Hurler syndrome is a rare lysosomal storage disease that causes organ swelling, muscle abnormalities, heart disease and a range of other problems that can lead to death in childhood. And it’s caused by a single gene mutation—making it a prime target for treatment with gene editing.
Researchers at the University of Pennsylvania say they now have proof of concept that correcting Hurler syndrome with the gene editing system CRISPR before birth is possible. In a study, they used an adeno-associated virus serotype 9 (AAV9) vector to deliver an editor to prenatal mouse models of Hurler syndrome, which corrected the mutation in cells of the liver and heart, they reported in Nature Communications.
The mutation that causes Hurler syndrome is known as a DNA “base” mutation, because the gene has an adenine nucleotide rather than the normal guanine nucleotide. To correct it, the Penn researchers used CRISPR base editing, which requires only a single strand of DNA to be broken so adenine can be converted to guanine. Such single-stranded editing approaches are thought to be safer than other CRISPR technologies, which can cause off-target effects.
Correcting the cells in both the liver and the heart in mice before birth had a positive ripple effect, improving skeletal, metabolic and cardiac functions and boosting survival over untreated animals, the researchers reported.
The Penn team also tested the gene editor on 10-week-old mice with Hurler syndrome, observing similar positive effects. Those mice did develop cardiac disease at four months of age, similar to control animals, but the CRISPR treatment seemed to slow the progression of heart decline. All of the prenatally and postnatally treated mice lived to the end of the study, while some of the control animals died, the researchers reported.
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Base editing has generated enthusiasm from biotech researchers and investors alike. Last month, for example, Beam Therapeutics struck a $75 million deal with Apellis Pharmaceuticals to use the former’s base-editing technology to tackle diseases caused by overactive immune responses.
That deal came just days after Intellia’s stock soared on its first-in-human data showing its gene-editing treatment could significantly cut levels of transthyretin in patients with transthyretin amyloidosis (ATTR).
The new Penn study was led by William Peranteau, M.D., a pediatric and fetal surgeon at Children’s Hospital of Philadelphia. It comes two years after Peranteau’s team used CRISPR to inactivate a gene mutation in mouse models of the lung disease surfactant protein C (SFTPC) deficiency. They also showed in that study that gene editing could be performed in mice before birth.
Last year, scientists at the Hubrecht Institute in the Netherlands targeted another lung disease, cystic fibrosis, with base editing. In that study, researchers used miniature guts, or intestinal organoids, to demonstrate that base editing can correct CFTR mutations that cause the disease.
Peranteau noted that more preclinical studies will be needed to determine the safety of base editing for mothers and fetuses, but the results show it could be a promising approach to Hurler syndrome. “Given the prenatal onset of disease, the potential for non-invasive prenatal diagnosis, and the progressive and morbid nature of the disease, Hurler syndrome and other lysosomal storage diseases represent attractive targets for treatment before birth,” he said in a statement.