New gene therapy delivery system aims for precision

In a novel approach to gene therapy, scientists funded by the National Eye Institute (NEI) report using gold nanoparticles and light to target specific cells in mouse retina. The technology has the potential to be safer and more broadly applicable than standard virus-based gene therapy methods, potentially treating rare eye diseases and common ones such as the wet and dry forms of age-related macular degeneration (AMD). The study, conducted by researchers at NanoScope® Technologies LLC, was published in the journal Molecular Therapy: Methods & Clinical Development. NEI is part of the National Institutes of Health.

“We initially started this project to restore vision loss from dry AMD by targeted delivery of a protein called Multi-Characteristic Opsin, but this technology is broadly applicable, and we think it will solve a lot of problems in gene therapy,” said Samarendra Mohanty, Ph.D., chief scientific officer at NanoScope® Technologies LLC and senior author of the study.

NanoScope’s system addresses challenges to existing ocular gene therapy methods. For example, most current methods, including the FDA-approved gene therapy treatment for Leber Congenital Amaurosis, use viral vectors to deliver therapeutic genes. While viral vectors can target specific cell types, they cannot be easily targeted to specific regions of the retina. Once delivered, viral vectors cannot be removed or deactivated. Controlling how long genes are expressed when delivered by viral vector is difficult. And viral vectors can activate the immune system, causing inflammation in the eye and immune rejection that may prevent follow-up doses.

Instead of piggy-backing therapeutic genetic material on top of a viral backbone, Mohanty and colleagues have used a minimally invasive combination of gold nanoparticles and low-intensity infrared light to trigger retinal cells to take up therapeutic genes.

The team first injects gold nanoparticles into the gel-like vitreous in the center of the eye. The nanoparticles are coated with proteins that bind specific retinal cell types. After the gold nanoparticles have bound their targets, usually within a couple of hours, the researchers inject therapeutic genetic material into the eye. Finally, the researchers train a narrow beam of infrared light at the retina, causing the tips of the nanoparticles to heat just enough to cause targeted cells to take up the genetic material – but only in the area lit by the infrared light. Because the power of the infrared light is extremely low, cells without nanoparticles attached are unaffected, as are cells outside the light. The researchers have found that the nanoparticles are metabolized out of the eye within approximately 7 days.

Using this technique, the researchers hope to restore vision to people with advanced dry AMD, or geographic atrophy (GA), which is currently untreatable. As GA progresses, the light-sensing photoreceptors in the retina begin to die, but the eye’s neuronal circuitry often remains. In this study, the researchers used mice to show that they can deliver the genetic code for opsin, a type of light-sensing molecule, to retinal ganglion cells in the region affected by GA, but not elsewhere in the retina. Retinal ganglion cells normally transmit information from photoreceptors to the brain but can’t directly respond to light. After receiving the opsin gene therapy, retinal ganglion cells were able to respond to light directly and send that information to the brain. While this solution may not provide normal sight, it could provide useful vision to some people with advanced GA.

“A number of prosthetic devices connect camera-like sensors and electrode arrays to retinal ganglion cells. Our technology does much the same thing, but without an external device,” said Subrata Batabyal Ph.D., senior technical officer at NanoScope® Technologies LLC and first author of the study.

This technology may also revolutionize how gene therapy is tested in the eye. Not only is this technology easily targetable to various cell types and different areas of the retina, it can accommodate a wide variety of genes, including those too large for viral vectors. And because most viral gene therapy is permanent, any detrimental effects of the gene can be a significant safety risk. This system allows for transient gene expression and much tighter localization, hopefully enabling therapeutic testing with a lower risk to the retina. The technology can also be used multiple times in the same eye, allowing repeat treatment as necessary, or can be adapted for long-term expression with a single dose.

While their initial results are based primarily on experiments in mice, Mohanty and colleagues are testing the technology in additional animal models. They hope to have this technology ready for early clinical trials in about two years.

In the meantime, the team is coordinating with a variety of academic labs to adapt their system for the clinic. “Because the laser we use for this technique is compatible with most eye imaging systems, like optical coherence tomography (OCT), we’ve been able to easily share the technology. The new laser-based gene delivery device is now being manufactured and commercialized by NanoScope® Instruments Inc. These collaborations will help us develop this method quickly,” Mohanty said.

“Gene therapies and regenerative medicine hold great promise for restoring lost vision, but most approaches take years to reach the clinic,” said Jerome Wujek, Ph.D., program officer for Small Business Innovation Research at NEI. “This study by NanoScope Technologies presents a novel treatment that may reach the clinic in a few short years and transform the gene therapy field.”

Reference: Batabyal S, Gajjeraman S, Tchedre K, Dibas A, Wright W, and Mohanty S. “Near-infrared laser based spatially targeted nano-enhanced optical delivery of therapeutic genes to degenerated retina.” Mol Ther Methods Clin Dev. 2020. Epub Apr 6. Pubmed.

This study was supported by NEI grants EY026483, EY025905, EY025717, and EY028216, through NEI’s Small Business Innovation Research (SBIR) program. The SBIR program is a competitive awards-based funding mechanism that supports U.S.-based small businesses engaged in research and development that has the potential for commercialization. The NEI SBIR program specifically provides funding to companies developing technologies and innovations relating to blinding eye diseases, visual disorders, preservation of sight, and addressing the special health problems and requirements of individuals with impaired vision.

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NEI leads the federal government’s research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

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