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
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)
Spinal Cord
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)
Non-injured paw is
not affected.
10
9
Withdrawal threshold (g)
8
7
***
***
6
***
***
***
(suggests PAP
selectively relieves
pain in body part that
hurts)
5
4
Control
Injured
3
2
hPAP
hPAP
1
0
0
1
2
3
4
5
6
Time (d)
• Makes long-term treatment of pain possible
(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
Active drug + P
(UNC543)
UNC 543 (10 mg/kg oral)
20
***
18
***
***
***
Withdrawal Latency (s)
16
***
14
12
10
8
WT
PAP KO
6
4
2
0
0
1
2
3
4
Time (hours)
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
Yvette
Chuang
Julie Hurt
Stephen Frye
Jian Jin
U. Helsinki (Finland)
Support
Pirkko Vihko
UNC Startup Funds, Sloan
Foundation, Whitehall, NARSAD,
Klingenstein, Searle, Rita Allen,
NINDS
Annakaisa Herrala
PAP purification from yeast
(Pichia)