632X

Yan Li, Virginia Smith, Sarah Skinner, Ashley Robertson, Leticia Lenkiu, Heather Cannon-Patron, Daisy Martinez, Hannah Hanson, James J. Hickman, David J. Eyerman,

Multiple Sclerosis Research Studies

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. Disclosure: Dr. Li has received personal compensation for serving as an employee of Apellis Pharmaceuticals, Inc. Dr. Smith has stock in Hesperos, Inc.. Dr. Skinner has received personal compensation for serving as an employee of Hesperos Inc. Ashley Robertson has received personal compensation for serving as an employee of Hesperos, Inc.. Ashley Robertson has stock in Hesperos, Inc.. Ms. Lenkiu has received personal compensation for serving as an employee of Hesperos inc`. Ms. Cannon has received personal compensation for serving as an employee of Hesperos, Inc.. Ms. Cannon has stock in Hesperos, Inc.. Ms. Martinez has received personal compensation for serving as an employee of Hesperos Inc. Hannah Hanson has received personal compensation for serving as an employee of Hesperos. Dr. Hickman has stock in Hesperos, Inc. Dr. Hickman has received research support from Hesperos, Inc. David Eyerman has received personal compensation for serving as an employee of Apellis Pharmaceuticals . David Eyerman has stock in Apellis Pharmaceuticals . David Eyerman has stock in Fulcrum Therapeutics . David Eyerman has stock in Alkermes . David Eyerman has stock in Denali Therapeutics. David Eyerman has stock in Beam Therapeutics. David Eyerman has stock in Passage Bio .