Researchers use prenatal editing in a preclinical model to correct lysosomal storage disease

Adding to the growing literature demonstrating the feasibility of correcting lethal genetic diseases before birth, researchers at Philadelphia Children’s Hospital (CHOP) have used DNA base editing in a prenatal mouse model to correct a lysosomal storage disease known as Hurler syndrome. Using an adenine base editor delivered in an adeno-associated viral vector, the researchers corrected the single base mutation responsible for the disease, which begins before birth and affects several organs, with the potential to cause death in the childhood if left untreated.

The findings were published today at Communications on Nature.

“This study demonstrates that editing prenatal bases for Hurler syndrome is feasible in a preclinical mouse model,” said lead author William H. Peranteau, MD, assistant surgeon in the Division of General Surgery, Thoracic and CHOP Fetal and Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery. “In addition to showing the benefits of treating the disease earlier birth, we also showed some correction of the disease with baseline editing after birth, highlighting the promise of baseline editing both pre- and postnatal for Hurler’s syndrome. “

Hurler’s syndrome, also known as type I mucopolysaccharidosis (MPS-IH), is a syndrome of lysosomal storage disease which affects about 1 in 100,000 babies in the western world and is usually caused by a single mutation in the base of DNA, where there is an adenine instead of a guanine. At 6 months of age, children may present with inflammation of the liver and spleen, hernias of the abdominal wall, musculoskeletal abnormalities, retinal and neurocognitive degeneration, and heart disease. Without treatment, patients can die from cardiorespiratory complications between the ages of 5 and 10 years. Even with treatment, patients experience complications, as current therapies have limited effectiveness, especially with delayed initiation.

Because the disease’s pathology begins before birth, the research team saw the syndrome as a candidate for prenatal treatment. To this end, the researchers used CRISPR base editing, which only requires a single-stranded DNA break and is believed to be more efficient and safer than other editing approaches, to convert mutated adenine into guanine in the MPS-IH mouse model.

The researchers used an associated adeno virus serotype 9 (AAV9) viral vector to deliver the base editor to a fetal mouse model. They showed that prenatally treated mice demonstrated greater survival and improvement in metabolic, skeletal, and heart disease. It should be noted that the researchers observed the corrected cells not only in the liver but also in the heart, proving that the treatment was effective in multiple organs.

To assess the feasibility of treatment after birth, the researchers tested the 10-week focus on MPS-IH mice and observed efficient targeting in the target and liver, which was also associated with cardiac improvement. While disease control models experienced cardiac decline between 4 and 6 months, sometimes causing death, postnatal-treated mice showed heart disease at 4 months, but progression slowed between 4 and 6 months. the 6 months. Similar to prenatally treated mice, none of the mice treated after birth died according to the final criterion of the study.

“Given the prenatal onset of the disease, the potential for noninvasive 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. said Peranteau. “While the safety of these approaches for mothers and fetuses has yet to be rigorously characterized prior to clinical translation, this proof-of-concept study offers hope for genetic diseases with limited postnatal treatments.”