Abstract
Purpose :
Retinal degeneration is an irreversible process that ultimately leads to blindness and preservation of existing vision is a promising therapeutic strategy. Ciliary neurotrophic factor (CNTF) and Oncostatin M (OSM) are two potent survival factors for neurons and oligodendrocytes. However, growth factors degrade quickly, and re-injections are needed to maintain its protective role. A stable delivery of these growth factors is required for translating its therapeutics into patients.
Methods :
Stable and biocompatible nanoparticles incorporated with CNTF and OSM (NP-CNTF and NP-OSM) were produced. To evaluate their neuroprotective effects, a novel in vitro assay platform using retinal photoreceptor precursor (RPP) cells and retinal ganglion progenitor cells (RGPC) derived from human induced pluripotent stem cells (iPSC) was developed. To investigate their neuroprotective effects in vivo, a single dose of NP-CNTF, NP-OSM, or control NPs were injected intravitreally in the Royal College of Surgeons (RCS) rats (n=6/group), a well-established rodent model for RP and electroretinography (ERG) and optokinetic response (OKR) were carried out at postnatal day 60 and 90 (P60 and P90). In addition, intravitreal injection of NP-CNTF or NP-OSM into an optic nerve crush (ONC) model (n=6) to examine retinal ganglion cell (RGC) survival. Retinal histology was performed at the end of experiments.
Results :
Significant pro-survival and pro-proliferation effects of both complexes were observed in both iPSC-RPP and iPSC-RGPC platforms within a broad range of doses (from 0.2 to 20 ng/ml). Significant preservation of vision as tested by ERG and OKR in NP-OSM treated animals as compared with other groups. However, both NP-CNTF/OSM showed significant RGC protection compared with controls in ONC model. Histological analyses showed a global photoreceptor preservation in NP-OSM treated RCS rats, dramatically different from NP-CNTF and controls. More importantly, an intact RPE layer was observed in NP-OSM treated retina, which is in contrast to hypertrophic and disorganized RPE layer observed in control P90 RCS retina.
Conclusions :
These results demonstrate that stable and biocompatible NP-OSM and NP-CNTF are neuroprotective both in vitro and in vivo, indicating a strong therapeutic value for retinal neurodegeneration diseases and other neurodegenerative diseases as well.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.