Base-edited gene therapies ‘may be superior’ for sickle cell disease
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Genomic alteration using adenine base editors demonstrated the most potency in restarting fetal hemoglobin expression in cells of patients with sickle cell disease, study results showed.
The genome editing technology proved more stable while producing higher and more uniform levels of fetal hemoglobin in human hematopoietic stem cells compared with CRISPR/Cas9-based editing approaches, according to findings published in Nature Genetics.
“We compared five clinically viable methods to determine which one was the best ‘bang for the buck’ in terms of potency at a basic science level,” Mitchell Weiss, MD, PhD, chair of the hematology department at St. Jude Children’s Research Hospital, told Healio. “A single mutation with base editing was more effective at raising fetal hemoglobin than a Cas9 indel by two- to threefold.”
Turn on instead of knock out
Gene-based therapies represent what may be the most promising chance to remedy a variety of inherited blood cell disorders, including sickle cell disease, according to researchers.
Most gene therapies attempt to increase levels of fetal hemoglobin, which has been demonstrated through previous research to lessen the severity of symptoms associated with sickle cell disease, Weiss said.
“We are starting to understand the hereditary basis for the existence of fetal hemoglobin, and there are several mutations Mother Nature has provided that can recreate this condition,” he said. “There are multiple ways genetically to induce fetal hemoglobin and different companies are trying different ways, but the best way isn’t known — and the best genome editing tool isn’t known.”
The investigators used preclinical tissue cultures and immunodeficient mouse models to evaluate the potency of fetal hemoglobin induction through one of five gene-editing techniques that involved either Cas9 disruption or adenine base editor installation.
Previous preclinical investigation suggested that base pair editing may provide a more potent product, Weiss said.
“Using CRISPR-Cas9 gene editing creates imperfect double-stranded breaks in DNA that are potentially problematic,” according to Jonathan Yen, PhD, genome engineering group director at St. Jude.
Conversely, base pair editing involves the swapping of base pairs in the DNA strand rather than cutting and replacement.
Whereas current CRISPR approaches try to disrupt, or “knock out,” a gene, base pair editing “changes the DNA sequence to create a new transcription factor binding site, where new activators can come to and turn on the hemoglobin,” Yen said.
Base pair editing to promote increased fetal hemoglobin production involves the creation of a new TAL1 transcription factor binding site, Yen explained. His group’s research showed this method generates more precise nucleotide changes, along with “highly more potent and uniform” induction of fetal hemoglobin, compared with CRISPR-based approaches.
“We saw a far more potent result because we were activating expression,” he said. “There are still risks involved, but with base editing we have more control over the outcome, and it has the potential to reduce the genotoxicity related to the use of nucleases in the gene editing process.”
Clinical implications
With preregistrational studies in the works, plans for clinical trials at St. Jude are moving forward to evaluate both base editing and CRISPR-based gene therapy approaches for treatment of sickle cell disease, according to Yen.
The results of their analysis suggest that base editing leads to more potent therapies, but results of trials evaluating CRISPR-based therapies have shown impressive results thus far, Yen added.
“We know that agents do well on these agents, but we do not yet understand the long-term effects of gene therapy on these patients,” he told Healio. “Base editing may be superior in preclinical studies, but until these treatments go into patients, only then will we know what therapy is best for them.”
Weiss agreed.
“This was all done in the laboratory, so we can’t be 100% sure this will translate into a better therapy,” he told Healio. “The only way to ensure this is through a clinical trial, but this is preclinical evidence that base editors may be superior.”
For more information:
Mitchell Weiss, MD, PhD, can be reached at mitch.weiss@stjude.org.
Jonathan Yen, PhD, can be reached at jonathan.yen@stjude.org.
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