Biomarker implications of gene editing in hematologic diseases: latest updates from ASH 2025

Abstract

The 2025 American Society of Hematology (ASH) Annual Meeting highlighted rapid advances in gene editing for hematologic diseases, with increasing emphasis on precision editing and early exploration of in vivo delivery strategies. Beyond technological development, several measurable parameters are emerging as potential biomarkers, including fetal hemoglobin (HbF), F-cell proportion, HbF/F-cell, editing durability, and long-term clonal monitoring. Clinical studies demonstrated that disruption of the BCL11A enhancer or editing of the HBG1/2 promoter can induce sustained HbF reactivation, which is associated with reduced transfusion burden or transfusion independence in transfusion-dependent β-thalassemia and improved clinical outcomes in sickle cell disease. Near-pancellular HbF distribution and HbF/F-cell levels above anti-sickling thresholds further support the pharmacodynamic value of HbF-related biomarkers. Long-term follow-up studies have also incorporated editing durability and clonal monitoring into safety assessment frameworks. Emerging platforms such as RNA Gene Writer and CD90-targeted virus-like particles have demonstrated the feasibility of in vivo hematopoietic stem cell editing, although challenges related to targeting efficiency, delivery specificity, immunogenicity, and long-term safety remain. Overall, ASH 2025 suggests a shift from achieving gene editing to quantifying efficacy, durability, and safety, with standardized biomarker frameworks likely to play an increasingly important role in future clinical translation.

To the Editor,

 Gene editing in hematologic diseases is increasingly focused on generating durable, safe, and clinically meaningful benefits. This correspondence, based on abstracts presented at the 2025 American Society of Hematology (ASH) Annual Meeting, highlights advances in efficacy assessment, long-term durability, and safety monitoring. Several studies not only demonstrated continued clinical improvement but also highlighted the potential biomarker value of fetal hemoglobin (HbF), F-cell proportion, HbF/F-cell, editing durability, and long-term clonal monitoring for evaluating pharmacodynamic responses, durability, and safety. These parameters are evolving from conventional experimental endpoints into integrated measures that may better reflect clinically meaningful benefit.

Efficacy-related biomarkers

Reactivation of HbF remains the most clinically advanced gene-editing strategy for β-thalassemia and sickle cell disease (SCD). As the focus shifts from editing success to quantifying therapeutic benefit, HbF-related parameters, including HbF levels, F-cell proportion, and HbF/F-cell, are emerging as candidate biomarkers of treatment response. ASH 2025 highlighted the association between these parameters and clinically meaningful outcomes. In addition, optimization of BCL11A regulatory elements, particularly through epigenetic insulation strategies, further supports HbF reactivation as a key therapeutic pathway [1].

The CS-101 study demonstrated sustained HbF induction and durable transfusion independence in transfusion-dependent β-thalassemia (TDT) [2], whereas the RUBY study reported sustained HbF elevation and hematologic improvement in SCD [3]. Optimized cytosine base editors (CBEs) are further improving the efficiency and safety of HbF reactivation. Recent studies have moved beyond total HbF levels to examine HbF distribution among red blood cells.

The RUBY study further demonstrated significant increases in both F-cell proportion and mean HbF content per F-cell (HbF/F-cell) following treatment [3]. Because sickling occurs in individual red blood cells, HbF/F-cell and F-cell proportion may better reflect anti-sickling capacity than total HbF alone. Consistently, the BEACON study showed that HbF/F-cell levels above the proposed anti-sickling threshold were associated with improvements in hemolytic markers and vaso-occlusive manifestations [4]. Together, these findings suggest that HbF-related parameters are evolving from conventional laboratory measurements into candidate pharmacodynamic biomarkers with direct clinical relevance.

Durability and clonal monitoring

As gene-editing therapies for hematologic diseases advance toward clinical application, long-term safety has become an increasing focus. Unlike earlier studies that primarily emphasized editing efficiency, research presented at ASH 2025 has begun to incorporate clonal monitoring, editing durability, and hematologic stability into long-term assessment frameworks [5, 6].

Studies in transfusion-dependent β-thalassemia (TDT) have highlighted the importance of monitoring clonal expansion and mutation burden to assess potential genomic risks associated with gene editing [5]. Long-term follow-up studies have also demonstrated sustained HbF induction and durable hematopoietic reconstitution without major safety concerns [6]. Preserving hematopoietic stem cell (HSC) function during editing has become an important consideration for long-term hematopoiesis [7]. Real-world studies of approved therapies, including Casgevy, underscore the need for safety surveillance [8].

Notably, a Prime Editing study in Shwachman-Diamond syndrome (SDS) expanded efficacy assessment beyond editing efficiency to include disease-specific functional restoration and phenotypic correction [9]. Together, these findings suggest that clonal monitoring, editing durability, and hematopoietic stability may serve as important indicators for long-term safety assessment following gene editing (Table 1).

Table 1.

