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AIVITA Biomedical has successfully engineered a three-dimensional transplantable retina construct and demonstrated connectivity and conductivity in an animal model of retinal degeneration.
Reviewed by Hans S. Keirstead, PhD
The development of a three-dimensional (3-D) transplantable retina may represent the greatest challenge that has ever been addressed in the area of stem cell-based tissue engineering. A team of researchers at AIVITA Biomedical led by Hans S. Keirstead, PhD, has made steady progress along the path and sees the launch of a clinical trial on the horizon.
Using human embryonic stem cells (hESCs), the group has successfully developed a complete retinal organoid consisting of laminated retinal progenitor cells and retinal pigment epithelium (RPE) and shown in preclinical studies that the injected material forms synaptic connections with the host and restores vision.
In 2016, AIVITA Biomedical received grants from both the National Eye Institute of the National Institutes of Health and the California Institute for Regenerative Medicine to develop the 3-D-transplantable retinas in collaboration with researchers at the Sue and Bill Gross Stem Cell Research Center at the University of California, Irvine.
The company is now gearing up the manufacturing operation to ensure it is clinically and commercially compliant.
Dr. Keirstead said he anticipates that entry into the clinical research phase may be as early as 2 years away.
“The cause for hope for transplanting a 3-D retina has never been greater,” explained Dr. Keirstead, chief executive officer, AIVITA Biomedical, Irvine, CA. “We have been on a relatively long journey, but are now at a point where we will be walking along a well-articulated path that will lead us to the beginning of our first in-human study.”
The target population for the 3-D retina is patients with degenerative diseases affecting the outer retina, such as age-related macular degeneration and retinitis pigmentosa.
The goal is to replace the diseased and non-functional photoreceptors and RPE with new cells that can establish functional connections with the inner neural retina in order to restore vision.
Other successful efforts in the area of retinal transplantation have primarily involved use of retinal progenitor cells alone rather than complex 3-D structures. The progenitor cells are not a tissue replacement but instead act to provide neurotrophic support for remaining functional cells. The idea of their use has been met with some reluctance from surgeons, however, who believe the risk of injecting foreign tissue into a degenerative environment outweighs the potential benefit, Dr. Keirstead said.
“Our goal is to create a structure with progenitor cells that will be able to incorporate into the host and differentiate to replace the damaged tissue,” he said. “Although generating such a 3-D retina is a much higher bar to aim for, it allows an opportunity to restore vision to patients with a very late stage of disease and not just an attempt to preserve a limited number of remaining viable cells.”
In developing the 3-D-transplantable retina, Dr. Keirstead and colleagues chose to use hESCs rather than other stem cell sources considering a number of characteristics, including stability, expansion potential, and cost of goods. They took into account pluripotency, proliferative potential, karyotypic stability, the ability to provide an adequate cell supply for transplantation, and the potential to be directed to desirable phenotypes with high purity.
“Embryonic stem cells are extremely viable from a commercial perspective because they are not expensive to grow, bank, and differentiate,” Dr. Keirstead said.
Creation of the 3-D-transplantable-retinas involves directing the hESCs toward early retinal differentiation that includes an RPE layer.
The transplantation procedure involves a transvitreal intraretinal injection and will be able to be done as an outpatient procedure, he explained.
In preclinical studies conducted in a rodent model of retinal degeneration, intraretinal transplantation of the retinal progenitor cell layers was found to restore visual acuity as demonstrated through electrophysiology recordings from the superior colliculus.
“The responses measured in the brain corresponded to the transplant location in the retina, and indicate incorporation of the transplanted cell layers into the host retina with subsequent signal transmission,” Dr. Keirstead said.
Assessments using confocal and electron microscopy confirmed the presence of donor cells and processes in the eyes of injected animals and provided ultrastructural confirmation of synaptic connectivity.
In addition, the studies included a number of behavioral tests that provided further demonstration of functional benefit by showing that the previously blind animals oriented themselves towards light following transplantation.
AIVITA Biomedical is now focusing on the manufacturing aspect of development and working toward clinical and commercial scalability of the 3-D transplantable retinas with guidance from a full complement of quality assurance, regulatory, and manufacturing experts.
Hans S. Keirstead, PhD
Dr. Keirstead has equity and compensation-based financial interest in AIVITA Biomedical.