Gene Editing Offers Hope for “Irreversible” Kidney Disease Damage Treatment

Recent animal research suggests that damage caused by the most prevalent hereditary kidney disease may not be as irreversible as previously thought. Researchers are using CRISPR gene editing to potentially reverse certain mutations responsible for the condition.

Polycystic kidney disease (PKD) gradually alters kidney function, leading to debilitating effects. “It was generally believed that correcting the mutations would not change the outcome,” says Michael Kaminski from Berlin University of Medicine.

PKD results in the formation of fluid-filled cysts in the kidneys and liver, leading to organ failure and necessitating dialysis or transplants. Besides organ failure, damage and swelling can lead to other severe issues, including high blood pressure and infections.

The disease typically affects adults, with approximately 12 million individuals globally estimated to be affected. Symptoms may not manifest until the cysts reach significant size in one’s 30s, by which point there may already be extensive damage to the kidneys and liver.

Kaminski’s team has utilized a CRISPR method known as base editing to correct mutations in the PKD1 gene in mice models.

This technique successfully corrected mutations primarily in the liver, resulting in a reduction in both the size and number of cysts post-treatment. Kaminski noted potential improvements in the kidneys as well.

Specifically, Xiaogang Li’s team at Mayo Clinic conducted a similar study using more precise methods targeting the kidneys, indicating a reduction in cyst size and quantity, according to Li.

Both teams employed viral vectors to deliver gene-editing tools, which poses challenges with repeated doses due to immune responses might hinder treatment. “This is a legitimate concern,” Li notes. “However, we’ve observed limited immune responses in our animal models so far.”

Utilizing lipid nanoparticles instead of viral vectors, as seen in mRNA vaccines, could mitigate immune-related issues, but Kaminski warns that these particles may struggle to penetrate deeply into the kidneys through the bloodstream. “I believe that the delivery method using [lipid nanoparticles] might become more feasible through urinary pathways,” he says.

Another limitation is that base editing primarily addresses single-character mutations, rendering it ineffective for individuals with longer mutation sequences. However, Li reports successful outcomes using a technique known as Prime editing.

These findings are poised to be published shortly in scientific journals, with plans for human trials to follow. “After our publication, I aim to organize a small clinical trial,” he states.

The broader implications of this research suggest that if PKD can indeed be reversed, it could ignite more research into this potential therapeutic avenue. Currently, the only approved treatment is tolvaptan, which only slightly slows disease progression and requires significant fluid intake.