GenSight Biologics Reports Evidence of GS010 DNA Transfer to Contralateral Eye of Primates Unilaterally Injected With GS010 Gene Therapy

Source: GenSight Biologics

GenSight Biologics reported positive proof of GS010 DNA transfer from one eye to the other eye following unilateral intravitreal injection of primates. In a nonclinical study to investigate the local biodistribution of GS010, tissue samples from the non-injected eye of monkeys that had been unilaterally injected with GS010 were found to contain GS010 DNA three months after injection, indicating the expression of the therapeutic gene in the contralateral eye.

“These results join a growing body of evidence suggesting the two eyes communicate not only in disease, but also in response to treatment,” David J. Calkins, PhD, O’Day Professor, Vice Chair and Director for Research Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States, said in a company news release. “With the new understanding these results provide, we can move forward with more precise treatments.”

Performed by CiToxLAB France, a leading CRO for preclinical research, the study was initiated by GenSight to investigate potential mechanisms behind the unexpected contralateral effect seen in two of GS010’s phase 3 trials, REVERSE and RESCUE. As previously reported, both trials, which this year completed the 2-year follow-up of patients unilaterally injected with GS010, documented sustained bilateral improvements in LogMAR mean visual acuity. The contralateral effect did not conform to expectations for gene therapies administered to only one eye.

The CiToxLAB study uses a purpose-bred species of monkeys, which is favored by scientists and accepted by regulatory bodies due to physiological similarities with humans. For testing at 3 months, a controlmonkey was given an intravitreal injection of saline solution in its right eye and was not injected in its left eye. Three test monkeys were given an intravitreal injection of GS010 in their right eyes and not injected in their left eyes. The dosage of GS010 was calibrated to be the allometric equivalent of that used in the GS010 phase 3 trials. Three months after the injection, tissues from the right and left eyes were sampled and tested using a qPCR test which had been validated in a dedicated prior study. The highly sensitive and accurate test contains a protocol that specifically targets a portion of the GS010 DNA and can detect the GS010 DNA matrix.

As expected, the qPCR test did not detect the GS010 DNA in any of the tissue samples from the control monkey unilaterally injected with saline solution. Also as expected, the test was able to detect, and in many cases, quantify the presence of GS010 DNA in tissue samples from GS010-injected right eye. Remarkably the qPCR test was also able to detect, and even quantify, viral DNA vector in thecontralateral eye, which had received no injection.

DNA was detected and quantified in the anterior segment, the retina, as well as the optic nerve of the non-injected contralateral eye. In addition, DNA was detected and quantified in the optic chiasm, suggesting that the anatomic route taken by the viral vector DNA from the treated eye to the non-treated eye was via the optic nerves and chiasm.

“The identification of viral vector DNA in the contralateral uninjected eye is an important observation with broader relevance to the design of gene therapy trials for optic neuropathies,” Dr. Patrick Yu-Wai-Man, Senior Lecturer and Honorary Consultant Ophthalmologist at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, London, United Kingdom, said in the news release. “Although the non-human primate study was not designed to determine the underlying mode of transfer, the presence of viral vector DNA in the optic chiasm and optic nerve of the contralateral uninjected eye points towards a possible diffusion pathway. Further experimental work will clarify these interesting findings.”

“We are excited about these scientifically significant results,” Bernard Gilly, Co-founder and Chief Executive Officer of GenSight, said in the news release. “Moreover, they vindicate the company’s position that the unexpected bilateral improvements seen in the REVERSE and RESCUE trials have a solid scientific basis. The results help provide a compelling argument in support of GS010’s marketing authorization application.”

GenSight is working with its panel of scientific experts to prepare the findings for submission to a peer-reviewed journal later this year.

Dr. Yu-Wai-Man will discuss these findings when he presents RESCUE results at the 2019 annual meeting of the American Academy of Ophthalmology in San Francisco, CA:

Session Date: Sunday, October 13

Paper Session: OP04 Neuro-Ophthalmology Original Paper

Session Time: 2:00 PM to 3:15 PM

Location: South 152

Presenter: Patrick Yu-Wai-Man, FRCOphth MBBS PhD

Presentation time: 3:00 p.m.



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