Glycosaminoglycan Targeting Treatment for Prostatic Hyperplasia and Fibrosis

Benign prostatic hyperplasia (BPH) is an age-related progressive pathologic condition in aging men. More than 50% of patients with BPH have lower urinary tract symptoms (LUTS), a condition affecting storage and voiding. LUTS is evaluated in the clinic using a validated scoring system, IPSS (International Prostate Symptom Score). High IPSS drives medical and surgical treatments. However, these treatments have variable efficacy and unwanted side effects. The pathobiology of BPH is progressive hyperplasia and fibrosis in the transitional zone (TZ) of the prostate with chronic inflammation as the major contributor. Hyaluronic acid (HA), a non-sulfated glycosaminoglycan, (GAG) is causally linked to inflammatory and fibrotic diseases. We discovered that HA and associated family members are highly elevated in BPH tissues from patients with high IPSS, regardless of the prostate volume. The overall objective of this study is to examine the clinical significance of elevated HA in BPH pathology and associated symptoms. Further, to test the efficacy of an orally bioavailable drug that inhibits HA synthesis. This drug has an excellent safety profile for prolonged use. Consistent with HA’s role in inflammation, tissues from patients with high IPSS showed heavy immune cell infiltration in a dense matrix, and related mitogenic and fibrosis hallmarks. Mouse models of inflammation-induced prostate hyperplasia and fibrosis mirrored the pattern of HA expression, and immune cell infiltration. Initial studies showed efficacy of the HA-inhibiting drug in a mouse model. The project will test the hypothesis that HA mediates inflammation-induced prostatic hyperplasia and fibrosis. Furthermore, its inhibitor effectively abrogates this pathology and improves symptoms, with little toxicity. Further, IPSS can stratify patients with BPH to the HA-inhibiting treatment. We will characterize HA and the related molecules from BPH tissues, investigate why HA is elevated in BPH tissues and determine HA functions in ex-vivo cultures (Aim 1). Efficacy of the HA inhibitor to prevent/treat inflammation- induced hyperplasia and fibrosis will be examined in mouse models, along with the evaluation of symptoms, toxicity, and tissue/cell analyses (Aim 2). Clinical significance of HA and associated family will be evaluated in BPH specimens to determine if their levels correlate with IPSS, while adjusting for clinical parameters (Aim 3). Impact: This study should establish HA as a critical mediator of inflammation-induced prostatic hyperplasia, fibrosis and associated voiding symptoms. Testing the efficacy of the HA-synthesis inhibitor in multiple models and evaluating if IPSS can stratify patients with BPH to this treatment should aid in the repurposing of the drug to treat BPH-related symptoms.