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
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)
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)
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
Preclinical Data in Mice
Thermal
Thermal test
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)(No desensitization)
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Time (d)
Wit
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ControlInjured
*** ******
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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)
PAP as prophylactic – inject prior to surgery to prevent post-op pain
Thermal Mechanical
PAP works by making adenosine
AMP(Adenosine
monophosphate)
ADO + P(Adenosine)
PAP
(Adenosine receptor knockout mice)
Adenosine is analgesic in humans
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)
UNC 543 (10 mg/kg oral)
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Time (hours)
With
draw
al L
aten
cy (s
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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)
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)
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
PAP purification from yeast (Pichia)