Candidate biomarkers and their potential significance in gene-editing studies presented at ASH 2025

Study/Strategy	Key Biomarker(s)	Key Findings	Potential Biomarker Significance	Reference
CS-101	HbF level	Sustained HbF induction and durable transfusion independence	HbF may serve as a pharmacodynamic biomarker of treatment response	[2]
RUBY	F-cell proportion, HbF/F-cell	Significant increases in F-cell proportion and mean HbF content per cell	HbF distribution at the single-cell level may better reflect anti-sickling capacity	[3]
BEACON	HbF/F-cell, hemolytic markers	HbF/F-cell exceeded the proposed anti-sickling threshold and was associated with improved hemolytic markers	HbF/F-cell may serve as a functional protective biomarker	[4]
Clonal monitoring study	Clonal monitoring, mutation burden	Long-term monitoring of clonal expansion and associated risks was recommended	Clonal dynamics may serve as indicators of long-term safety	[5]
Long-term follow-up study	Editing durability, hematologic stability	Sustained HbF induction and hematopoietic reconstitution over several years	Editing durability may be useful for long-term efficacy assessment	[6]
Casgevy pharmacovigilance	Real-world safety signals	Post-marketing pharmacovigilance data from real-world settings	Potential indicators for long-term safety assessment	[8]
Prime Editing in SDS	Disease-specific functional restoration	Precise correction of SDS-associated mutations	Functional restoration may serve as a novel efficacy endpoint	[9]

HbF, fetal hemoglobin; F-cell, HbF-containing red blood cell; HbF/F-cell, mean fetal hemoglobin content per F-cell; SDS, Shwachman-Diamond syndrome

Translational challenges and evaluation metrics for delivery strategies

As novel delivery approaches continue to emerge, the evaluation framework for gene editing in hematologic diseases is also evolving. Although most clinical studies still rely on ex vivo editing and have achieved encouraging outcomes in β-thalassemia and sickle cell disease, challenges related to manufacturing complexity, conditioning-associated toxicity, and treatment costs remain, highlighting the need for more accessible therapeutic strategies.

Several studies presented at ASH 2025 explored emerging platforms for HSC editing, including RNA Gene Writer, CD90-targeted virus-like particles (VLPs), and lipid nanoparticle (LNP)-based systems [10–12]. These approaches demonstrated feasibility in non-human primates, humanized models, or ex vivo settings, although significant challenges remain before broader clinical translation.

As delivery strategies evolve, evaluation is increasingly extending beyond editing efficiency alone. Parameters such as delivery specificity, hematopoietic reconstitution, editing durability, immunogenicity, and off-target tissue editing may serve as indicators of efficacy and safety (Table 2).

Table 2.

Translational challenges and potential evaluation metrics for gene-editing delivery strategies in hematologic diseases

Strategy	Current Progress	Major Challenges	Potential Evaluation Metrics	Reference
HSPC-based ex vivo editing	Durable clinical benefit has been achieved in β-thalassemia and sickle cell disease	Complex manufacturing process, conditioning-associated toxicity, and high cost	Editing durability and long-term hematopoietic reconstitution may indicate treatment stability	[2], [6]
RNA Gene Writer	In vivo HSC editing has been achieved	Editing efficiency and long-term stability remain to be validated	Editing rate and durability may serve as important evaluation metrics	[10]
CD90-targeted VLP	Improved HSC-targeting capability	Delivery specificity and long-term safety require further evaluation	HSC-targeting efficiency may influence long-term hematopoietic reconstitution	[11]
LNP-based ex vivo delivery	Enhanced HSPC editing efficiency with potential for scalable manufacturing	Further optimization of editing efficiency and preservation of cellular function is needed	Editing rate and long-term hematopoietic reconstitution may serve as important evaluation metrics	[12]

HSC, hematopoietic stem cell; HSPC, hematopoietic stem and progenitor cell; VLP, virus-like particle; LNP, lipid nanoparticle

Overall, ASH 2025 highlights a shift toward more comprehensive assessment of gene-editing outcomes. HbF-related parameters, editing durability, and clonal monitoring are increasingly being explored as candidate biomarkers, while standardized biomarker frameworks may support clinical translation.

Abbreviations

ASH

American Society of Hematology

HbF

Fetal hemoglobin

TDT

Transfusion-dependent β-thalassemia

SCD

Sickle cell disease

CBE

Cytosine base editor

HSC

Hematopoietic stem cell

HSPC

Hematopoietic stem and progenitor cell

VLP

Virus-like particle

LNP

Lipid nanoparticle

SDS

Shwachman-Diamond syndrome

Author contributions

ZZ drafted the manuscript. WZ and RX prepared the tables. SC provided direction and guidance throughout the preparation of the manuscript. All authors participated in the process of drafting and revising the manuscript. All authors read and approved the final manuscript.

Funding

This work was financially supported by National Natural Science Foundation of China (No. 82574790); ShanDong Provincial Medical Association (No. YXH2025YS080).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable for this summary.

Consent for publication

Not applicable for this summary.

Competing interests

The authors declare no competing interests.