Novel Inhibitor PK007 Reduces Muscle Inflammation and myonecrosis in mdx mouse models

Topic:

Pre-Clinical Research

Poster Number: O140

Author(s):

Sai Yarlagadda, PhD, The University of Queensland, School of Biomedical Science, Chynna-Loren Sheremeta, PhD, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Mark Smythe, Associate Professor, PhD, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Miranda Grounds, Emeritus Professor, PhD, School of Anatomy and Human Biology at the University of Western Australia, Peter Noakes, Associate Professor, PhD, School of Biomedical Sciences, The University of Queensland, Brisbane

Background: During the acute phase of DMD, in boys aged 2-8, muscle wasting initiates a complex immune-inflammatory response. Prostaglandin D2 (PGD2) is recognised for enhancing pro-inflammatory chemokine signalling and recruiting infiltrating immune cells such as pro-inflammatory macrophages, in turn exacerbating muscle damage.

Methods: Novel hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor, PK007, was characterised for potency and pharmacokinetic profiles. Mdx mice (3-weeks) and the recently engineered D2.mdx (12-weeks) mice were orally treated over 10 days with PK007 and vehicle. We assessed the effect of HPGDS inhibitor PK007 on muscle strength, locomotion, myonecrosis, and macrophage infiltration.

Results: PK007 exhibited low clearance (50.4 mL/min/kg), high potency (11 nM), a long half-life (3.0 hours), and good oral bioavailability (81%). Treatment with PK007 resulted in decreased serum PGD2 levels (33.36%) in mdx mice and lower PGD2 lysate levels in gastrocnemius (GA, 47.98%), extensor digitorum longus (EDL, 47.98%), and tongue (61.13%) muscles in D2.mdx mice. Enhanced grip strength (69.05% increase in mdx mice and 30.47% increase in D2.mdx mice) and improved locomotor activity (69.05% increase in mdx mice and 48.24% increase in D2.mdx mice) were observed following PK007 treatment compared to vehicle-treated mice. Echocardiography assessment of the heart in PK007-treated D2.mdx mice showed decreased LV mass (36.85%) and a significant increase in stroke volume (22.73%) and cardiac output (32.86%). Histological analysis revealed a significant reduction in the total myonecrotic area in PK007-treated GA (49.75%), tibialis anterior (TA, 73.87%), EDL (60.31%), diaphragm (48.02%), and tongue (37.93%) muscles, with approximately 20% fewer regenerated muscle fibres in PK007 treated GA and TA muscles of mdx mice. Additionally, a decrease in macrophage cell area of 55.56% in GA and 47.83% in EDL muscles was observed.

Conclusion: Our findings suggest that PK007 holds promise as a potential drug-based intervention for DMD by effectively reducing inflammation, necrosis, and muscle damage in DMD.