How Can Gene Editing Breakthroughs Help Prevent Congenital Disease Before Birth?

The findings:

In a first-of-its kind study, scientists performed prenatal gene editing in animals to prevent a lethal metabolic disorder and effectively open the door for similarly treating congenital diseases in humans before birth. Using gene editing technology, the team successfully targeted a gene that regulates cholesterol levels to lower cholesterol and, additionally, turned off the effects of a mutation that causes a lethal liver disease called hereditary tyrosinemia type 1 (HT1) in mice.

Why it matters:

The study provides unprecedented proof-of-concept for prenatal use of an advanced low-toxicity tool that can edit DNA building blocks in disease-causing genes. The approach may eventually be translated to treatments for severe human diseases diagnosed early in pregnancy, particularly those with no effective treatment options or that result in death or severe complications for infants. HT1, for example, appears during infancy in humans, and though it is treatable, patients are at risk for liver failure or cancer when treatments fail.

Who conducted the study:

A team of researchers at CHOP and the University of Pennsylvania’s Perelman School of Medicine conducted the study, co-led by William H. Peranteau, MD, a pediatric and fetal surgeon at CHOP’s Center for Fetal Diagnosis and Treatment, and Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn.

How they did it:

The team designed a CRISPR-mediated strategy for in utero genome editing that uses CRISPR CAS-9 and base editor 3 (BE3) and carries enzymes to a specific genetic location in the liver cells of fetal mice. Once there, the enzyme chemically modifies the genetic sequence and changes one type of DNA base to another; in the study, this resulted in the mice carrying stable amounts of the edited liver cells for up to three months. The subgroup of mice bioengineered to model HT1 showed improved liver function and survival.

Quick thoughts:

“A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach,” said Dr. Peranteau in a press release. “Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist.”

What’s next:

In the CHOP press release, Dr. Musunuru said that the team plans to use the same base-editing technique to go beyond disrupting a mutation’s effects and directly correct the disease-causing mutation. Furthermore, the team will study application of their approach to other diseases beyond those in the liver.

Where the study was published:

The team published their findings in Nature Medicine.

Where to learn more: 

Read more about this research in the press release, and about related work at the Center for Fetal Diagnosis and Treatment.