A Novel Approach to Treating Autoimmune Diseases by Modulating Immune Cell Proliferation

The invention provides methods for inhibiting the lipid kinase, PIKFYVE, to induce the proliferation of T-regulatory cells. This technology offers a significant advantage by restoring the balance of immune cells, specifically the Treg/Th17 ratio, to treat inflammatory and autoimmune diseases.

Description

The invention is a method for treating immune disorders by inhibiting the PIKFYVE lipid kinase. The research shows that PIKFYVE is a critical regulator of the signaling pathways that drive the differentiation of pathogenic Th17 cells. Specifically, PIKFYVE generates PtdIns(3,5)P2, which in turn activates mTORC1 to phosphorylate STAT3, a crucial step for Th17 differentiation. By blocking PIKFYVE activity, the technology effectively reduces the differentiation of Th17 cells and promotes the development of T-regulatory (Treg) cells, which can suppress inflammation. This modulation of the immune cell fate decision re-establishes a healthy Treg/Th17 ratio, which is clinically relevant for managing various inflammatory diseases.

Applications

- Autoimmune Disease Treatment: The technology could be applied to treat a wide range of Th17-driven autoimmune disorders, including multiple sclerosis, psoriasis, and various forms of arthritis.
- Inflammatory Bowel Disease: Potential applications include treating chronic inflammatory conditions such as Crohn's disease and ulcerative colitis.
- Genetic Therapies: The use of gene editing technologies like CRISPR-based methods to specifically inhibit PIKFYVE in targeted cell types, such as CD4+ T cells, presents a potential commercial path.
- Drug Development: The research provides a rationale for the development of new small molecule inhibitors or antibody-based therapies.

Advantages

- Modulates Immune Response: The invention provides a method to induce the proliferation of T-regulatory cells, which helps to treat immune disorders and autoimmune diseases.
- Treats Autoimmune Pathology: Inhibition of PIKFYVE activity has been shown to reduce Th17 differentiation and ameliorate autoimmune pathology in a murine model of multiple sclerosis.
- Novel Therapeutic Target: The technology identifies PIKFYVE as a critical regulator of Th17 differentiation and a potential therapeutic target for a range of autoimmune diseases.
- Versatile Treatment Options: The inhibition of PIKFYVE can be achieved through various means, including small molecules, antibodies, or gene editing technologies.
- Solid Rationale for New Drug Development: The research provides a strong basis for developing next-generation PIKFYVE inhibitors to overcome previous bioavailability challenges.

Invention Readiness

The technology is currently at the stage of in vivo validation, with a significant amount of data generated from both in vitro and in vivo studies in a murine model of multiple sclerosis. The data has successfully demonstrated that inhibiting PIKFYVE reduces Th17 differentiation and autoimmune pathology. Further studies are needed to identify and develop these new inhibitors and to investigate additional signaling pathways regulated by PIKFYVE.

IP Status

Patent Pending

Related Publication(s)

Prado, D. S., Cattley, R. T., Sonego, A. B., Sutariya, P., Wu, S., Lee, M., Boggess, W. C., Shlomchik, M. J., & Hawse, W. F. (2024). The phospholipid kinase PIKFYVE is essential for Th17 differentiation. Journal of Experimental Medicine, 222(2). https://doi.org/10.1084/jem.20240625