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Scientists are looking at gene therapy as a potential treatment for a specific type of kidney disease. VICTOR TORRES/Stocksy
  • Autosomal dominant polycystic kidney disease (ADPKD) is an inherited life-threatening condition that involves the formation of cysts in the kidney and impairment of kidney function.
  • More than three in four cases of ADPKD cases are caused by a mutation in the PKD-1 gene that encodes the polycystin-1 (PC1) protein.
  • The PC1 protein is cleaved to form fragments of different sizes, including a fragment called the C-terminal tail (PC1-CTT) fragment.
  • A recent study using a mouse ADPKD model showed that the PC1-CTT fragment could ameliorate the development of cysts in the kidney and help preserve kidney function.

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder that affects between 1 in 1,000 people and 1 in 2,500 people around the globe.

ADPKD is characterized by the development of cysts in the kidney and a decline in kidney function. Mutations affecting the PC1 protein, which is encoded by the PKD-1 gene, are responsible for the most prevalent form of ADPKD.

Although the expression of the non-mutated PC1 protein can revert ADPKD in animal models, the length of the PKD-1 gene has been an obstacle to its use in gene therapy.

A recent study published in the journal Nature Communications reports that expressing a small fragment of the PC1 protein, known as the C-terminal tail (CTT) fragment, helped reduce disease severity in an ADKPD mouse model. Researchers said the reduced length of the gene encoding CTT fragment could make it more amenable for use in gene therapy.

The study also revealed how the CTT fragment could help to reverse ADPKD.

“Our research shows that a tiny fragment of the PC1 protein — just 200 amino acids from the very tail end of that protein — is enough to suppress the disease in a mouse model,” Dr. Michael Caplan, a professor at Yale University and a study co-author, said in a press statement. “Our work will provide new insights into the underlying disease mechanisms for polycystic kidney disease and reveal new avenues for developing therapies.”

Polycystic kidney disease (PKD) is a genetic disease marked by the development of fluid-filled sacs, called cysts, in the kidney. This condition impedes the ability of the kidneys to filter waste and can cause kidney failure.

Autosomal dominant polycystic kidney disease (ADPKD), the most common form of PKD, is also the most prevalent life-threatening inherited disorder. ADPKD is caused by a mutation in either the PKD1 or PKD2 genes.

The presence of a single copy of the mutated gene inherited from either parent is sufficient to cause ADPKD.

About 78% of all ADPKD cases are caused by a mutation in the PKD1 gene that encodes the polycystin-1 (PC1) protein. Expression of the PC1 protein in animal models in which the PKD1 gene has been turned off can reduce the development of cysts and reverse other pathological changes. However, the length of the PKD1 gene encoding the PC1 protein makes it unsuitable for gene therapy.

Animal and cell culture models of ADPKD have shown disruption of metabolic pathways in this condition, including those involved in energy production. Several of these processes occur in the cell organelles called the mitochondria that convert nutrients to chemical energy in the form of ATP. ATP can then be used to fuel various biological processes in the cell.

Studies in animal models have shown that therapeutics or interventions that target these metabolic pathways can help alleviate the symptoms of ADPKD. Yet, the mechanisms through which mutations in the PKD1 gene impact metabolic function are poorly understood.

In the recent study, the researchers examined the mechanisms through which the PKD1 gene could impact metabolic pathways.

The PC1 protein is found in the cell membrane, but it is also cleaved to produce smaller fragments that localize to other compartments in the cell. Given the disruption of metabolic pathways, the researchers focused on a specific fragment of the PC-1 protein called the C-terminal tail fragment (PC1-CTT). This protein fragment consists of 200 amino acids and localizes to the mitochondria.

The recent study’s authors examined the ability of this fragment to prevent the development of cysts in an animal model of ADPKD.

In the present study, the researchers used a genetically-engineered mouse model of ADPKD that did not express the PKD-1 gene.

The researchers reported that the expression of the gene encoding the PC1-CTT fragment in these animals helped slow down the growth of cysts and preserve kidney structure and function. Notably, the levels of markers of kidney function in mice expressing the CTT fragment without the PKD-1 gene were similar to those in wild-type mice with an intact PKD-1 gene.

To identify the molecular pathways mediating these effects of the PC1-CTT fragment, the researchers then examined the interaction of the PC1-CTT fragment with other proteins in kidney cells. The enzyme Nicotinamide Nucleotide Transhydrogenase (NNT) localized in the mitochondria showed the highest level of interaction with PC1-CTT. Moreover, NNT plays a vital role in reducing oxidative stress and other metabolic functions.

Further experiments in mice that did not express the NNT and the PKD-1 genes showed that the expression of the PC1-CTT fragment failed to reduce cyst formation or prevent changes in kidney structure in these mice. Only mice expressing both the NNT gene and PC1-CTT fragment showed suppression of cyst formation and preservation of kidney structure.

The researchers said these experiments suggest that the ability of PC1-CTT to attenuate the severity of ADPKD is mediated by its interaction with NNT.

The researchers then examined how the PC1-CTT fragment influenced the levels of metabolites, which are the intermediate or end products of metabolism, in the ADPKD mouse model.

The researchers reported that the PC1-CTT fragment helped normalize the metabolic profile in mice lacking the PKD-1 gene and reduced markers of oxidative stress.

The researchers said the expression of the PC1-CTT fragment in the ADPKD mouse model increased the expression of NNT compared with their counterparts that did not express the CTT fragment.

These results were consistent with findings from human samples, with tissue samples from the kidneys of individuals with ADPKD showing lower levels of the NNT than their healthy counterparts.

In addition, PC1-CTT also increased the expression of certain enzymes involved in oxidative phosphorylation, the pathway involved in energy production, in the ADPKD mouse model.

Dr. Diane Triolo, a nephrologist at Holy Name Medical Center in Teaneck, NJ, told Medical News Today that “the latest therapies for treatment include slowing the progression of the cysts but unfortunately have not shown to prevent them from forming which ultimately these cysts lead to end-stage renal disease.”

“Prior research has isolated the genes that have been shown to cause ADPKD,” she added. “[The present study provides] nephrologists and their patients hope for a potential cure rather than delay to end-stage renal disease in ADPKD. They have shown that expressing the C-terminal fragment of PC1 through interaction with Nicotinamide Nucleotide Transhydrogemase can suppress these cysts and preserve renal function in mouse tissue. This gives hope to millions of people and shows how important gene therapy is not only for ADPKD but for many other diseases as well.”