Multifarious Biologic Loaded Liposomes that Stimulate the Mammalian Target of Rapamycin Signaling Pathway Show Retina Neuroprotection after Retina Damage

Abstract

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 administration of liposomes reduced both RGC death and loss of retina electrophysiological function. Furthermore, combining liposomes with transplantation of induced pluripotent stem cell derived RGCs led to an improved electrophysiological outcome in mice. The results presented here show that liposomes carrying multiple signaling pathway modulators can facilitate neuroprotection and transplant electrophysiological outcome.

Suppression of AMD-Like Pathology by Mitochondria-Targeted Antioxidant SkQ1 Is Associated with a Decrease in the Accumulation of Amyloid β and in mTOR Activity

“…A study on premature rats suggests that this effect may be due to suppressed mTOR signaling in the hippocampus [51]. Experimental upregulation of mTOR signaling promotes retinal ganglion cell survival and axon regeneration after optic nerve crush injury [52,53]. Zhang and coauthors [54] demonstrated a critical role of muscle mTOR catalytic activity in the regulation of whole-body growth and homeostasis.…”

Semi-Automated Approach for Retinal Tissue Differentiation

“…Retinal ganglion cells were isolated from mES-derived organoids at day 21 of differentiation by magnetic microbead-assisted sorting for Thy1 (CD90). 16 The C90+ cells were replated on laminin-coated 16-well chamber glass slides in RGC medium (Neurobasal medium A, 1× B27, 5 µmol/L Forskolin, 50 ng/mL BDNF, 50 ng/mL CNTF, 1× Glutamax, 1× ITS-X) at 8000 cells per well and cultured for two days before functional assay. For the calcium analysis RGCs were loaded with Fluo-4 AM dye (Thermo Fisher): 1 mmol/L stock solution was diluted in BrainPhys medium to make 1 µmol/L loading solution.…”

Ten Years of Knowledge of Nano-Carrier Based Drug Delivery Systems in Ophthalmology: Current Evidence, Challenges, and Future Prospective

“…Their findings demonstrated significant experimental upregulation of mTOR signaling promoting RGC survival and axon regeneration after an optic nerve crush injury. 129 …”