Saturday, June 10, 2023

Immunosuppressive cocktail helps advance stem cells for blindness

What if, in people with indiscriminate retinal disorders, one could simply introduce retinal healthy photoreceptor cells derived from stem cells into a dish, and restore vision?

This is a technically straightforward strategy to correct blindness, yet this approach has been met with several scientific obstacles, including the introduced cells dying rapidly or failing to integrate with the retina.

A new study published in stem cell report, overcomes these challenges and marks significant progress towards cell-based medicine. The work, led by a team from the University of Pennsylvania School of Veterinary Medicine, in collaboration with researchers from the University of Wisconsin-Madison, Children’s Hospital of Philadelphia, and the National Eye Institute (NEI) of the National Institutes of Health, introduced the pioneers of the study. Human photoreceptor cells in the retina of dogs. A cocktail of immunosuppressive drugs enabled the cells to survive for months in the recipients’ retinas, where they began to bond with existing retinal cells.

“In this study, we wanted to know whether we could improve the surgical delivery of these cells into the subretinal space; two, image the cells in vivo; three, improve their survival; and four, migrate them to the retinal layer.” Look where they should be and start integrating,” says William Beltran, professor of ophthalmology at Penn Vet and the study’s senior author. “The answer to all those questions was yes.”

Beltran and Gustavo Aguirre at Penn Vet have long been interested in addressing retinal blinding disorders and have had great success so far in producing corrective gene therapies for conditions with known causative genes. But in many cases of inherited retinal degeneration, the gene has not been identified. In other patients, the disease has progressed so far that no photoreceptor cells are sufficiently intact for gene therapy. In any scenario, a regenerative medicine approach, in which photoreceptors can be reprogrammed outright, would be extremely valuable.

To develop the cell therapy, Beltran’s team joined with groups led by CHOP’s John Wolfe and Penn Waite; David Gamm at the University of Wisconsin-Madison; and Kapil Bharti at NEI, in a consortium supported by NEI’s Audacious Goals Initiative for Regenerative Medicine. The partnership combined Beltran’s team’s expertise in canine models of retinal degeneration and vast experience in cell-based therapy approaches from the Wolff, Gamm and Bharti labs.

Photoreceptor cells, which are made up of rods and cones, form a layer of the outer retina that is important for initiating the process of vision, converting the energy of light into an electrical signal. To function properly, they must form a connection, or synapse, with the cells of the inner retina to pass along visual information. Thus, the goal of this cell therapy is to regenerate this layer and enable it to integrate with other cell types in the retina to relay signals from one layer to the next.

In the current work, the team used stem cell-derived precursors of human photoreceptor cells grown in the Gamm lab to serve as the basis for cell therapy. In collaboration with the Bharti Lab, they developed a new surgical approach to inject cells, labeled with fluorescent markers, into the retinas of seven dogs with normal vision and three with inherited retinal degeneration, then Various types of non-invasive imaging techniques are used to track cells over time.

Gamm says, “Using a large animal model that undergoes a naturally occurring form of retinal degeneration and a human-sized eye, there is a safe and efficient way to dose the cells that can be used in patients.” plays an important role in optimizing the surgical procedure.”

The researchers found that animals with retinal degeneration had significantly better cell uptake than animals with normal retinas.

“What we showed was that, if you inject the cells into a normal retina, which has its own photoreceptor cells, the retina remains very much intact and acts as a physical barrier, so introduced The cells don’t connect to second-order neurons. In the retina, bipolar cells,” Beltran says. “But in the three dogs that were in advanced stages of retinal degeneration, the retinal barrier was more permeable. In that environment, the cells had a better ability to move into the right layer of the retina.”

Because the transplanted human cells could be interpreted by the dogs’ immune systems as foreign entities, the researchers did what would be done in other tissue transplant procedures: They gave the dogs immunosuppressant drugs. The trio of drugs was first tested by Oliver Garden, a veterinary immunologist with Penn Vet at the time of the study, who is now dean of the Louisiana State University School of Veterinary Medicine.

Indeed, while the injected cell population decreased significantly in the dogs that did not receive the immune-suppressing drugs, the cell numbers dipped but then remained in the dogs that received the cocktail.

Further characterization of the introduced cells revealed evidence of potential synapses. “We saw that yes, some appeared to ‘shake hands’ with those second-order neurons,” Beltran says. “There appears to be contact.”

The next step for this project will be to continue to optimize the therapy, and then test whether its recipients have a functional response – in other words, improved vision.

Reference: Ripolls-Garcia A, Dolgova N, Phillips MJ, et al. Systemic immunosuppression promotes survival and integration of sub-transplanted human ESC-derived photoreceptor precursors in dogs. stem cell representative, 2022. doi: 10.1016/j.stemcr.2022.06.009

This article has been republished from the following materials. Note: Content may have been edited for length and content. For more information, please contact the cited source.

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