DNA nanoparticles are safe and nontoxic in non-human primate eyes

Abstract

Introduction DNA nanoparticles (NPs) comprising polylysine conjugated to polyethylene glycol efficiently target murine photoreceptors and the retinal pigment epithelium (RPE) and lead to long-term phenotypic improvement in models of retinal degeneration. Advancing this technology requires testing in a large animal model, particularly with regard to safety. So, herein we evaluate NPs in non-human primates (baboon). Methods and results NPs with plasmids carrying GFP and a ubiquitous, RPE-specific, or photoreceptor-specific promoter were delivered by either subretinal or intravitreal injection. We detected GFP message and protein in the retina/RPE from eyes dosed with NPs carrying ubiquitously expressed and RPE-specific vectors, and GFP message in eyes injected with NPs carrying photoreceptor-specific vectors. Importantly, we observed NP DNA in the retina/RPE following intravitreal injection, indicating the inner limiting membrane does not prevent NP diffusion into the outer retina. We did not observe any adverse events in any baboon, and there were no NP-associated changes in retinal function. Furthermore, no systemic or local inflammatory reaction to the vectors/injections was observed, and no NP DNA was found outside the eye. Conclusion Taken together with the well-established rodent safety and efficacy data, these findings suggest that DNA NPs may be a safe and potentially clinically viable nonviral ocular therapy platform for retinal diseases.

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

“…Following IV administration of the polyplex, the mixture would not be expected to significantly penetrate the eye or other organs of the body in vivo, other than the lung. Therefore, treatment of the eye required a sub-retinal injection of the polyplex (Kelley et al, 2018). Similarly, AAV-based gene therapy of retinal disease is performed with a 1-time sub-retinal injection in each eye (Maguire et al, 2019).…”

Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review

“…However, insertional mutagenesis is a potentially serious complication of lentiviruses [ 6 ]. Nonviral vector platforms may eventually resolve many of the aforementioned obstacles of viral vectors [ 7 ].…”

Research Models and Gene Augmentation Therapy for CRB1 Retinal Dystrophies

“…These nanoparticles are also able to infect RPE and PRC, and can drive gene expression on a comparable scale and longevity than AAVs in mice ( Cai et al, 2009 ; Han et al, 2012 ). CK30-PEG nanoparticles have a tolerable safety profile and is non-toxic in mouse and non-human primate eyes ( Ding et al, 2009 ; Akelley et al, 2018 ). To our knowledge, there is no successful clinical study described using these nanoparticles so far.…”