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Rusalatide Acetate (TP508) Mitigation Effect on Radiation Induced Keratopathy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41EY034773-01
Agency Tracking Number: R41EY034773
Amount: $341,302.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NEI
Solicitation Number: PA21-262
Timeline
Solicitation Year: 2021
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-30
Award End Date (Contract End Date): 2024-09-29
Small Business Information
10709 EHLERS RD
Conroe, TX 77302-4025
United States
DUNS: 059314482
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 USHA ANDLEY
 (636) 253-2934
 andley@wustl.edu
Business Contact
 JANE HICKS
Phone: (936) 520-6156
Email: jlhicks@affirmedpharma.com
Research Institution
 TUFTS MEDICAL CENTER
 
800 WASHINGTON ST
BOSTON, MA 02111-1552
United States

 Domestic Nonprofit Research Organization
Abstract

Abstract
Radiation induced keratopathy results in significant ocular surface disease, stem cell deficiency, vision loss,
discomfort, and subsequent poor quality of life, affecting up to 23% of patients receiving radiation therapy
for head and neck malignancies [1]. Studies have pointed out functional roles of corneal neurons and
secretory cells of the lacrimal gland in the etiology of radiation induced keratopathy. This study is aimed to
investigate the effect of a known radio-mitigating drug, rusalatide acetate (TP508), to protect or repair
corneal epithelial cells, corneal neurons and lacrimal cells in an irradated mouse model. Studies in a murine
model of keratopathy indicate that the breakdown of immune homeostasis can be attributed to corneal
nerve damage which may be a key pathologic mechanism of radiation keratopathy [2]. One study
demonstrated significant nerve loss and increase in leukocyte influx and activation within months of
irradiation and implicated the effects of chronic nerve loss on corneal immune homeostasis [2]. Studies
have also shown that the lacrimal gland is directly affected by radiation with decreased aqueous secretion
occurring within 3 days of irradiation and persisting beyond 30 days [3]. A persistent ocular inflammatory
response often leads to a self-perpetuating adaptive immune T-cell response to self-antigens that further
perpetuates the pathology. TP508, through its Arginine, Glycine, and Aspartate (RGD) binding site is a
ligand for integrin receptors and has been previously shown through this mechanism to down regulate
proinflammatory pathways and upregulate regenerative mechanisms for apoptosis mitigation and stem cell
activation. The hypothesis for this study is that the known molecular activity of TP508 demonstrated in
previous radioprotection studies across a wide range of cells will have a similar effect in reversing corneal
and lacrimal gland radiation damage. Studies will include systemic and topical routes of drug delivery. Balb/
c mice will receive a metered radiation dose of 11 Gy, previously shown to be sublethal to Balb/c mice and
to cause keratopathy [2]. Aim 1 will investigate an intraperitoneal injection of TP508 administered one day
(24 hours) post irradiation for effects in protecting corneal epithelial cells, corneal neurons and lacrimal
gland structure. Effects from TP508 doses of 200 µg/ml (5mg/kg) and 500 µg/ml (12.5mg/kg), will be
evaluated. Analysis will include fluorescein corneal staining for presence or absence of lesions at 1 month
and 2 months and immunohistochemistry for immune markers for corneal neurons and lacrimal cells with
ultrastrucural analysis of lacrimal gland structure at 2 months. Aim 2 will investigate a topical eye drop
delivery of the same 2 doses, administered one day (24 hours) and biweekly for two weeks post irradiation
with the same data points collected at the 1- and 2-month time points. Investigations are expected to
suggest potential effects of TP508 in mitigation of radiation keratopathy and optimal routes of delivery.

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

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