Investigating Coupled Immunomodulation in the Eye

Article: A new vision for AAV-delivered gene therapies
Source: Wyss Institute at Harvard University, via NEI
Published: February 10, 2021

Analysis of the retinas of pigs receiving subretinal injections
of either an unmodified AAV vector (left) or an engineered AAV
vector with TLR9-inhibitory sequences in its genome (right)

Researchers at the Wyss Institute at Harvard University are investigating a new generation of adeno-associated virus (AAV) vectors for the delivery of gene therapy. This research is relevant to eye care in the sense that the eye is a prime testbed for gene therapies. Though the eye is considered immune-privileged due to the blood-retina barrier, several clinical trials have reported intraocular inflammation following delivery of therapeutically relevant doses of AAV into the eye, demonstrating a limit to immune privilege. The more ideal delivery of AAV vectors is intravitreally, compared to subretinally, though intravitreal injection results in more inflammation. The new generation of AAV vectors incorporates “inflammation-inhibiting oligonucleotide” (IO) sequences to address this obstacle. Results of intravitreal injection in mice showed that the incorporation of IO sequences reduced inflammation and produced a multifold increase in expression of the vector-encoded gene in the retina. Similarly, subretinal injection in pigs "ameliorated distinct pathologies triggered by control AAV viruses" and reversed infiltration of immune cells into the photoreceptor layer of the retina. Studies of intravitreal injection in macaque monkeys, however, did not produce as pronounced results, though there was delay of onset of inflammation (uveitis) and mild improvement in expression of the therapeutic gene. As with any new therapy, these kinds of investigations are necessary to guide future directions toward improved safety and efficacy of gene therapies.

My rating of this study: ⭐⭐⭐

Chan YK, Wang SK, Chu CJ, et al. "Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses." Science Translational Medicine.  13(580):8eabd3438. 10 February 2021. https://doi.org/10.1126/scitranslmed.abd3438