prostatic acid phosphatase (pap) - a potent analgesic for treating pain mark j. zylka university of...

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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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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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)