Prostatic acid phosphatase (PAP) -

a potent analgesic for treating pain

Mark J. Zylka University of North Carolina at Chapel Hill

More Americans suffer from chronic pain than heart disease, diabetes and cancer combined

•

Inflammatory and surgical pain

(~27 million Americans have arthritis of knee) •

Neuropathic pain

nerve injury, shingles, diabetic neuropathy (~15 million Americans)

Prostatic Acid Phosphatase (PAP)

Pain-sensing neurons Spinal Cord 1. Found in pain-sensing neurons (makes it a “natural” product) 2. Drug-like (Use secreted version as drug; like insulin) 3. Recombinant PAP (can produce in yeast, secreted into medium) * Provides clear path to FDA-approval 4. Potently suppresses pain (>8x better than morphine)

Possible Markets

1. Orthopedic surgery (prophylactic; preemptive analgesia) 2. Neuropathic pain, including postherpetic neuralgia 3. Lower back pain (inflammatory pain) 4. Cancer pain

Preclinical Data in Mice

Thermal test Thermal

Mechanical Test Mechanical

Analgesic effects last 3 days

PAP is >8x more effective than morphine; no side effects

PAP suppresses chronic inflammatory pain Thermal Mechanical ….as well as Neuropathic pain (not shown)

Repeated injections are effective

(No desensitization)

5 4 7 6 10 9 8 3 2 1 0 0 1 hPAP *** 2 *** *** 4 hPAP *** 5 Control Injured *** 6 3

Time (d)

• Makes long-term treatment of pain possible Non-injured paw is not affected.

(suggests PAP

selectively

relieves pain in body part that hurts) (multiple injections or intrathecal pump = repeated sales) • Gene Therapy (PAP in Adenoassociated virus; rAAV)

PAP as prophylactic – inject prior to surgery to prevent post-op pain Thermal Mechanical

PAP works by making adenosine

AMP

(Adenosine monophosphate) PAP

ADO + P

(Adenosine) (Adenosine receptor knockout mice)

Adenosine is analgesic in humans

Preemptive analgesia: i.v. adenosine during surgery provides long lasting pain relief in humans (much better than an opioid) Fukunaga et al (2003) Pain 101:129

PAP-selective prodrugs

(

orally active

) PAP Inactive Prodrug-P (UNC543) Active drug + P ***

UNC 543 (10 mg/kg oral)

*** *** *** 20 18 16 14 12 10 8 6 4 2 0 0 WT PAP KO *** 1 2

Time (hours)

3 4 In collaboration w/ Stephen Frye’s group at UNC 5

Use of PAP as an analgesic

1. Use as biologic a. Acute: Intrathecal injection b. Chronic: repeated injections or in intrathecal pump (like morphine, Prialt) 2. PAP-selective prodrugs (orally active)

Acknowledgments

University of North Carolina

Nate Sowa Bonnie Taylor-Blake Jennifer Coleman Stephen Frye Jian Jin

U. Helsinki (Finland)

Pirkko Vihko Annakaisa Herrala Yvette Chuang Julie Hurt

Support

UNC Startup Funds, Sloan Foundation, Whitehall, NARSAD, Klingenstein, Searle, Rita Allen, NINDS

PAP purification from yeast (Pichia)