Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination

Acta Neuropathologica Communications

Research

Isharat Yusuf¹  Zachary Naiman¹  Laura Carter¹  Warren Plaisted¹  Suzana Marušić²  Kirsten Scarlett Evonuk²  Brandon Carrier²  Tara Petrosino²  Ethan Sprague²  Evelyn Martinez²  Željko Ferenčić²  Zachary Stewart²  Josh Mattie²  Timothy Delp²  C. J. Cracchiolo²  Gregory Andrew Johnson²  Kai Schofield²  Reine Mager²  Sen Wang² 

[1] Gossamer Bio, 3013 Science Park Road, Suite 200, 92121, San Diego, CA, USA;Hooke Laboratories, LLC, 439 South Union Street, 01843, Lawrence, MA, USA;

关键词: Multiple sclerosis;    Secondary progressive;    Demyelination;    Microglia;    B cells;    Myeloid cells;    Experimental autoimmune encephalomyelitis;   

DOI  :  10.1186/s40478-023-01614-w

 received in 2023-05-23, accepted in 2023-06-29,  发布年份 2023

来源: Springer

【 摘 要 】

Bruton’s tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

41116_2023_38_Article_IEq243.gif

41116_2023_38_Article_IEq235.gif

41116_2023_38_Article_IEq221.gif

41116_2023_38_Article_IEq213.gif

Fig. 1

41116_2023_38_Article_IEq187.gif

41116_2023_38_Article_IEq151.gif

41116_2023_38_Article_IEq147.gif

41116_2023_38_Article_IEq144.gif