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Oregon Health & Science University Researchers Make Strides in Gene Therapy for Kidney Disorders
Groundbreaking research from Oregon Health & Science University (OHSU) has opened up new possibilities for people suffering from chronic kidney disease through gene therapy. In a recent study published in Nature Communications, researchers have unveiled promising advancements in improving gene therapies using adeno-associated virus (AAV) vectors, which have been a focal point in the fight against genetic disorders.
While AAV-based treatments have already shown potential, the challenge of delivering these therapies effectively to the kidneys has remained a significant hurdle. AAV vectors, which are used to deliver therapeutic genes to cells, can be injected intravenously, but this approach often has limited success in targeting kidney cells and may lead to undesirable side effects, particularly in the liver.
However, OHSU scientists have uncovered critical insights into how AAV gene therapy can be improved. The research identified multiple factors that could enhance gene delivery, including the choice of AAV capsids, delivery routes such as direct injection into the renal vein or renal pelvis, and the condition of the kidneys themselves.
AAV vectors come in many different types of capsids, the protein shells that carry the therapeutic genes. The OHSU team tested 47 different AAV capsids in mice, evaluating various delivery methods. One particular capsid, AAV-KP1, proved especially effective when administered directly to the kidneys through the renal vein or renal pelvis, reaching kidney cells with minimal liver impact. On the other hand, AAV9, which isn’t effective in healthy kidneys, showed improved kidney targeting when injected intravenously in cases of chronic kidney disease.
According to Dr. Hiroyuki Nakai, a distinguished professor at OHSU’s School of Medicine and the study’s senior author, these findings challenge previous assumptions about the feasibility of using AAV vectors for kidney gene therapy. “There was a misconception based on the literature already out there that AAV doesn’t work well on the kidney,” Nakai stated. “Our study shows that it is possible to deliver genes to the renal tubules and podocytes, the two key cell types for gene therapy, especially in certain kidney diseases.”
Lead author Dr. Taisuke Furusho, a clinical nephrologist, emphasized the importance of this research in addressing genetic kidney diseases, which have traditionally been thought to affect only pediatric patients. “Recent studies have shown that genetic causes are more common than previously thought, affecting both children and adults with chronic kidney disease. If we can correct gene expression in these cases, it would have huge potential for improving patient outcomes,” he explained.
One of the most significant findings of the study was the distinct behavior of AAV capsids in terms of their accumulation and distribution within the body. While AAV-KP1 effectively targeted kidney cells when injected locally, AAV9 spread widely throughout the body, even with direct delivery to the kidneys.
Furthermore, the study revealed notable differences in how AAV vectors interacted with kidney cells in mice versus nonhuman primates. In nonhuman primates, the viral vectors were able to bypass pre-existing immunity and enter kidney cells even in the presence of anti-AAV-neutralizing antibodies. This finding underscores the importance of selecting the right AAV capsid and delivery method, as results may vary across species and disease conditions.
The research marks a significant milestone in understanding how to optimize gene delivery to the kidneys, offering hope for future treatments for those battling chronic kidney disease. With these new insights, scientists can now develop more precise and effective therapies tailored to the specific needs of patients.
As Nakai concludes, “This research opens up new doors for kidney gene therapy, showing that it is possible to overcome barriers and deliver therapeutic genes with high specificity, especially for certain types of kidney diseases.”
For more information, the study titled “Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids” was published in Nature Communications (2024). DOI: 10.1038/s41467-024-54475-9.
