Why microscope-integrated OCT is vital to gene therapy


Intraoperative optical coherence tomography (OCT) allows surgeons to visualize retinal anatomy and provides the surgeon with real-time feedback on instrument-tissue interaction.

Intraoperative microscope-integrated OCT can serve as confirmation for the surgeon that gene therapy injections have reached the subretinal space rather than the suprachoroidal space, said Ninel Z. Gergori, MD, of the Bascom Palmer Eye Institute (BPEI) in Miami.

Finally, the use of intraoperative OCT can be helpful to monitor for possible complications, including an impending macular hole.

Gene therapy can be delivered via intravitreal injection or subretinal delivery, with the latter being more common (AAV and lentivirus vectors). However, these vectors do not penetrate the retina well and the vectors must be delivered subretinally if photoreceptor or retinal pigment epithelial (RPE) cells are targeted.

"These gene therapy products must transduce the photoreceptor or RPE cells," she said.

Dr. Gregori and Janet Davis, MD, (also at BPEI) have performed 31 subretinal gene therapy surgeries since 2016. These have included phase I/II and phase III choroideremia trials (sponsored by Nightstar) and a phase I/II achromatopsia trial (sponsored by AGTC).

The two mentor each other, Dr. Gregori said, and now use their technique on 3 eyes undergoing voretigene therapy (voretigene is the first gene therapy to receive U.S. regulatory approval for the treatment of inherited retinal disorders.

"Confirming subretinal injection as opposed to suprachoroidal or sub-REP injection is crucial for correct product delivery," she said.

Injecting into the suprachoroidal space is more likely with very thin retinal and choroidal tissue seen in choroideremia.

At BPEI, microscope-integrated OCT (ReScan 700, Carl Zeiss Meditec) "has been used for every gene therapy case by our surgical team since 2016," she said.

The group published on their technique,[1] with video of three choroideremia patients undergoing a subretinal injection of adeno-associated viral serotype 2 vector (AAV2) encoding Rab-escort protein 1 (REP1) as part of a phase II clinical trial (NCT02553135).The microscope-integrated OCT technique has been shown to assist visualization of the retinal microanatomy during the creation of a small subretinal bleb with balanced salt solution in preparation for subretinal viral vector injection.1 Expansion of the subretinal bleb can then be directly observed as gene therapy is injected.Advantages of microscope-integrated OCT

Dr. Gregori said there are several advantages for surgeons who use these devices.

"First, there is the ability to raise subretinal bleb under direct microscope-integrated OCT guidance," she said. "First, we assess, and then we inject virus into the space. Multiple instances of sub-RPE or suprachoroidal injections have thus been avoided."

She said it's common to see the subretinal pocket visualized, but also a suprachroidal fluid pocket, so surgeons "must be sure the cannula containing virus goes into the subretinal fluid and that that pocket is enlarging as you're injecting."

Second, the technology has the ability to scan and determine the area and dimensions of subretinal blebs in order to ensure coverage of the therapeutic target zone.

"After scanning the macula, we ensure we use preoperative OCT maps in order to inject and cover the area of interest," she said.

Third, the technology can ensure the delivery of gene therapy is safe.

"It helps us avoid overstretching the fovea, avoid creating a macular hole, and avoid pre-existing macular holes or thin foveas while delivering the virus," she said.

Macular holes are a potential complication "because you could lose all of your virus into the vitreous cavity," she said. "We also avoid pre-existing macular holes and fovea while injecting virus, sometimes making a second bleb to cover the treatment target zone but avoiding creating a macular hole in an area of thinning."

Pearls for gene therapy injection include moving gradually, avoiding overstretching the fovea, and ensuring the fovea remains intact. 

Dr. Gregori described one case where the use of the microscope-integrated OCT identified a pending macular hole; the surgeons decided at that point to halt the procedure and create a second bleb in order to avoid a macular hole formation.

"We also try to avoid injecting air onto the retina," she said. "Small bubbles don't seem to cause issues, but larger air bubbles can cause tissue damage."

Drs. Gregori and Davis recently published a video of their techniques using microscope-integrated OCT on the American Academy of Ophthalmology website, she said.

"This technology provides real-time feedback to guide viral vector injections and allows the detection of complications that may include incorrect layer injection or an impending macular hole that would otherwise not be visible," she said.

Using microscope-integrated OCT "would likely make gene therapy accessible to more surgeons and clinical centers," she said.



Dr. Gregori has no financial disclosures related to her comments.



1. Gregori NZ, Lam BL, Davis JL. Intraoperative use of microscope-integrated optical coherence tomography for subretinal gene therapy delivery. Retina. 2017;April 19. doi: 10.1097/IAE.0000000000001646

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