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Base Editing Being Tested to Treat Rare Genetic Immune Disorder in NIAID-Sponsored Trial

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NEW YORK – A first-in-human clinical trial is underway for an experimental treatment for X-linked chronic granulomatous disease (X-CGD) using a new approach to base editing, a type of gene editing.

For the open-label Phase I/II trial, sponsored by the US National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID), investigators plan to recruit about 10 patients with X-CGD and a particular missense mutation in the CYBB gene, c.676C>T, to receive a single infusion of the base-editing treatment.

"The expectation is that we will repair the mutation," said Suk See De Ravin, a senior research physician and chief of NIAID's gene therapy development unit.

The base-editing treatment was developed by researchers at the NIAID and Massachusetts General Hospital (MGH). The researchers have worked together for years to investigate genome-editing approaches to target specific areas of the genome and correct genetic mutations. Within this clinical trial, they're studying the efficacy and safety of the base-editing treatment.

X-CGD is a type of rare and inherited immune disorder known as an inborn error of immunity (IEI) that can be caused by mutations in the CYBB gene. Patients with this genetic condition, in which white blood cells don't work properly, are highly susceptible to infections and tend to experience hyperinflammation and inflammatory bowel disease, among a range of symptoms.

Available treatments include supportive care, such as antibiotics to treat bacterial infections, or an allogeneic stem cell transplant of healthy cells from an appropriately matched donor.

By directly fixing the mutation in the CYBB gene with base editing, "the hope is that we can improve the clinical symptoms," De Ravin said.

But other issues that arise from X-CGD won't be able to be cured. For instance, some patients may have developed organ damage, which base editing won't reverse. Repairing the mutation, though, may be able to help patients avoid further damage.

Within the Phase I/II trial, which launched last year, investigators will extract hematopoietic stem and progenitor cells (HSPCs) from patients and modify them ex vivo using adenine base editors to correct the mutation. These cells are infused back into the patient after they undergo a conditioning regimen with the chemotherapy drug busulfan.

Investigators will monitor patients for adverse events related to the treatment, as well as whether it improves the function of patients' white blood cells and results in fewer infections related to X-CGD. The study will track patients for five years, with long-term follow-up under a separate NIH protocol that will continue through 15 years posttreatment.

The base editor used within the study specifically is designed to correct the CYBB c.676C>T mutation, but De Ravin said she hopes to be able to use a similar approach to treat patients with other CYBB mutations in future studies.

Investigators wanted to create a treatment that would correct a genetic mutation, rather than introduce an entire copy of a gene into cells like in traditional gene therapy, said Benjamin Kleinstiver, an associate professor in the Center for Genomic Medicine at MGH and Harvard Medical School who researches and develops genome-editing technologies.

"We're changing a single base, in principle, instead of integrating a large genetic cassette randomly throughout the genome," he said, referring to the difference between base editing and traditional lentivirus-based gene therapies. Kleinstiver is on the scientific advisory boards of multiple companies developing gene-editing therapeutics, including Acrigen Biosciences, Life Edit Therapeutics, and Prime Medicine.

Kleinstiver and De Ravin have filed a patent application related to their work in X-CGD.

Investigators are betting this approach will carry numerous benefits. For example, in traditional gene therapy, the treatment carries the risk of unintentionally integrating genetic material within or near genes that have been linked with cancer, while this base-editing approach would target and modify a particular genetic mutation.

Base editors, unlike other gene editors that use CRISPR-Cas9, also don't require double-strand breaks and can make changes to single nucleotides, giving it greater specificity.

However, base editors typically use Cas9 enzymes that require the presence of a short base pair DNA sequence that immediately follows the portion of the genome being edited. This DNA sequence, known as a protospacer adjacent motif (PAM), enables the enzyme to target the binding region precisely.

If there's not a PAM in an appropriate location, a target site won't be accessible for base editing.

To address this issue, Kleinstiver, De Ravin, and colleagues developed a highly permissive, PAMless Cas9 enzyme, called SpRY, that tolerates PAMs with a broader array of possible nucleotides. They evaluated this approach in a preclinical study of HSPCs, results of which were published this past fall in Science Translational Medicine.

In that study, which supported the first-in-human trial that's underway, investigators extracted HSPCs from two patients with different genetic mutations at the root of their X-CGD diagnosis. They developed adenine base editors with which to treat these cells and test whether they could correct the mutations.

The base editors achieved sufficiently high levels of on-target edits, according to investigators, and minimal off-target mutations, or cases in which the base editor creates unintended genetic changes, which have been a source of concern for gene-editing treatments. The edited alleles persisted after the HSPCs were translated into immunodeficient mice.

"By enabling the correction of the underlying genetic mutations, rather than overexpressing a corrective transgene, genome editing approaches could offer an improved safety profile with broad applicability for many IEIs," corresponding authors Kleinstiver and De Ravin and their colleagues wrote in the paper.

Investigators believe this approach to base editing could be used to correct other genetic mutations, Kleinstiver said.

He said he hopes to continue to test and refine the approach in new disease settings, such as other IEIs. "This is in many ways a blueprint," Kleinstiver said. "It's a nice demonstration that these technologies work and are scalable."