MultifariousBiologic Loaded Liposomes that Stimulatethe Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotectionafter Retina Damage

摘要

A common event in optic neuropathies is the loss of axons and death of retinal ganglion cells (RGCs) resulting in irreversible blindness. Mammalian target of rapamycin (mTOR) signaling pathway agonists have been shown to foster axon regeneration and RGC survival in animal models of optic nerve damage. However, many challenges remain in developing therapies that exploit cell growth and tissue remodeling including (i) activating/inhibiting cell pathways synergistically, (ii) avoiding tumorigenesis, and (iii) ensuring appropriate physiological tissue function. These challenges are further exacerbated by the need to overcome ocular physiological barriers and clearance mechanisms. Here we present liposomes loaded with multiple mTOR pathway stimulating biologics designed to enhance neuroprotection after retina damage. Liposomes were loaded with ciliary neurotrophic factor, insulin-like growth factor 1, a lipopeptide N-fragment osteopontin mimic, and lipopeptide phosphatase tension homologue inhibitors for either the ATP domain or the c-terminal tail. In a mouse model of N-methyl-d-aspartic acid induced RGC death, a single intravitreal administrationof liposomes reduced both RGC death and loss of retina electrophysiologicalfunction. Furthermore, combining liposomes with transplantation ofinduced pluripotent stem cell derived RGCs led to an improved electrophysiologicaloutcome in mice. The results presented here show that liposomes carryingmultiple signaling pathway modulators can facilitate neuroprotectionand transplant electrophysiological outcome.