Gene therapy research offers hope for people with chronic kidney disease microbiologystudy

Gene therapy research offers hope for people with chronic kidney disease
A mechanistic model of AAV9 and AAV-KP1-mediated renal transduction. Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-54475-9

Researchers are making strides in improving gene therapies for genetic diseases, particularly chronic kidney disease, using adeno-associated virus, or AAV, vectors. While AAV-based treatments have shown promise, delivering these therapies effectively to the kidneys has remained a challenge—until now.

There are many different types of AAV capsids—the protein shells of virus particles—that have been used to deliver genes to cells, each with unique effects. Most commonly, AAV capsids are delivered into the body via intravenous injection, but this method has limited success in targeting kidney cells and can sometimes cause harmful side effects, especially to the liver.

New research by Oregon Health & Science University scientists, however, has uncovered multiple factors to improve gene delivery to the kidney, including AAV capsids, delivery routes such as IV injection or direct injection into the renal vein or renal pelvis—areas closer to the kidneys—and kidney disease conditions.

The study results were published in Nature Communications.

Hiroyuki Nakai, M.D., Ph.D., OHSU School of Medicine Distinguished Professor in Molecular Medicine, Department of Molecular and Medical Genetics, and colleagues tested 47 different AAV capsids in mice, examining the effects of various delivery routes.

One capsid, AAV-KP1, stood out as particularly effective when administered directly to the kidneys via the renal vein or pelvis, reaching kidney cells with minimal impact on the liver. In contrast, AAV9, which is not an effective capsid in healthy kidneys, showed better kidney targeting when injected intravenously in cases of chronic kidney disease.

The team’s research suggests that these local injections may improve the targeting of kidney cells and reduce unwanted side effects, while IV injection emerges as an effective approach to deliver genes to the kidney when the kidney is diseased, but not when it is healthy.

“There was a misconception based on the literature already out there that AAV doesn’t work well on the kidney,” said Nakai, senior author of the paper.

“Our study shows that we can deliver genes to renal tubules and podocytes [highly specialized cells] in the kidney, the two important target cell types for gene therapy, and while there is a significant barrier, we now know that it is possible, especially for certain types of kidney diseases.”

Taisuke Furusho, M.D., Ph.D., lead author of the paper, was a postdoctoral scholar in Nakai’s lab when they worked on this study. His expertise as a clinical nephrologist helped identify the combinations of AAV capsids and delivery routes that turned out to be most effective.

“The kidney is difficult to target with gene therapy because it is composed of many different cell types and shows structural complexity compared to other organs,” he said.

“Genetic kidney diseases were considered mainly to be found in pediatric patients, but recent studies have shown that genetic causes are more commonly found than previously thought in both children and adults with chronic kidney diseases. If we can correct that gene expression in those cases, that would be a huge potential.”

One of the most significant findings of the study was that the two capsids behave differently in terms of how they accumulate in the injection site and spread in the body. The researchers discovered that injecting AAV-KP1 directly into the kidney resulted in effective and specific targeting of kidney cells, while AAV9 spread all over the body even by local delivery.

The study also highlighted an important point: The results varied significantly between species, showing big differences between mice and nonhuman primates in how the virus enters kidney cells following injection into the renal pelvis. The cell entry mechanism found in nonhuman primates enabled AAV vectors to enter kidney cells in the presence of anti-AAV-neutralizing antibodies, overcoming pre-existing immunity in nonhuman primates, which was not the case in mice.

These observations underlined the need for careful selection of the right AAV capsid and injection method, depending on the species and the disease condition.

Nakai said this research provides valuable insights into how to optimize AAV-based gene delivery to the kidney in both basic research and gene therapy.

It shows that the best results come not just from choosing the right virus capsid, but also from carefully considering how and where to administer it, depending on the disease condition. These findings could pave the way for more effective treatments for people suffering from kidney diseases in the future.

More information:
Taisuke Furusho et al, Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids, Nature Communications (2024). DOI: 10.1038/s41467-024-54475-9

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Oregon Health & Science University


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Gene therapy research offers hope for people with chronic kidney disease (2024, December 31)
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