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Prostatic acid phosphatase (PAP) - a potent analgesic for treating pain

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

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Prostatic acid phosphatase (PAP) - a potent analgesic for treating pain

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  1. Prostatic acid phosphatase (PAP) - a potent analgesic for treating pain Mark J. Zylka University of North Carolina at Chapel Hill

  2. 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)

  3. 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)

  4. Possible Markets • Orthopedic surgery (prophylactic; preemptive analgesia) • Neuropathic pain, including postherpetic neuralgia • Lower back pain (inflammatory pain) • Cancer pain

  5. Preclinical Data in Mice

  6. Thermal test Thermal

  7. Mechanical Test Mechanical

  8. Analgesic effects last 3 days

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

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

  11. Repeated injections are effective (No desensitization) Non-injured paw is not affected. (suggests PAP selectively relieves pain in body part that hurts) • Makes long-term treatment of pain possible • (multiple injections or intrathecal pump = repeated sales) • Gene Therapy • (PAP in Adenoassociated virus; rAAV)

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

  13. PAP works by making adenosine PAP AMP ADO + P (Adenosine monophosphate) (Adenosine) (Adenosine receptor knockout mice)

  14. Adenosine is analgesic in humans

  15. 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

  16. PAP-selective prodrugs (orally active) PAP Inactive Prodrug-P Active drug + P (UNC543) In collaboration w/ Stephen Frye’s group at UNC

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

  18. Acknowledgments University of North Carolina Nate Sowa Bonnie Taylor-Blake Jennifer Coleman Yvette Chuang Julie Hurt Stephen Frye Jian Jin Support UNC Startup Funds, Sloan Foundation, Whitehall, NARSAD, Klingenstein, Searle, Rita Allen, NINDS U. Helsinki (Finland) Pirkko Vihko Annakaisa Herrala

  19. PAP purification from yeast (Pichia)

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