Gene-specific response to MuSK agonist antibody in the treatment of Congenital Myasthenic Syndromes

Ho, K.; Adjei-Afriyie, O.; Carmona-Martinez, R.; Ray, R.; O'Neil, D.; Zeldin, J.; Oury, J.; De Clercq, L.; Burden, S.; Vankerckhoven, B.; Vanhauwaert, R.; Spendiff, S.; Lochmüller, H.

doi:10.1101/2025.08.29.673058

bioRxiv · 10.1101/2025.08.29.673058

Gene-specific response to MuSK agonist antibody in the treatment of Congenital Myasthenic Syndromes

Ho, K.·Adjei-Afriyie, O.·Carmona-Martinez, R.·Ray, R.·O'Neil, D.·Zeldin, J.·Oury, J.·De Clercq, L.·Burden, S.·Vankerckhoven, B.·Vanhauwaert, R.·Spendiff, S.·Lochmüller, H.

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Abstract

Congenital myasthenic syndromes (CMS) are a group of rare disorders characterized by fatigable muscle weakness and caused by impaired neuromuscular junction (NMJ) function. CMS symptoms are highly variable, but can be detrimental and lead to death. There are over 40 different genetic subtypes, including Agrn-CMS and ColQ-CMS. Agrn encodes for neural AGRIN, which is released from the nerve terminal and triggers muscle-specific kinase phosphorylation (pMuSK). pMuSK is essential for NMJ development and maintenance, thus AGRIN deficiency causes NMJ impairment. ColQ encodes for collagenous subunit Q (ColQ), which anchors acetylcholinesterase and stabilizes MuSK. As a result, ColQ deficiency results in NMJ degeneration from prolonged transmission signals and decreased pMuSK. Current treatments for Agrn-CMS and ColQ-CMS are limited, highlighting the importance of finding more efficient therapies. Recently, a MuSK agonist antibody with high affinity for the Frizzled-like domain showed remarkable rescue of a Dok7-CMS mouse model. We hypothesized a similar antibody could benefit Agrn- and ColQ-CMS mouse models. Agrn-CMS mice were treated at postnatal day 5 (P5), P15 and P35, and ColQ-CMS mice were treated weekly from P22 to P57. In Agrn-CMS mice, 3B2 treatment rescued survival, bodyweight, fibre type switching and pMuSK levels, and improved grip strength and NMJ morphology. In ColQ-CMS mice, 3B2 treatment was unable to rescue deficits observed. Our findings suggest that MuSK agonists may benefit patients with Agrn-CMS, which should be tested in clinical trials. Our study emphasizes that effective CMS treatment is gene-dependent and relies on an accurate genetic diagnosis.

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Ho, K., Adjei-Afriyie, O., Carmona-Martinez, R., Ray, R., O'Neil, D., Zeldin, J., Oury, J., De Clercq, L., Burden, S., Vankerckhoven, B., Vanhauwaert, R., Spendiff, S., Lochmüller, H.. 2025-08-30. Gene-specific response to MuSK agonist antibody in the treatment of Congenital Myasthenic Syndromes. https://doi.org/10.1101/2025.08.29.673058

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