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Targeting TLR4-lipid rafts to prevent postoperative pain

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42NS132622-01
Agency Tracking Number: R42NS132622
Amount: $414,835.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 108
Solicitation Number: NS20-009
Solicitation Year: 2020
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-21
Award End Date (Contract End Date): 2025-08-31
Small Business Information
San Diego, CA 92121-3938
United States
DUNS: 081343492
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (713) 745-0438
Business Contact
Phone: (858) 337-1801
Research Institution
HOUSTON, TX 77030-4009
United States

 Nonprofit College or University

Postoperative pain is a prevalent source of pain requiring appropriate management to reduce its impact upon
quality of life. Even with the availability of several analgesics, postoperative pain is often undermedicated
because of concern related to the adverse consequence of the available therapeutics (e.g., NSAIDs and opiates),
including addiction and decreased survival of cancer patients. To this end we have undertaken development of
RFT1124, a modified apolipoprotein A-I binding protein (AIBP), which exerts its action through specific targeting
of membrane lipid rafts by altering local membrane cholesterol dynamics in dorsal root ganglion (DRG) neurons
and macrophages and in spinal microglia that express TLR4 (TLR4-rafts) and are known to be engaged in
processing acute and chronic pain secondary to nerve and tissue injury. We have discovered that TLR4-rafts
are heavily expressed on macrophages and exclusively on nociceptive DRG neurons. We have shown that it is
possible to specifically target these TLR4-rafts through the actions of RFT1124 (AIBP), which binds to TLR4 and
specifically disrupts the associated lipid rafts. In vitro, AIBP blocks the ectopic activity of human DRG nociceptors
isolated from painful dermatomes. In vivo, intravenous injection of AIBP prior to paw incision prevented the
development of tactile allodynia in rats. These exciting new data, together with our published studies showing
AIBP efficacy and mechanism of action in chemotherapy-induced peripheral neuropathy, suggest the potential
of AIBP (RFT1124) in treatment of postoperative pain. In Phase I of this Fast-Track STTR proposal, we will
define the efficacy of intravenous RFT1124 delivery on postoperative pain in rats, including: (i) dose response;
(ii) dependence on the time of pre or post incision administration; (iii) sex differences. In Phase II, we plan to
manufacture and release RFT1124 drug product for expanded efficacy and toxicology studies using cGMP-
compatible processes and analytical assays. Further, a pharmacokinetics of RFT1124 in blood and DRG and a
non-GLP safety assessment of intravenous delivery of RFT1124 will be conducted to establish an estimate of
safety margin and target organs. As an independent biomarker of activity, we will characterize the effects of
RFT1124 on hyperactivity in rat DRG neurons otherwise produced by surgical incision in male and female rats.
The efficacy studies will be extended to human DRG nociceptive neurons in culture, with the DRG obtained from
donors of both sexes. Target engagement will be tested with an AIBP variant, which like RFT1124 alters lipid
rafts but does not bind TLR4. We anticipate significant suppression of allodynic behavior and ectopic activity
induced by surgical injury after incision by RFT1124 but not the AIBP variant lacking the TLR4-binding domain.
These studies will provide the enabling data set to initiate a pre-IND meeting with the FDA in anticipation of
moving RFT1124 into first-in-human clinical trials.

* Information listed above is at the time of submission. *

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