
via Medical Xpress
CHOP/Penn Medicine Team Shows first example of base-editing tool to treat a disease in utero in animal models
For the first time, scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory animals, offering the potential to treat human congenital diseases before birth. Published today in Nature Medicine, research from Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania offers proof-of-concept for prenatal use of a sophisticated, low-toxicity tool that efficiently edits DNA building blocks in disease-causing genes.
Using both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools, the team reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1).
HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.
“Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy,” said study co-leader William H. Peranteau, MD, a pediatric and fetal surgeon in CHOP’s Center for Fetal Diagnosis and Treatment. “We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants.”
“We used base editing to turn off the effects of a disease-causing genetic mutation,” said study co-leader Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn. “We also plan to use the same base-editing technique not just to disrupt a mutation’s effects, but to directly correct the mutation.” Musunuru is an expert in gene-editing technology and previously showed that it can be used to reduce cholesterol and fat levels in the blood, which could lead to the development of a “vaccination” to prevent cardiovascular disease.
In this study, the scientists used base editor 3 (BE3), which takes clustered regularly interspersed short palindromic repeats (CRISPR), joins it with a modified CRISPR-associated protein 9 to form a partially active version of the CRISPR-Cas 9 tool, and harnesses it as a homing device to carry an enzyme to a highly specific genetic location in the liver cells of fetal mice. The enzyme chemically modified the targeted genetic sequence, changing one type of DNA base to another. BE3 is potentially safer than CRISPR-Cas9, because it does not fully cut the DNA molecule and leave it vulnerable to unanticipated errors when the cut is repaired, as has been seen with the CRISPR-Cas9 tool.
After birth, the mice in the study carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bioengineered to model HT1, BE3 improved liver function and preserved survival. The BE3-treated mice were also healthier than mice receiving nitisinone, the current first-line treatment for HT1 patients.
To deliver CRISPR-Cas9 and BE3, the scientists used adenovirus vectors, which have often been used in gene therapy experiments. Because previous gene therapy research has shown that adenovirus vectors may cause unintended and sometimes deleterious responses from the host’s immune system, the team is investigating alternate delivery methods such as lipid nanoparticles, which are less likely to stimulate unwanted immune responses.
A future direction for the team, in addition to using base editing to directly correct disease-causing mutations, will be to investigate its application to other diseases, including those based in organs beyond the liver.
“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 Peranteau, who added, “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.”
Learn more: Guided by CRISPR, Prenatal Gene Editing Shows Proof-of-Concept in Treating Congenital Disease before Birth
The Latest on: Prenatal gene editing
via Google News
The Latest on: Prenatal gene editing
- Genetic Testing Market Next Big Thing | Major Giants GeneTests, United Gene, Counsyl, Asper Biotech, GenePlaneton February 17, 2021 at 2:49 am
What's keeping GeneDx, Invitae, Pathway Genomics, Counsyl Inc, Asper Biotech, GenePlanet, Courtagen Life Sciences, Gene By Gene ... Genetic Diagnosis , Prenatal Diagnosis , Predictive and ...
- Habitual Snoring and Depressive Symptoms During Pregnancyon February 13, 2021 at 4:00 pm
In summary, maternal snoring appears to be independently associated with prenatal depressive symptoms ... assisted with manuscript editing, and approved the final version. LMS assisted with ...
- Gene Editing Market Revenue Poised for Significant Growth During the Forecast Period of 2020-2027on February 12, 2021 at 10:16 am
Gene editing refers to the technique of altering the genetic piece of infected cells caused by disease-causing microorganisms to prevent harmful mutations. The global gene editing market was ...
- Organoids News and Researchon February 11, 2021 at 4:00 pm
A new study of autism risk genes by UC San Francisco and UC Berkeley scientists implicates disruption in prenatal neurogenesis ... swallowing the virus. Gene editing therapies, including CRISPR ...
- ‘Hidden Biological Link’ Among Autism Genes Revealed in Studyon February 5, 2021 at 3:08 pm
Image by Helen Rankin Willsey A new study of autism risk genes by UC San Francisco and UC Berkeley scientists implicates disruption in prenatal neurogenesis ... have identified gene mutations strongly ...
- Webinar Review: Single-Use System Design for Cryogenic and Cold Temperature Operationson February 3, 2021 at 3:57 am
Promising novel cell and gene therapeutics have brought cold processing and cryogenic operations to the forefront. But these stressful environments can be a supply chain hurdle. The right material ...
- Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaineon February 2, 2021 at 4:00 pm
Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibition of histone deacetylase, which caused global histone ...
- In utero gene editing for monogenic lung diseaseon February 2, 2021 at 4:00 pm
Using CRISPR-Cas9 gene editing to correct lung diseases during later prenatal developmental stages has the potential to reverse such genetic abnormalities before transition to postnatal life when ...
- Protecting the Developing Brain from Prenatal Stresson February 1, 2021 at 10:30 am
Researchers from the University of Iowa (UI) and University Hospitals Cleveland Medical Center report that offspring can be protected from the effects of prenatal stress by administering a ...
via Bing News