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Summary: Genome editing therapies represent a significant advancement in next‐generation, precision medicine for the management of haematological diseases, and CRISPR/Cas9 has to date been the most successful implementation platform. From discovery in bacteria and archaea over three decades ago, through intensive basic research and pre‐clinical development phases involving the modification of therapeutically relevant cell types, CRISPR/Cas9 genome editing is now being investigated in ongoing clinic trials. Despite the widespread enthusiasm brought by this new technology, significant challenges remain before genome editing can be routinely recommended and implemented in the clinic. These include risks of genotoxicity resulting from off‐target DNA cleavage or chromosomal rearrangement, and suboptimal efficacy of homology‐directed repair editing strategies, which thus limit therapeutic options. Practical hurdles such as high costs and inaccessibility to patients outside specialised centres must also be addressed. Future improvements in this rapidly developing field should circumvent current limitations with novel editing platforms and with the simplification of clinical protocols using in vivo delivery of editing reagents. [ABSTRACT FROM AUTHOR]

We present the case of an 8-year-old girl with chronic idiopathic thrombocytopenic purpura (ITP) and a short history suggestive of raised intracranial pressure. Urgent computed tomography scan of the head showed a large bleed into a left cerebellar lesion. She underwent treatment with intravenous immunoglobulin (IVIg) and steroids to increase her platelet count, followed by excision of the lesion, which was found to be a benign pilocytic astrocytoma. The patient made a complete recovery and shortly afterwards underwent splenectomy, following which there was complete resolution of her thrombocytopenia. [ABSTRACT FROM AUTHOR]

Sickle cell disease and β-thalassemia are common monogenic disorders that cause significant morbidity and mortality globally. The only curative treatment currently is allogeneic hematopoietic stem cell transplantation, which is unavailable to many patients due to a lack of matched donors and carries risks including graft-versus-host disease. Genome editing therapies targeting either the BCL11A erythroid enhancer or the HBG promoter are already demonstrating success in reinducing fetal hemoglobin. However, where a single locus is targeted, reliably achieving levels high enough to deliver an effective cure remains a challenge. We investigated the application of a CRISPR/Cas9 multiplex genome editing approach, in which both the BCL11A erythroid enhancer and HBG promoter are disrupted within human hematopoietic stem cells. We demonstrate superior fetal hemoglobin reinduction with this dual-editing approach without compromising engraftment or lineage differentiation potential of edited cells post-xenotransplantation. However, multiplex editing consistently resulted in the generation of chromosomal rearrangement events that persisted in vivo following transplantation into immunodeficient mice. The risk of oncogenic events resulting from such translocations therefore currently prohibits its clinical translation, but it is anticipated that, in the future, alternative editing platforms will help alleviate this risk., Competing Interests: H.P.K. has received support as the inaugural recipient of the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Stephanus Family Endowed Chair for Cell and Gene Therapy. H.P.K is or was a consultant to and has or had ownership interests with Rocket Pharmaceuticals, Homology Medicines, VOR Biopharma, and Ensoma. H.P.K has also been a consultant to CSL and Magenta. Other authors have no competing interests., (© 2021 The Authors.)