The immune system is a tightly regulated network that maintains a balance of immune homeostasis under healthy conditions. However, in patients with autoimmune disease and chronic inflammation, this equilibrium becomes disrupted. Dysregulation of the adaptive immune system is the core of immune-mediated disease pathogenesis. Hyperactivation of autoreactive effector T cells (TEFF) such as TH1, TH2 and TH17 cells and a concomitant defect in regulatory T cells (TREG) results in the breakdown of immune homeostasis and the development of autoimmune diseases.
DYRK1A in Autoimmunity
Furthermore, the inflammatory responses described above may be further enhanced by the innate immune system including monocytes, macrophages and dendritic cells. Toll-like receptors (TLRs) relay signals through the adaptor protein MyD88 to activate NF-kB and induce inflammation. Alternatively spliced isoforms of MyD88 have been shown to play an important regulatory role for the TLR signaling pathway. The MyD88 gene produces two alternatively spliced isoforms, MyD88-L (long) and MyD88-S (short). MyD88-L induces inflammation when TLRs are activated. In contrast, MyD88-S expression, is induced by TLR activation and acts as a dominant-negative inhibitor of inflammation. Thus, under healthy conditions, MyD88 alternative splicing is regulated by the TLR4-MyD88 signaling pathway. However, in chronic inflammatory conditions this regulation may be impaired resulting in an overactivation MyD88-dependent receptor signaling with substantial cytokine and chemokine secretion exacerbating the autoimmune disease.
Current Treatment Options and Limitations
Current treatments for autoimmune conditions are broadly immunosuppressant and can lead to debilitating side effects, including increased risk for developing serious infections that can lead to hospitalization and may even be life-threatening. Further, many of these approaches do not restore the healthy equilibrium of functional T REG / T EFF – the main cause and driver of autoimmune disease development.
Restoring Immune Equilibrium
Restoring immune homeostasis through the re-balance of TREG and TEFF is a novel, differentiated approach with curative potential across many autoimmune diseases. In addition, BBI-02 provides the unique potential to also target the innate immune response by inhibiting MyD88/IRAK4-related signaling pathways, offering a large potential to target a variety of autoimmune conditions, including:
- Atopic dermatitis: The most common chronic inflammatory skin disease. More than 28 million adults in the U.S. are affected with atopic dermatitis and about 40% have moderate or severe symptoms, leading to substantial effects on quality of life characterized by severe pruritus and eczematous lesions. Currently, there are no curative treatments for atopic dermatitis, but only symptomatic treatments.
- Rheumatoid Arthritis: A chronic inflammatory joint disease that can cause cartilage and bone damage, as well as disability. Rheumatoid Arthritis affects approximately 1.5 million adults in the U.S. and as of to date no curative therapies exist. While existing therapies provide large benefit to patients by slowing disease progression, up to 20% become refractory to standard therapy and are in need for novel treatment options to prevent rapid disease progression and debilitating joint destruction.
- Type 1 Diabetes (T1D): One of the most common chronic diseases in childhood, T1D is caused by insulin deficiency following destruction of the insulin-producing pancreatic beta cells. T1D remains the most common form of diabetes in children, accounting for approximately 80% of new diabetes diagnoses in patients ≤19 years in the U.S. There are currently no curative treatments available, and the key therapeutic focus remains the control of blood glucose levels.
BBI-02 is a potential first-in-class, oral DYRK1A inhibitor that aims to restore immune homeostasis by targeting both the adaptive and innate immune responses in autoimmune and inflammatory diseases.
1. Kuchroo, V. K., Ohashi, P. S., Sartor, R. B. & Vinuesa, C. G. Dysregulation of immune homeostasis in autoimmune diseases. Nat. Med. 18, 42–47 (2012).
2. Khor, B. et al. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife 4, 1–27 (2015).
3. Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4. J. Exp. Med. 197, 263 (2003).
4. 25 th Annual Meeting of the RNA Society 2020: Lee F et al. Signal-dependent Regulation of Alternative Splicing in Innate Immunity
5. Kaplan, M. J. Targeting the myddosome in systemic autoimmunity‐ ready for prime time? Arthritis Rheumatol. Art. 41951 (2021).
6. Liu Y.A. et al. Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133. J. Med. Chem. 63, 2958–2973 (2020).
7. Seo, D. H. et al. P001 The novel DYRK1a inhibitor VRN024219 alleviates disease severity on the IBD mouse models by modulating T-cell differentiation. J. Crohn’s Colitis 14, S129–S129 (2020).
8. Langan, S. M., Irvine, A. D. & Weidinger, S. Atopic dermatitis. Lancet 396, 345–360 (2020).
9. Smolen, J. S. et al. Rheumatoid arthritis. Nat. Rev. Dis. Prim. 2018 41 4, 1–23 (2018).
10. DiMeglio, L. A., Evans-Molina, C. & Oram, R. A. Type 1 diabetes. Lancet 391, 2449–2462 (2018).