A mechanistic mannequin of AAV9 and AAV-KP1-mediated renal transduction. Credit score: Nature Communications (2024). DOI: 10.1038/s41467-024-54475-9
Researchers are making strides in bettering gene therapies for genetic illnesses, significantly continual kidney illness, utilizing adeno-associated virus, or AAV, vectors. Whereas AAV-based remedies have proven promise, delivering these therapies successfully to the kidneys has remained a problem—till now.
There are lots of several types of AAV capsids—the protein shells of virus particles—which were used to ship genes to cells, every with distinctive results. Mostly, AAV capsids are delivered into the physique through intravenous injection, however this methodology has restricted success in focusing on kidney cells and might typically trigger dangerous negative effects, particularly to the liver.
New analysis by Oregon Well being & Science College scientists, nonetheless, has uncovered a number of components to enhance gene supply to the kidney, together with AAV capsids, supply routes comparable to IV injection or direct injection into the renal vein or renal pelvis—areas nearer to the kidneys—and kidney illness situations.
The examine outcomes have been printed in Nature Communications.
Hiroyuki Nakai, M.D., Ph.D., OHSU College of Medication Distinguished Professor in Molecular Medication, Division of Molecular and Medical Genetics, and colleagues examined 47 totally different AAV capsids in mice, inspecting the results of varied supply routes.
One capsid, AAV-KP1, stood out as significantly efficient when administered on to the kidneys through the renal vein or pelvis, reaching kidney cells with minimal influence on the liver. In distinction, AAV9, which isn’t an efficient capsid in wholesome kidneys, confirmed higher kidney focusing on when injected intravenously in circumstances of continual kidney illness.
The crew’s analysis means that these native injections could enhance the focusing on of kidney cells and scale back undesirable negative effects, whereas IV injection emerges as an efficient method to ship genes to the kidney when the kidney is diseased, however not when it’s wholesome.
“There was a misconception based on the literature already out there that AAV doesn’t work well on the kidney,” mentioned Nakai, senior creator 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 creator of the paper, was a postdoctoral scholar in Nakai’s lab once they labored on this examine. His experience as a scientific nephrologist helped determine the mixtures of AAV capsids and supply routes that turned out to be only.
“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 mentioned.
“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 vital important findings of the examine was that the 2 capsids behave in a different way by way of how they accumulate within the injection web site and unfold within the physique. The researchers found that injecting AAV-KP1 instantly into the kidney resulted in efficient and particular focusing on of kidney cells, whereas AAV9 unfold all around the physique even by native supply.
The examine additionally highlighted an vital level: The outcomes diversified considerably between species, exhibiting huge variations between mice and nonhuman primates in how the virus enters kidney cells following injection into the renal pelvis. The cell entry mechanism present in nonhuman primates enabled AAV vectors to enter kidney cells within 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 necessity for cautious choice of the appropriate AAV capsid and injection methodology, relying on the species and the illness situation.
Nakai mentioned this analysis gives useful insights into the way to optimize AAV-based gene supply to the kidney in each primary analysis and gene remedy.
It reveals that one of the best outcomes come not simply from choosing the proper virus capsid, but additionally from fastidiously contemplating how and the place to manage it, relying on the illness situation. These findings may pave the way in which for more practical remedies for folks affected by kidney illnesses sooner or later.
Extra info:
Taisuke Furusho et al, Enhancing gene switch to renal tubules and podocytes by context-dependent choice of AAV capsids, Nature Communications (2024). DOI: 10.1038/s41467-024-54475-9
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