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Rusalatide Acetate (TP508) Mitigation of Genotoxic Radiation Damage in Human Lens Epithelial Cells

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41EY033583-01
Agency Tracking Number: R41EY033583
Amount: $388,773.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NEI
Solicitation Number: PA20-272
Timeline
Solicitation Year: 2020
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-02-01
Award End Date (Contract End Date): 2023-01-31
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
 JOHN WEATHERSPOON
 (571) 276-1155
 jweatherspoon@affirmedpharma.com
Business Contact
 JANE HICKS
Phone: (936) 520-6156
Email: jlhicks@affirmedpharma.com
Research Institution
 UNIVERSITY OF TX MD ANDERSON CAN CTR
 
1515 HOLCOMBE BLVD
HOUSTON, TX 77030-4009
United States

 Nonprofit College or University
Abstract

Cancer patients benefit from radiation therapy but can incur side effects to normal tissues including the ocular
lens, leading to cataracts. Although not directly life threatening, cataract disease has major medical, economic,
and social impacts on individuals, families, and society as a whole. Radiation-induced lens opacification is a
complex event and has been attributed to DNA double strand breaks (DSB) in the germinative epithelium,
leading to defective differentiation of lens fiber cells and subsequent abnormal folding of lens proteins.
Rusalatide acetate (TP508) is a radio-modulating peptide that has been shown to increase survival of
irradiated animals via activation of signal transduction pathways in endothelial cells, initiating repair of DSB,
increasing NO levels and reversing of endothelial cell dysfunction. This investigation will determine if TP508
will have a similar effect on human lens epithelial cells (HLEC) and mitigate radiation-induced
pathophysiological pathways that are associated with abnormal differentiation of fiber cells, abnormal protein
folding and opacification. The hypothesis is that through the direct activation of molecular pathways in
irradiated HLEC, TP508 treatment will mitigate or repair DSB and restore normal cell differentiation. In contrast
to other investigative approaches that focus on a single downstream mechanism, this investigation will
examine molecular activity of TP508 across multiple pathophysiological pathways associated with normal
differentiation of HLEC. Study aims are to establish the molecular activity and optimum dosage thresholds, and
timing of treatments of TP508 in mitigating X-ray or proton damage with single fraction exposures of 0.5, 1.0,
2.0, or 4 Gy in HLEC (CRL-11421 [B3], SRA01/04 and HLEpiC cells. Aim (1) is to determine drug toxicity
levels using clonogenic survival assays and cell doubling times to identify the optimum TP508 concentration
and administration schedule (before or after radiation) for producing protective effects on radiation induced
HLEC viability. Aim (2) will determine if TP508 can maintain or restore normal cell differentiation required for
normal protein folding, using the most optimized dosage and administration schedule established in Aim 1.
Investigations will include the effects of TP508 on molecular markers and proteins associated with abnormal
differentiation of lens fiber cells (CRYAB [αB-crystallin], CRYBB2 [βB2-crystallin]) and proteins involved in
signaling pathways for apoptosis, necrosis, senescence, and mitotic catastrophe. Studies are expected to
provide the following: (i) determine limits of toxicity with increasing doses of TP508 and the survival effect on
irradiated HLEC at different doses applied before and after radiation; and (ii) identify if the molecular
mechanisms and protein markers associated with the progression of lens opacification are mitigated by the
optimum doses of TP508 (from Aim 1) in HLEC at different levels of radiation. Successfully developed, future
investigations of TP508 could expand its application to mitigate additional ocular radiation therapy side effects
including dry eye and retinopathy.Cataracts are the leading cause of preventable blindness worldwide and a frequent adverse
effect of radiation therapy used to treat cancer patients. This study will investigate the
regenerative activity and optimum dosage of an investigational peptide drug, rusalatide acetate
(TP508), to mitigate radiation induced DNA damage to lens epithelial cells which has been
suggested as the initiating event in cataract formation. Successfully developed, a drug to
mitigate cataract progression could mean improved outcomes and health related quality of life
for a significant population of people who are at risk of therapeutic and occupational exposures
of radiation.

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

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