CRISPR-edited liver cell transplant could replace life of injections for hemophilia B

A Salk Institute team transplanted liver cells into mouse models of hemophilia B, finding that the treatment restored their ability to form blood clots for a year. The hope is that this one-and-done treatment could replace the frequent injections of clotting factors that are currently used to treat the inherited blood disorder.

Hemophilia B is caused by a faulty F9 gene, which codes for clotting factor IX (FIX). Hemophiliacs produce limited amounts of FIX, or none at all, which causes potentially life-threatening prolonged bleeding. To ward off abnormal bleeding and its complications, patients receive regular injections of clotting factors, sometimes multiple times a week. This treatment is expensive and time-consuming. And because it requires an injection, patient adherence can become an issue.

The Salk scientists previously tried to address the genetic defect by injecting mice with messenger RNA encoding the FIX gene. While their blood was able to clot within hours of the treatment, its effects lasted less than a week, necessitating constant injections.

So they set about to find a more permanent solution. FIX is made in the liver, so they thought transplanting liver cells into hemophilic mice might restore FIX production.

To avoid supply issues that come with organ donation, the researchers decided to grow synthetic livers. They took blood cells from patients with hemophilia B and reprogrammed them into induced pluripotent stem cells. They then fixed the genetic mutation using CRISPR and nudged the cells to become liver precursor cells, called hepatocyte-like cells (HLCs).

They injected the HLCs into the mice and found the treatment restored clotting function. The improvement was “at least 10-fold higher than the levels that would be needed for a significant improvement in treating the disease,” they wrote in their study. And it was durable—the HLCs survived in the mice and continued making FIX for at least one year after transplantation. The study is published in Cell Reports.

First author Suvasini Ramaswamy, who recently left Salk for Boston Consulting Group, cautioned that more work is needed before the approach can be translated into humans. But creating healthy, FIX-producing HLCs from a patient’s own cells could prevent immune complications that often accompany cell therapies, the team said.

While patients with hemophilia can control bleeding with clotting factors and drugs, there is no cure for the disorder. Spark Therapeutics’ gene therapy SPK-9001 aims to tackle the same mutation as Salk’s method. But rather than editing the gene before infusing healthy cells into the patient, it does so by delivering a functional copy of the gene to the patient.

One-year data from a phase 1/2 trial showed that nine out of the 10 hemophilia patients had no bleeding episodes after undergoing the gene therapy. Eight of them no longer needed FIX infusions. A December editorial in the New England Journal of Medicine suggested that replacing clotting factor infusions with gene therapy could save up to up to $200,000 per patient per year in healthcare costs.

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