New American research suggests gene therapy for kidney disease


Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal genetic disease — about half a million people in the US alone suffer from the condition. There is currently no cure, but new research could open the door for new gene therapies to treat most cases of this kidney disease.

For decades, researchers have known that mutations in the PKD1 gene, which encodes the protein polycystin-1 (PC1), can cause disease in about 80% of cases. However, the protein is too large to be modified through gene therapy strategies.

Now, a research team led by Laura Onuchic, postdoctoral researcher in Yale’s Department of Cellular & Molecular Physiology and Michael Caplan, chair and CNH Long Professor of Cellular & Molecular Physiology and professor of cell biology, have found that only a small percentage of these proteins may hold the key to prevent kidney disease. These findings may lead to opportunities to develop new classes of therapies.

The team published its findings March 30 in Nature Communications.

“Our research shows that a small fragment of the PC1 protein—only 200 amino acids from the very end of the protein—is sufficient to suppress disease in a mouse model,” said Caplan, principal investigator of the study.

“Our work will provide new insights into disease mechanisms underlying polycystic kidney disease and uncover new avenues for developing therapies.”

Kidney failure

ADPKD is a genetic disorder that affects about one in 1,000 people. The affected kidney develops cysts that grow in number and size. The human kidney has about a million nephrons. In this disorder, over several decades, some nephrons develop into large, fluid-filled cysts that crowd out normal tissue. Over time, this can put pressure on and degrade the functional parts of the kidney, leading to loss of kidney function.

“By that time, the patient’s kidneys were very large – they could be as big as a soccer ball,” said Onuchic, the study’s first author.

Normal kidneys are about the size of a fist.

About half of people with this disease will develop kidney failure requiring dialysis or a kidney transplant. The disease can be passed from parents to offspring—if one parent is a carrier, half of their children are likely to be affected.

“So you have all these extended families where a lot of people carry the condition,” Onuchic said.

protein switch

A little over a year ago, a team led by Stefan Somlo, Long Professor of Medicine (nephrology) and professor of genetics, found that if they removed the PC1 protein in a mouse model, the kidneys enlarged. Once the protein is re-expressed, the kidneys return to normal.

“They did a really beautiful experiment showing that in a mouse model of polycystic kidney disease, where these animals get large cysts on their kidneys, even when those cysts have grown, re-enabling normal protein expression makes the cysts go away,” said Caplan.

“The problem with this as a therapeutic strategy is that this protein is 4,300 amino acids long,” said Onuchic.

“It’s too big for gene delivery.”

The solution, according to Onuchic and Caplan, may be bringing gene therapy for ADPKD to a manageable scale.

Gene therapy usually involves viral vectors, which means size is an issue.

“Viruses can be Trojan horses that deliver the genes you are interested in into the cells you need to insert them, but they only have room in their trunks,” says Caplan.

Because the PC1 protein is very large, it poses a problem for treating polycystic kidney disease.

“PC1 is too big to fit in the Volkswagen Beetle which is a large part of the gene therapy vector, but right now only 200 of these amino acids can fit in a drawer.”

Using small fragments

In the new study, the team used a mouse model they had genetically modified to enable them to turn off a gene associated with polycystic kidney disease. As a result, the model developed a cyst. Then, the team activated the expression of a protein fragment 200 amino acids long.

“Imagine flipping a light switch where one light is off and one light is on,” explains Caplan.

“We turned off the normal polycystic kidney disease gene and activated the expression of only a small part of this protein.”

The team found that this dramatically reduced the size of the cyst.

“Even though we removed the full-length PC1 protein, which usually causes significant cystic disease, simply activating this small segment was sufficient to suppress the disease,” he said.

The team reveals clues to the mechanics behind why this tiny piece is sufficient on its own. Through immunoprecipitation, they used antibodies to isolate proteins, and then used mass spectrometry to identify which proteins they interacted with. They found that a mitochondrial protein called nicotinamide nucleotide transhydrogenase (NNT) interacts with the PC1 fragment.

“From a basic biology standpoint, this tells us something completely new about what the polycystic kidney disease protein does and opens up a whole avenue for studying its normal function,” said Caplan.

The team plans to continue pursuing use of gene therapy, initially in a mouse model, for just 200 amino acids, in the hope that their work will one day benefit humans.

“From a therapeutic point of view, it is very exciting that we hope to at least slow the progression of the disease,” concluded Onuchic.

There have been some positive developments in treating kidney disease recently. Last month, to mark World Kidney Day (9 March), Labiotech looked at five of the latest advances in the treatment of kidney disease.


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