# Pharmacology and macrophage modulation of HPGDS inhibitor PK007 demonstrate reduced disease severity in DMD-affected muscles of the mdx mouse model

## TL;DR

A new drug called PK007 reduces muscle damage and inflammation in a mouse model of Duchenne Muscular Dystrophy, potentially offering a promising treatment.

## Contribution

PK007 is a novel HPGDS inhibitor that specifically targets PGD2 to reduce inflammation and muscle necrosis in DMD.

## Key findings

- PK007 significantly reduced serum PGD2 levels and myonecrosis in multiple muscles of mdx mice.
- Treatment improved muscle grip strength and locomotor activity in juvenile mdx mice.
- PK007 decreased macrophage infiltration and pro-inflammatory cytokine expression in dystrophic muscles.

## Abstract

Duchenne Muscular Dystrophy (DMD) is an X-linked disease characterised by chronic inflammation, progressive muscle damage, and muscle loss. Typically, initial symptoms affect lower limb muscles, including the gastrocnemius (GA), tibialis anterior (TA), and extensor digitorum longus (EDL). During the acute phase of DMD, particularly in boys aged 2–8 years, muscle damage resulting in necrosis (myonecrosis) involves a complex immune-inflammatory response. Prostaglandin D2 (PGD2) is recognised for enhancing pro-inflammatory chemokine and interleukin signalling and recruiting infiltrating immune cells such as pro-inflammatory macrophages, exacerbating myonecrosis.

To reduce levels of PGD2, a novel hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor, PK007, was characterised (i) for potency and pharmacokinetic profiles and then tested in the mdx mouse model of DMD during the acute early onset of disease progression. Juvenile mdx and wild type (WT) C57Bl/10Scsn mice were orally treated with PK007 and control vehicle solution for 10 days, from postnatal day 18 to 28. This builds upon a previous study with PK007 with (ii) additional analyses of disease progression assessed for muscle grip strength, metabolic and locomotor activity, myonecrosis in a wide range of muscles (3 from hindlimb, diaphragm, heart, and tongue), macrophage infiltration and pro-inflammatory cytokines (TNF-α, IL-1β and iNOS).

PK007 exhibited high potency (17.23 ± 12 nM), a long half-life (3.0 ± 0.3 h), and good oral bioavailability (81%). Treatment with PK007 decreased serum PGD2 levels (33.36%) in mdx mice compared to control (vehicle-treated) mdx mice. In mdx mice (compared with controls), PK007 enhanced grip strength (69.05% increase) and improved locomotor activity (69.05% increase). Histological analysis revealed a significant reduction in the total myonecrotic area in PK007-treated GA (49.75%), TA (73.87%), EDL (60.31%), diaphragm (48.02%), and tongue (37.93%) muscles of mdx mice (compared with controls). Additionally, PK007 decreased macrophage cell area by 55.56% in GA and 47.83% in EDL muscles. Further expression of pro-inflammatory cytokines and enzymes such as TNF-α, IL-1β and iNOS were significantly reduced in PK007 treated mice. These results demonstrate that PK007 significantly reduces the inflammatory response, protects muscles from necrosis and increases strength in juvenile mdx mice.

This study lays a strong foundation for progressing the use of HPDGS inhibitors such as PK007, which specifically inhibit PGD2 and reduce inflammation, as a viable therapeutic approach for DMD. This approach protects dystrophic muscles from necrosis and reduces the severity of this debilitating disease, improving outcomes and quality of life.

The online version contains supplementary material available at 10.1186/s13395-025-00379-1.

• Novel therapeutic approach: PK007 is a selective hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor targeting Duchenne Muscular Dystrophy (DMD).

• Efficacy in mdx mice: PK007 significantly reduces PGD2 levels, myonecrosis, and macrophage infiltration in dystrophic muscles.

• Functional benefits: PK007 improves muscle strength and locomotor activity in juvenile mdx mice during acute disease progression.

• Clinical potential: PK007 demonstrates potential as a targeted therapy for DMD.

The online version contains supplementary material available at 10.1186/s13395-025-00379-1.