AN ATYPICAL CASE OF OPTIC DISK PSEUDO-DUPLICATION WITH PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To present a unique case of optic disk pseudo-duplication with proliferative diabetic retinopathy. METHODS: Case report. RESULTS: A 63-year-old white diabetic man presented with an apparent duplicated optic disk in the superonasal midperiphery of his left eye. A large flat frond of neovascularization fanned out from this structure. Optical coherence tomography scanning showed a noncolobomatous scar with a large plume of blood vessels sprouting from the choroid, thru the retina and branching out into the vitreous. Magnetic resonance imaging scanning revealed a normal left globe and orbit with a single optic nerve. The neovascularization regressed after panretinal photocoagulation and anti-vascular endothelial growth factor therapy. CONCLUSION: We describe a unique case of proliferative diabetic retinopathy associated with pseudo-duplication of the optic disk. This case is unique in the peripheral location of the pseudo-duplication, the presence of spontaneous choroidovitreal neovascularization in proliferative diabetic retinopathy, and the appearance of neovascularization elsewhere mimicking neovascularization of the duplicated disk.

Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses.

Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.