Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD

PROJECT SUMMARYABSTRACT
Age related macular degenerationAMDis the leadingand due to the aging baby boomersa growing cause
of irreversible vision loss in the United Statesand is strongly associated with exposure to cigarette smokeCSand high fat dietsHFDWhile effective treatment is available for neovascular AMDthe AREDS II
antioxidant vitamins are the only proven treatment for intermediate dry AMDUnfortunatelyAREDSII is not
effective for early or late dry diseaseand in intermediate AMDit merely slows the progression to advanced
diseaseTreatments that target dry AMD will have a huge impact on the afflicted individual and save billions of
health care dollars per yearImpairment of the oxidative stress responseautophagymitochondrial functionand the unfolded protein responseas well as dysregulated innate immunity have been implicated in AMDand
thushave been investigated as treatment targetsUltimatelythese abnormalities cause death of retinal
pigment epithelialRPEcells and photoreceptorsPRleading to permanent vision lossFas mediated cell
death is the major mechanism of outer retinal cell loss in many retinal diseases including AMDWith no
therapy to prevent Fas mediated outer retinal cell death in AMDa logical treatment strategy is to prevent Fasmediated signalingirrespective of the upstream impairmentONL Therapeuticsan ophthalmic biotechnology
company developing innovative therapies that prevent retinal cell death to improve visual outcomes for
patientshas demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model
of AMDAdditionallya gene therapy that inhibits Fas signaling has been developed and tested in acute and
chronic models of glaucomawherein the vector provided significant inner retinal neuroprotectionDue to the
role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stressthis proposal
will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMDPhase I of this Fasttrack STTR proposal will idetermine the feasibility of using Fas inhibition to protect against acute CS induced
retinal damageand iidemonstrate that the duration of inhibition is clinically meaningfulPhase II will test the
ocular safety and effectiveness of repeated intravitreal injections of our peptide Fas inhibitorIn additionwe
will test the effectiveness of repeated intravitreal injections of the peptide Fas inhibitor as well as a single
intravitreal injection of a Fas inhibitor vector in a novelpeer reviewed chronic model of atrophic AMD in which
apoBmice exposed to CS and HFD develop a geographic atrophy phenotype that closely resembles
human diseaseThis proposal combines the expertise of ONL and the Wilmer Eye Institute to test these Fas
inhibitors in models of atrophic AMDSuccessful execution of the project will support the continued pre clinical
development of the Fas inhibitors for dry AMD and help attract additional investor interest in the company PROJECT NARRATIVEAge Related Macular DegenerationAMDis the leading and growing cause of irreversible blindness in
the United States and the developed worldresulting in tremendous social and economic impact for patients
and societyONL TherapeuticsIncis dedicated to developing innovative therapies that will prevent outer
retinal cell death and improve visual outcomes for patients with retinal diseaseand our treatments exhibited
strong evidence of their potential utility in treating atrophicdryAMDfor which no approved therapies existThe successful extension of our inhibitors to the treatment of dry AMD will have a large and positive impact on
the life quality of millions of patients every year