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Adenine Base Editing Shows Promise in X-Linked Chronic Granulomatous Disease Trial

• Researchers utilized adenine base editors to correct disease-causing mutations in stem cells from X-CGD patients, showing high efficiency and minimal off-target effects. • The gene editing approach corrected mutations in the CYBB gene, crucial for immune function, with efficiency 3.5 times higher than previous methods. • A first-in-human clinical trial is underway to evaluate the benefits of base-edited stem cell treatments for patients with X-CGD. • Adenine base editors offer advantages over traditional gene therapies by correcting the native genomic sequence without introducing new genetic material.

A collaborative study by the National Institutes of Health (NIH) and Massachusetts General Hospital (MGH) has demonstrated the potential of adenine base editors to correct mutations in stem cells from patients with X-linked chronic granulomatous disease (X-CGD), a rare genetic disorder characterized by heightened susceptibility to infections. The findings, published in Science Translational Medicine, pave the way for a first-in-human clinical trial.
X-CGD is marked by recurrent invasive infections, hyperinflammation, and inflammatory bowel disease, leading to increased morbidity and early mortality. The research team focused on optimizing gene editing to correct X-CGD mutations, aiming to develop a safe and effective treatment.

Precise Gene Editing with Adenine Base Editors

The study, led by Vera Bzhilyanskaya (NIAID) and Linyuan Ma (MGH), involved using hematopoietic stem and progenitor cells from two patients with different X-CGD-causing mutations. These cells were treated with adenine base editors to correct mutations in the CYBB gene. Adenine base editors enable direct correction of mutations, distinguishing this approach from traditional gene therapies that overexpress a corrective gene.
"We're excited about the use of base editing to directly correct mutations since this approach is distinguished from traditional gene therapies that overexpress a corrective gene," said Kleinstiver. "Our results demonstrate how the improved capabilities of engineered CRISPR-Cas9 enzymes can be beneficial, and together motivate additional studies using base editors to correct other mutations that cause inborn errors of immunity and other diseases."
The approach proved highly effective, achieving an efficiency rate 3.5 times higher than previous methods, while also minimizing off-target effects. This precision is crucial for reducing potential adverse effects associated with gene editing.

Advantages of Adenine Base Editors

The scientists emphasized that adenine base editors could overcome challenges associated with other gene therapy approaches. The treatment is better tolerated by cells compared to Cas9 nuclease-based methods, as base editors correct the native genomic sequence without permanently introducing new genetic material. This may diminish risks compared to lentivirus-based gene therapies. Furthermore, the flexible CRISPR-Cas9 enzymes can access a broader range of target sites, potentially correcting many different genetic mutations.

Clinical Trial Launch

Building on these promising results, a first-in-human clinical trial is now underway to assess the potential benefits of base-edited stem cell treatments in patients with X-CGD. This trial represents a significant step forward in translating gene editing technology into clinical applications for rare genetic diseases.
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Reference News

[1]
Gene editing approach helps launch first-in-human clinical trial for rare genetic disease
medicalxpress.com · Oct 17, 2024

A collaboration between NIAID and MGH demonstrates adenine base editors' potential to correct X-CGD mutations in stem ce...

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