First-in-Human Clinical Translation of a Near-Infrared, Nerve-Specific Fluorophore to Facilitate Tissue-Specific Fluorescence-Guided Surgery - 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.
