Sometimes referred to as mucopolysaccharidosis type 1, Hurler syndrome is a rare lysosomal storage disease that develops before birth. Lysosomes are subcellular structures containing enzymes responsible for digesting compounds in the cell that are no longer needed. Patients may have organ swelling, neurocognitive degeneration and heart disease by the age of six months. As the result of a single DNA base mutation, where the base guanine is substituted for adenosine, Hurler syndrome is a prime candidate for treatment through genome editing.
'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,' said senior author Dr William Peranteau, fetal surgeon and researcher at the Children's Hospital Philadelphia (CHOP), in Pennsylvania.
Base editing, whereby only a single DNA base is changed, was carried out using the CRISPR approach to insert a break into a single DNA strand allowing the mutated adenosine to be converted to guanine. Single strand editing techniques are often preferred due to the reduced risk of introducing unwanted off-target effects. Moreover, recent improvements in base editing techniques have enhanced the precision with which CRISPR technology can be used for genome editing (see BioNews 1035).
The study, published in Nature Communications, delivered the base editor into fetal mouse models using the adeno-associated virus serotype 9 (AAV9). In the prenatally treated mice, researchers observed increased survival and corrections of cells in both the liver and heart, crucially indicating the effectiveness of the treatment in multiple organs.
Furthermore, to establish the effectiveness of the treatment postnatally, researchers used the same AAV9 approach in ten-week-old mice possessing the Hurler syndrome mutation. Positive findings were again reported, with on-target base editing observed in the heart and liver, as well cardiovascular improvements.
Dr Peranteau highlighted the importance of the findings in both the pre- and postnatal mice: 'In addition to showing the benefit of treating the disease before birth, we also showed some correction of the disease with base editing after birth, highlighting the promise of both pre- and postnatal base editing for Hurler syndrome'.
Hurler syndrome is a serious genetic disorder for which there is currently no cure. The findings reported in this study provide a platform from which further research can be carried out to develop the AAV9 base editing delivery model towards a potential therapy. Additionally, the study provides proof-of-concept for the therapeutic use of base editing in multiple organs thereby making it clinically relevant to numerous genetic disorders.