Synthetic Preimplantation Factor (sPIF)* Improves Survival and GI Function in Acute Lethal Radiation Syndrome in a Clinically Relevant Murine Model.

Ionizing radiation (IR) damage, whether intentional, accidental, or therapeutic, reverberates throughout the body. The FDA has approved the use of palliative care and leukocyte growth factors for hematologic depletion (H-ARS), but no treatments have been approved for gastrointestinal damage (GI-ARS). Synthetic PIF (sPIF) safely replicates endogenous PIF's preventative, reparatory, and regenerative effects. Specifically relevant for radiation-induced damage, sPIF reduces oxidative stress. Subcutaneous (SC) sPIF prevents LD100/30 mortality at 2 w post-treatment and restores GI function post-6Gy exposure (in mice). Daily SC sPIF for 14 d, starting 24 h post-LD85/40 (7.17 Gy) total-body ɣ-irradiation (TBI), increases survival 2.76-fold (14.7% (5/34) to 40.7% (24/59); p = 0.0036) by 4 w post-therapy. All sPIF-treated mice survived for the first 10 d, while only 80% survived in the sham group (p = 0.0034). The sPIF-treated group reached 50% survival at 23 di, while this figure was reached at 19 d in the sham-treated group, with a 21% delay. Importantly, sPIF delays weight loss for up to 25 d, increasing weight by ~12% above baseline and improving colon architecture; in the sham, both weight and colon recovery failed. sPIF partially prevents declines in hemoglobin and platelets, with no bleeding/sepsis observed, while WBC counts declined. sPIF's safety and lack of deleterious drug-to-drug interaction were documented in a First-in-Human, FDA-approved clinical trial for autoimmune disease. Chronic FDA-guided toxicology/toxicokinetic studies demonstrated NOAEL and the highest safety margin. Collectively, sPIF safely and significantly increases survival, weight gain, and colon crypt scale, directly supporting its suitability for FDA-ARS animal-rule approval.