Small-Molecule Stabilizers of TFEB for Local Ocular Delivery in Age-Related Retinal Disease
Researchers at the University of Pittsburgh have developed a first-in-class small-molecule approach for activating Transcription Factor EB (TFEB)—the master regulator of lysosomal biogenesis and autophagy—through local ocular delivery. The lead compound, GT300, has been reformulated exclusively for intravitreal (IVT) administration, enabling direct, targeted activation of TFEB within retinal pigment epithelium (RPE) and adjacent ocular tissues without systemic exposure.Lysosomal dysfunction is increasingly recognized as a root cause of early AMD and geographic atrophy. Enhancing TFEB locally within the eye offers a new disease-modifying strategy for preserving retinal homeostasis and mitigating progression of dry AMD.
Description
The GT300 chemical series prevents DCAF7-mediated TFEB nuclear degradation, stabilizing and enhancing TFEB transcriptional activity and thereby boosting the autophagy-lysosome system. Key attributes: • Designed for local delivery to bypass systemic variability and toxicity associated with oral or systemic routes. • Sterilizable intravitreal formulation developed and tested in rabbit ocular PK/PD studies, demonstrating sustained drug levels in retina and choroid for ≥7 days after a single injection. • Demonstrated TFEB target engagement in vivo, shown by CLEAR gene activation in retinal tissues following IVT dosing. • Strong proof-of-concept efficacy in a genetic model dry AMD/GA. GT300 represents a differentiated, disease-modifying therapeutic candidate for dry AMD and other ocular disorders characterized by lysosomal dysfunction. With a completed IVT formulation, strong mechanistic rationale, validated in vivo efficacy, and an extensive pre-existing systemic safety package, GT300 is positioned as a near-IND, ophthalmology-dedicated asset well suited for a partner with clinical and commercial expertise in retinal medicines.Applications
• Dry Age-Related Macular Degeneration / Geographic Atrophy• Inherited retinal degenerations with proteostasis defects
• Other age-related retinal disorders with impaired lysosomal homeostasis
• Ocular conditions with autophagy dysregulation such as early diabetic retinopathy or glaucoma (mechanistic rationale)
Advantages
1. Targeted exposure to the RPE, retina, and choroid with minimal systemic drug levels2. Avoids the PK variability and tolerability issues observed during oral Phase 1 development.
3. Sustained pharmacodynamic activity following single IVT dose, including CLEAR gene activation.
4. Disease-modifying biology distinct from complement inhibition—addresses upstream pathophysiology (lysosomal failure, lipofuscin/drusen load).