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ASH Agenda

Genome Editing and Gene Therapy: New Opportunities to Correct Inherited Blood Disorders

Inherited genetic alterations are responsible for a range of devastating hematologic diseases, including sickle cell anemia and other hemoglobinopathies, as well as bleeding disorders due to abnormalities of coagulation and platelet function. Correction of the genetic defects that cause these disorders would allow for cure, rather than life-long palliation. Clinically valuable curative methods not only must be efficacious, but should also be durable, safe, cost-effective, and, ideally, widely available.

Previous therapeutic approaches for these disorders have included transplantation to replace hematopoietic stem cells or gene therapy using viral vectors to express normal copies of the affected gene in hematopoietic cells. Early efforts were met with challenges including transient gene expression, transplant-related toxicities, and leukemia induced by the integration of viral vectors into the host genome. However, great progress has been made in addressing these issues, and current gene transfer methods have demonstrated improved safety and long-term efficacy in correcting a number of monogenic diseases. In parallel, modification of transplant conditioning regimens has significantly reduced transplant-related toxicities.

In recent years, transformative advances have emerged in the use of genome editing approaches to precisely manipulate cellular genomes and correct mutations. These techniques include a range of nuclease systems that can target, cleave, and repair specific genomic sequences at sites of inherited disease-generating mutations, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the Clustered Regularly Interspaced Short Palindrome Repeats and their associated Cas proteins (CRISPR/Cas9) system. Each of these systems can generate breaks at specific DNA sites that are corrected by the cell’s own DNA repair machinery.

The CRISPR/Cas9 system potentially offers the greatest flexibility for genome editing because of its striking efficiency. As an experimental tool, this system has tremendous power to help researchers develop and manipulate experimental models of benign and malignant hematologic disorders. Emerging data attest to the ability of the CRISPR/Cas9 system to correct hematologic disorders, with proof-of-principle data for correcting β-thalassemia in stem cells. Ideal targets for these gene correction strategies are hematologic disorders such as hemoglobinopathies and coagulation disorders such as hemophilia, since existing treatment approaches have shown that only partial restoration of gene function is required to ameliorate the disease, and hematopoietic progenitors that are corrected can be easily re-transfused into the patient. The gene correction strategies developed for inherited disorders will likely also be attractive for other hematologic diseases, including autoimmune disorders (e.g., lupus, rheumatoid arthritis, type I diabetes), as well as for transplant rejection (either hematopoietic stem cell or solid organ transplants).

Raising the Potential for Cure: Priorities to Advance Genome Editing Technologies
While genome editing technology represents a highly promising area to advance the future of therapy for hematologic disorders, critical questions must be addressed to effectively translate this approach into clinical use.

Widely used CRISPR/Cas9 and TALEN genome editing approaches have shown great promise in proof-of-principle preclinical studies and have attracted great interest as potential therapeutic approaches, particularly for therapeutic correction of monogenic disease. Two important areas for future research include the development of proper clinical trial infrastructure and basic research to further advance understanding of the biology of genome editing. Efforts to test the potential for gene therapy in clinical trials have been hindered by contraction of federal funding budgets and the fragmented nature of funding and regulatory mechanisms needed to develop clinical trials. These issues were previously highlighted by the American Society of Gene and Cell Therapy in relation to gene transfer technology,1 and their recommendations are relevant to clinical trials of genome editing. A unified federal grant review process is needed that encompasses all phases of research from bench to bedside.

1.1 Development of an National Institutes of Health (NIH)-funded clinical trial infrastructure is essential to advance research on this important emerging technology. Once preclinical efficacy is established, support is needed for clinical vector production, toxicity testing of the vectors/reagents used to manipulate the genome, and the conduct and monitoring of the clinical trial. A modified version of the NIH funding and review process can encompass each of these areas in a single review and funding process.
1.2 With this infrastructure, basic and preclinical research in genome editing technology is critical to identify the optimal genome editing approach to maximize efficacy and minimize toxicity. Areas for investigation include:
1.2.1 The potential utility of other CRISPR/Cas9 systems, full elucidation of the mechanism of action, and optimization of both target specificity and methods of delivery in order to maximize efficacy and flexibility while minimizing undesired off-target effects.
1.2.2 Optimization of the accuracy, safety and efficiency of targeting vectors to minimize off-target mutations and chromosomal rearrangements and identify strategies to reduce the toxicity of gene modification.
1.2.3 Studies on potential advantages to in utero genome editing versus childhood or adult genome editing, and strategies to implement this type of editing infrastructure, particularly when considering the treatment of under-resourced patient populations.
1.2.4 Evaluation of the potential application of existing monitoring strategies for toxicity from traditional approaches for gene modification trials.
1.3 Because genome editing currently requires culturing hematopoietic stem cells (HSCs) for extended periods (days) and selection of gene-corrected cells, optimized protocols for ex vivo propagation are needed; these need to be paired with rigorous methods to monitor genetic alterations in the modified and expanded cells and determine the functional/safety consequences of these alterations.
1.4 The introduction of nonsense codons into the genes encoding minor and major histocompatibility antigens that are immune targets would reduce transplant rejection and have broad applicability.

Recent research findings indicate broad therapeutic potential for genome editing technologies across a variety of hematologic disorders. The promise of genome editing to correct HSCs was recently demonstrated by targeting a corrective complementary DNA into the interleukin-2 receptor subunit gamma (IL2RG) gene of a subject with X-linked severe combined immunodeficiency (SCID).2 The edited HSCs sustained normal hematopoiesis and gave rise to functional lymphoid cells that possessed a selective growth advantage over those carrying the IL2RG mutations.

Advancement of these techniques within hematologic disorders would build the foundation for translation of genome editing to a wide range of human diseases, including genetic alterations of other organs (e.g., alpha-1 antitrypsin deficiency) as well as non-genetic disorders.

2.1 Studies must determine which disorders are amenable to genome editing correction (e.g., immune deficiencies, including SCID), whether certain disorders can be characterized by more complex mutations, and which gene alterations should be targeted. Further, evaluations are needed to determine if this approach can circumvent the risks associated with HSC gene therapy, including insertional mutagenesis and unregulated transgene expression.
2.2 Single nucleotide variants that result in hemoglobinopathies or immunodeficiencies (e.g., thalassemias, SCID) may be the most amenable to correction by gene editing, and therefore are ideal platforms for initial research programs. Assessments must address specific concerns, including the potential off-target activity of these nucleases.


  1. NIH Funding of Gene Therapy Trials. Position Statement. American Society of Gene & Cell Therapy. September 29, 2006
  2. Genovese P et al. Targeted genome editing in human repopulating haematopoietic stem cells. Nature. 2014 Jun 12;401(7504);235-240.