New gene editing approach for alpha-1 antitrypsin deficiency shows promise

October 20, 2017 by Jim Fessenden, University of Massachusetts Medical School
Credit: CC0 Public Domain

A new study by scientists at UMass Medical School shows that using a technique called "nuclease-free" gene editing to correct cells with the mutation that causes a rare liver disease leads to repopulation of the diseased liver with healthy cells. Alpha-1 antitrypsin deficiency is an inherited disease that causes liver and lung damage; the Mueller lab's approach to the disease, led by postdoc Florie Borel, PhD, and published in the journal Molecular Therapy, combines the use of RNA interference with gene augmentation, using an RNAi-resistant version of the alpha-1 antitrypsin gene. This dual treatment has the potential to prevent both liver and lung damage from forming in very young patients.

"This is a significant win for ," said Christian Mueller, PhD, associate professor of pediatrics and senior author of the study. "If healthy or gene-corrected liver have a selective advantage over cells with the alpha-1 antitrypsin deficiency mutation, then it is possible that by treating only a few cells, those will 'outcompete' the diseased cells. And because liver cells regenerate easily, this can create a big advantage therapeutically."

Alpha-1 antitrypsin deficiency, or "alpha-1," is a single gene disorder. A mutation causes the misfolding of the alpha-1 protein, leading to the loss of its normal biological function. Without the protective activity of this protein, certain enzymes damage the lungs, leading to emphysema and chronic obstructive pulmonary disease, a debilitating and potentially deadly condition that often remains undiagnosed. In about 10 percent of patients, this misfolded protein, which also accumulates in the liver, can cause damage leading to cirrhosis of the liver.

Currently, there is no curative treatment for the disease; many people with the disease manage the symptoms with intravenous infusions of alpha-1 antitrypsin purified from donated human plasma. New clinical approaches using gene therapy and gene editing form the basis of a treatment to remove the source of the toxic protein in the liver, while ramping up production of healthy alpha-1 proteins.

Alpha-1 antitrypsin deficiency affects at least 100,000 people in the United States. An estimated 20 million people carry the gene for the disease and could pass it to their children. That's as many as carry mutations for cystic fibrosis, which is much more widely recognized.

"Gene editing with alpha-1 antitrypsin deficiency alone can do a lot of what CRISPR/Cas9 [currently the most widely-studied gene editing tool] does, just at a lower efficiency," said Mueller. "In cases where there is a competitive advantage, only a low-level of editing is necessary, allowing the corrected cells to expand and, in this case, both prevent liver disease and make therapeutic levels of the normal alpha-1 protein."

The key to the new discovery was inspired by a collaboration with Lenny Schultz, PhD, professor at the Jackson Laboratory, and the labs of Michael Brehm, PhD, associate professor of molecular medicine; Dale Greiner, PhD, the Dr. Eileen L. Berman and Stanley I. Berman Foundation Chair in Biomedical Research and professor of molecular medicine; and Terence R. Flotte, MD, the Celia and Isaac Haidak Professor of Medical Education, executive deputy chancellor, provost and dean of the School of Medicine, at UMMS. They worked to develop a new humanized mouse model with the mutation that causes alpha-1 antitrypsin deficiency. Other mouse models are very fragile, explained Mueller.

Future research will include a formal toxicology study. Currently, there is no large animal model of alpha-1 antitrypsin deficiency that would allow preclinical testing.

"What we have here is a proof of concept that this approach would potentially help patients," said Mueller. "And for very young patients with actively growing livers that could potentially be treated early in life, this could be very meaningful."

Explore further: A finding that could help Alpha-1 sufferers breathe more easily

More information: Florie Borel et al. Survival advantage of both human hepatocyte xenografts and genome edited hepatocytes for treatment of α-1 antitrypsin deficiency, Molecular Therapy (2017). DOI: 10.1016/j.ymthe.2017.09.020

Related Stories

A finding that could help Alpha-1 sufferers breathe more easily

December 13, 2012
Scientists have identified a new mutation in the gene that causes the inherited disease known as Alpha-1 Antitrypsin Deficiency (Alpha-1), which affects roughly one in 2,500 people of European descent.

New targeted gene therapy could lead to improved treatment for emphysema

July 5, 2016
Researchers have developed a new strategy using lung-targeted gene therapy that may lead to improved treatments for inherited diseases including emphysema.

Oxidative stress and altered gene expression occurs in a metabolic liver disease model

October 30, 2012
A team of researchers under the direction of Dr. Jeffrey Teckman in the Department of Pediatrics at St. Louis University, have demonstrated that oxidative stress occurs in a genetic model of alpha-1-antitrypsin deficiency. ...

RCSI research breakthrough in understanding hereditary emphysema

January 13, 2014
Researchers from the Royal College of Surgeons in Ireland (RCSI) and Beaumont Hospital have made an important breakthrough in the understanding and treatment of hereditary emphysema.  Their research findings were published ...

Study shows treatment for genetically caused emphysema is effective

May 28, 2015
A landmark clinical study in the Lancet provides convincing evidence that a frequently overlooked therapy for genetically-caused emphysema is effective and slows the progression of lung disease.

Recommended for you

Variants in non-coding DNA contribute to inherited autism risk

April 19, 2018
In recent years, researchers have firmly established that gene mutations appearing for the first time, called de novo mutations, contribute to approximately one-third of cases of autism spectrum disorder (ASD). In a new study, ...

Researchers discover link between gene variation and language

April 18, 2018
What shapes the basic features of a language?

Natural selection still at work in humans

April 18, 2018
Evolution has shaped the human race, with University of Queensland researchers finding signatures of natural selection in the genome that influence traits associated with fertility and heart function.

Gene therapy for beta-thalassemia safe, effective in people

April 18, 2018
In a powerful example of bench-to-bedside science showing how observations made in the lab can spark life-altering therapies in clinic, an international team of clinician-investigators has announced that gene therapy for ...

Potential lines of attack against prostate cancer

April 17, 2018
Researchers from The University of East Anglia (UEA) have contributed to the world's largest study into genes that drive prostate cancer – identifying 80 molecular weaknesses that could be targeted by drugs to treat the ...

Epstein-Barr virus linked to seven serious diseases

April 16, 2018
A far-reaching study conducted by scientists at Cincinnati Children's reports that the Epstein-Barr virus (EBV)—best known for causing mononucleosis—also increases the risks for some people of developing seven other major ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.