Moving Gene Editing Advances Into the Clinic

Gene therapy has long promised to provide a solution for genetic blood disorders, but delivering on that promise has proven complex due to challenges including difficulties delivering the editing tools and off-target effects. Now, advances in base editing technology are potentially offering better options. A recent study conducted by scientists from Emory University, Harvard Medical School, and Beam Therapeutics demonstrated how editing the mutation responsible for sickle cell disease (SCD) can eliminate cell sickling and restore normal hemoglobin function using a naturally benign gene variant.¹ With high editing efficiency and minimal cellular disruption, this approach could redefine what is possible in hematologic disease treatment.

In this Innovation Spotlight, Andrew Mancini, the senior corporate development manager for MaxCyte, discusses the potential of adenine base editing for SCD treatment and beyond, highlighting the high-tech platforms that are required to take gene therapy to the next level.

What would having effective gene therapies mean for patients with sickle cell disease (SCD) and other hematological diseases?

A durable, one-time gene therapy would be transformative for patients with SCD and other hematologic disorders. Current treatments such as transfusions, hydroxyurea, and bone marrow transplants come with significant limitations and often only manage symptoms. Gene editing offers the potential to correct the root cause of disease and provide curative or functionally curative outcomes.

For individuals with SCD, this could mean eliminating painful vaso-occlusive crises, chronic anemia, organ damage, and reduced life expectancy. These benefits would be especially meaningful for underserved populations worldwide. More broadly, editing hematopoietic stem cells (HSCs) allows for permanent correction of genetic defects and long-term restoration of a healthy blood system. We are already witnessing a shift from symptom management to genetic cures, and gene editing is catalyzing that transition.

What is adenine base editing, and how did researchers use it to repair a mutation leading to SCD?

Adenine base editors (ABEs) precisely convert A-T base pairs into G-C without introducing double-strand DNA breaks. In the SCD base editing study, the researchers used ABE8e to change the Glu6Val mutation in sickle hemoglobin to Glu6Ala, producing a naturally occurring benign protein variant called HbG-Makassar.

HbG-Makassar is similar to adult hemoglobin (HbA) in that it does not polymerize under low oxygen conditions and carries oxygen normally. The previously mentioned study demonstrated that editing both beta-globin alleles to HbG-Makassar in red blood cells derived from patient stem cells eliminated sickling and restored normal function.

Why would scientists use adenine base editing instead of other editing technologies?

Unlike CRISPR nucleases, ABEs do not cut DNA, which helps avoid error-prone repair, large deletions, chromosomal rearrangements, or p53 activation. ABEs provide high on-target editing efficiency, often above 80 percent, with very low rates of insertions or deletions, making them ideal for editing sensitive cells such as HSCs.

While prime editing offers greater flexibility, it is currently more complex and less clinically advanced. For single-base mutations like the one that causes SCD, ABEs represent the cleanest and most efficient editing approach available today.

How did the study authors assess the impact of their editing strategy?

The researchers edited CD34+ HSCs from sickle cell disease patients using ABE8e mRNA delivered via MaxCyte electroporation. Edited cells were differentiated into red blood cells for evaluation. Editing efficiency was measured by deep sequencing, showing over 80 percent conversion to the HbG-Makassar gene variant. Protein analysis confirmed replacement of the pathogenic hemoglobin HbS with HbG, and functional assessments were conducted, including hypoxia-induced sickling tests, hemoglobin polymerization assays, and structural modeling of HbG-Makassar tetramers at 2.2 Å resolution. The scientists also transplanted edited HSCs into immunodeficient mice, demonstrating successful engraftment and long-term expression of the edited hemoglobin.

What did the scientists find, and were you surprised by any of their results?

They found that editing both beta-globin alleles to HbG-Makassar completely eliminated red blood cell sickling in vitro. Even heterozygous cells with one HbS and one HbG allele showed significantly reduced sickling, resembling the clinical presentation of milder forms of SCD such as HbSC.

What stood out was the benign nature of HbG-Makassar. Despite targeting the same position in the protein as the sickle mutation, the Glu-to-Ala substitution avoided disease entirely. This result validates the concept that precision base editing can generate therapeutic alleles that occur naturally and have already been validated through evolution.

What difficulties do researchers face when employing gene editing strategies, and what tools or technologies can they use to circumvent these challenges?

Common challenges include delivering editing tools into hard-to-transfect cells such as HSCs, maintaining cell viability and stemness during editing, avoiding off-target effects, and ensuring durable engraftment after transplantation.

MaxCyte’s electroporation platform helps address these issues by enabling efficient delivery of mRNA and ribonucleoproteins into CD34+ cells while preserving cell health and function. The platform avoids the risks associated with viral vectors and has been used successfully across multiple clinical-stage programs. Additional advances such as engineered guide RNAs, high-fidelity editor variants, and optimized cell processing protocols continue to improve the safety and reliability of gene editing workflows.

How can scientists better bridge the gap between the bench and the clinic when it comes to gene editing strategies in general and for hematologic diseases?

The key is translating strong academic findings into clinically actionable, scalable therapies, which requires access to enabling platforms. Electroporation systems such as MaxCyte’s help reduce the friction between research and GMP-compliant delivery, allowing academic labs to efficiently test and scale therapeutic edits. Incorporating naturally occurring, benign variants like HbG-Makassar provides a biologically validated path to safety and efficacy. Collaboration among academic institutions, biotechnology developers, such as Beam Therapeutics, and enabling technology providers is essential to accelerate progress while maintaining safety.

As delivery methods, regulatory frameworks, and editing tools continue to evolve, the timeline from discovery to clinical application is shortening—what previously took a decade can now happen in just a few years.