Sustained release of next-generation aptamers to treat wet AMD

Abstract SignificanceWet AMD affectsM Americans and is the leading cause of blindness in those agedor olderVision improvement from anti VEGF treatment is neither permanent nor completeand patients must receive intravitreal injections everymonthscreating a major treatment burden for patientsphysicians and payersEmerging combination therapies could address the efficacy problembut they do not solve the treatment burdenSustained release formulation is the most promising means to dramatically reduce injection frequencyWhile proven for small molecules in other indicationsit has not been achieved with standard of care anti VEGF A drugs becauseas biologicsthey are much larger and more fragilelimiting molar dose and stabilityAptamersa validated modality in AMD treatmentcan be just as potent but are much smaller and more stableand support long term sustained release formulationHypothesisWe can overcome this problem withnext generation aptamers that inhibit all isoforms of VEGF A as well as SDFand that aremodified to yield long term in vivo stabilityformulation in an injectable PLGA matrix to enablemonth sustained releasePreliminary DataWe have developed Chemically Augmented Particle DisplayCAPDa novel platform that yields next gen aptamers with unprecedented affinityspecificity and in vivo stabilityPLGA has been FDAapproved for use in the eyeand our team has previously demonstrated its potential with aptamersAimsWe will develop next generation aptamers against VEGF A and SDFand compare their potency to standard of care anti VEGF A agentsWe will formulate the aptamer in PLGA microparticles to achieve in vitro release profile lasting at leastmonths with minimal burst and high linearityWe will test PK and efficacy in a mouse laser CNV model and a rabbit NV modelWe expect to demonstrate sustained in vivo efficacy formonthsIf successfulthis will establish feasibility to yieldmonth durabilityand enable subsequent sustained release combination therapies to address both efficacy and treatment burden needs NarrativeWet Age Related Macular Degeneration is the leading cause of blindness in individuals agedand olderyet current treatment is not complete or long lastingand patients require intravitreal injections everymonthsStandard of care drugswhile potentare too fragile for long term sustained releaseWe aim to develop next generation aptamers that are as potent as standard of care drugsbut much more robustand we will encapsulate them in a sustained release matrix to reduce injection frequency to twice per year or less and lay the foundation for long lasting combination therapies in the future