prostatic acid phosphatase (pap) - a potent analgesic for treating pain mark j. zylka university of...
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Prostatic acid phosphatase (PAP) - a potent analgesic for treating pain
Mark J. Zylka
University of North Carolina at Chapel Hill
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More Americans suffer from chronic pain than heart disease, diabetes and cancer combined
• Neuropathic painNeuropathic pain nerve injury, shingles, diabetic neuropathy
(~15 million Americans)
• Inflammatory and surgical painInflammatory and surgical pain (~27 million Americans have arthritis of knee)
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Prostatic Acid Phosphatase (PAP)
1. Found in pain-sensing neurons1. Found in pain-sensing neurons (makes it a “natural” product)
Pain-sensing neurons Spinal Cord
2. Drug-like 2. Drug-like (Use secreted version as drug; like insulin)
3. Recombinant PAP3. Recombinant PAP (can produce in yeast, secreted into medium)
* Provides clear path to FDA-approval
4. Potently suppresses pain4. Potently suppresses pain (>8x better than morphine)
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Possible Markets
1.1. Orthopedic surgery (prophylactic; preemptive analgesia)Orthopedic surgery (prophylactic; preemptive analgesia)
2.2. Neuropathic pain, including postherpetic neuralgiaNeuropathic pain, including postherpetic neuralgia
3.3. Lower back pain (inflammatory pain)Lower back pain (inflammatory pain)
4.4. Cancer painCancer pain
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Preclinical Data in Mice
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Thermal
Thermal test
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Mechanical Test
Mechanical
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Analgesic effects last 3 days
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PAP is >8x more effective than morphine; no side effects
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PAP suppresses chronic inflammatory pain
Thermal Mechanical
….as well as Neuropathic pain (not shown)
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Repeated injections are effective (No desensitization)(No desensitization)
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*** ******
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hPAP hPAP
• Makes long-term treatment of pain possible
(multiple injections or intrathecal pump = repeated sales)
• Gene Therapy
(PAP in Adenoassociated virus; rAAV)
Non-injured paw is
not affected. (suggests PAP selectively relieves pain in body part that hurts)
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PAP as prophylactic – inject prior to surgery to prevent post-op pain
Thermal Mechanical
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PAP works by making adenosine
AMP(Adenosine
monophosphate)
ADO + P(Adenosine)
PAP
(Adenosine receptor knockout mice)
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Adenosine is analgesic in humans
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Fukunaga et al (2003) Pain 101:129
Preemptive analgesiaPreemptive analgesia: i.v. adenosine during surgery provides long lasting pain relief in humans (much better than an opioid)
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UNC 543 (10 mg/kg oral)
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WTPAP KO
***
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In collaboration w/ Stephen Frye’s group at UNC
Inactive Prodrug-P(UNC543)
Active drug + PPAP
PAP-selective prodrugs (orally active)
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Use of PAP as an analgesic
1.1. Use as biologicUse as biologic
a. Acute: Intrathecal injection
b. Chronic: repeated injections or in intrathecal pump (like morphine, Prialt)
2.2. PAP-selective prodrugs (orally active)PAP-selective prodrugs (orally active)
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U. Helsinki (Finland)
Pirkko Vihko
Annakaisa Herrala
AcknowledgmentsAcknowledgments
Support
UNC Startup Funds, Sloan Foundation, Whitehall, NARSAD, Klingenstein, Searle, Rita Allen,
NINDS
Nate Sowa Bonnie Taylor-Blake
Jennifer Coleman
Yvette Chuang
University of North Carolina
Stephen Frye
Jian Jin
Julie Hurt
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PAP purification from yeast (Pichia)