1. Academic Validation
  2. Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination

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

  • Acta Neuropathol Commun. 2023 Jul 12;11(1):115. doi: 10.1186/s40478-023-01614-w.
Kirsten Scarlett Evonuk 1 Sen Wang 2 Josh Mattie 2 C J Cracchiolo 2 Reine Mager 2 Željko Ferenčić 2 Ethan Sprague 2 Brandon Carrier 2 Kai Schofield 2 Evelyn Martinez 2 Zachary Stewart 2 Tara Petrosino 2 Gregory Andrew Johnson 2 Isharat Yusuf 3 Warren Plaisted 3 Zachary Naiman 3 Timothy Delp 2 Laura Carter 3 Suzana Marušić 4
Affiliations

Affiliations

  • 1 Hooke Laboratories, LLC, 439 South Union Street, Lawrence, MA, 01843, USA. k.evonuk@hookelabs.com.
  • 2 Hooke Laboratories, LLC, 439 South Union Street, Lawrence, MA, 01843, USA.
  • 3 Gossamer Bio, 3013 Science Park Road, Suite 200, San Diego, CA, 92121, USA.
  • 4 Hooke Laboratories, LLC, 439 South Union Street, Lawrence, MA, 01843, USA. s.marusic@hookelabs.com.
Abstract

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.

Keywords

B cells; Demyelination; Experimental autoimmune encephalomyelitis; Microglia; Multiple sclerosis; Myeloid cells; Secondary progressive.

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