Abstract
Purpose :
Intravitreally injected cell therapies show promise for retinal diseases but demonstrate limited durability and efficacy, likely due to shear stress-induced viability loss upon administration without biomaterials shielding. We developed IGT001, comprising human rod precursor cells (hRPs) within a hyaluronic acid/gelatin hydrogel, as a sustainably delivered intervention for retinitis pigmentosa (RP). In vitro modeling reveals significant apoptosis protection from injection shear stress. In vivo, the gel fully degrades over months while hRP are naturally cleared without immune activation, enabling durable responses through redosing. These findings showcase hydrogel encapsulation solving key cell therapy challenges around delivery, persistence, immunogenicity, and potency for efficacious repeated dosing.
Methods :
To evaluate protection conferred by IGT001's gel component (Gel-HA), we utilized shear stress models including syringe needle extrusion of suspended human retinal cultures, quantifying viability with Calcein AM. In vivo, rat intravitreal injections with IGT001 or naked hRPs underwent longitudinal cell tracking using human photoreceptor markers.
Results :
In vitro modeling exposed up to 90% hRPC death from shear forces mitigated over 5-fold through gel encapsulation, supporting its cytoprotective capacity. Long Evans rats mirrored improved in situ viability with ~10X more live hRPCs at 2 days post-injection for IGT001 versus naked cells. Subsequently, similar natural clearance profiles were observed for but substantially extended duration for encapsulated cells. Rd10 testing found 150k cells containing IGT001 maximally preserved retinal function acutely, whereas 225k cells containing IGT001 performed less than 75K indicating less tolerance to higher dose.
Conclusions :
Gel-HA shielding enables safer delivery, extending therapeutic hRP survival allowing efficacy maintenance through clearance. The acute protection particularity aids cell therapies vulnerable from implantation stresses. Sustained function via delayed release can further permit minimizing effectual doses for patient benefit. With hydrogels addressing multiple barriers, incorporating biomaterials can progress cell-based ophthalmic treatments from transitory injections towards durable, encouraging drug platform.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.