First-in-human clinical translation of a near-infrared, nerve-specific fluorophore to facilitate tissue-specific fluorescence-guided surgery

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PROJECT SUMMARY Safe and effective surgery accomplishes the required intervention, leaving the patient with the minimum necessary morbidity. To accomplish this goal, surgeons must distinguish between tissue types, preserving those of high value. Peripheral nerves are critically important for life-sustaining functions. When severed, peripheral nerves heal poorly and rarely recover full function. Iatrogenic nerve injury can have long-term, catastrophic consequences for the patient. Standard white-light visualization is often adequate to guide surgery in normal anatomy, however, in the setting of trauma, tumors, prior surgery, congenital anomalies, and radiation therapy, critical nerves may be difficult to recognize. Additionally, positive identification of nerve tissue during minimally invasive surgery can be challenging due to the reliance on anatomical landmarks that are inconsistent across patients. Fluorescence-guided surgery (FGS) is a nascent form of surgical navigation that seeks to increase the safety and efficacy of surgery through enhanced recognition of important anatomical structures using tissue- and disease-specific fluorophores. To date, research in FGS has focused primarily on the identification of cancers; comparatively little effort has been applied to the identification of normal structures. Because of their critical importance to function and limited healing capacity, successful translation of a nerve-specific fluorophore to provide visual identification of nerves would lead to a rapid, global shift in surgical methods and a reduction in morbidity from iatrogenic nerve injuries. Our research group has cooperatively developed a new, near-infrared (NIR) fluorescent contrast agent (IT01-08) that binds to nerve tissue with high specificity in rodent and swine models and is compatible with existing clinical FGS systems. In the proposed studies, we will advance IT01-08 toward human use by scaling its synthesis and formulation using good manufacturing practice (GMP) compliant methods and completing good laboratory practice (GLP) compliant pre-clinical testing that will enable us to successfully apply for IND approval to initiate a Phase I, first-in-human study of IT01-08. Our group has a strong history of early human trialing of novel fluorophores for FGS. We will further enhance our ability to analyze the performance of IT01-08 by performing this study in patients undergoing lower extremity amputation, whereby we will be able to excise patient nerve tissue and evaluate it histologically for toxicity. Our primary study endpoints will be surgical signal detection and nerve signal-to-background tissue ratio (SBR) >2. This study will deliver: synthesis of GMP-grade formulated, lyophilized, sterile IT01-08 for systemic administration, GLP-compliant preclinical toxicology testing of formulated IT01-08, and Phase I data that will position our team to move to Phase II trialing of IT01-08. This work will result in an expedient pathway to clinical translation of a fluorescent reporter that will be revolutionary in its ability to reduce iatrogenic nerve injury.