Gene therapy for hemophilia, a condition in which the ability of the blood to clot is severely reduced, as a result of a lack of a coagulation factor, may offer a single intervention to patients that will have a long-lasting effect and free them from the need for treatment with frequent intravenous infusions of the missing coagulation protein to either treat or prevent bleeding episodes.
Such a therapy may potentially illuminate the need for weekly, or in some cases, more frequent administration of recombinant factor VIII (FVIII) or factor IX (FIX), which is costly, burdensome and complicated.
But, as shown by the increasing number of clinical trials the opportunities for gene therapy in the treatment of patients with hemophilia are advancing. And as reported last year in ASH Clinical News, results from a number of trials have restored patients’ anticoagulant factor activity levels to normal or near-normal levels and reduced patients’ annualized bleeding rates by nearly 90%. 
Role of antibody-drug conjugates
Researchers at the Blood Research Institute, Versiti Wisconsin, Milwaukee, WI and the Institute of Medical Laboratory Science and Technology, Harbin Medical University, Daqing, China, have shown that hematopoietic stem cell (HSC)–based platelet-specific factor VIII (FVIII) (2bF8) gene therapy can produce therapeutic protein and induce antigen-specific immune tolerance in hemophilia A (HA) mice, even in the presence of inhibitory antibodies. 
To examine whether antibody-drug conjugate (ADC-) conditioning is capable of creating a niche for engrafting 2bF8LV-transduced hematopoietic stem cells, the researchers monitored peripheral blood counts and leukocyte chimerism after transplantation of 2bF8LV-transduced HSCs. 
For hematopoietic stem cell-based gene therapy, traditional preconditioning using cytotoxic chemotherapy or total body irradiation has been required.
But the potential toxicity associated with total body irradiation or chemotherapy is often considered a deterrent preventing patients with hemophilia to accept treatment. This is especially the case especially with nonmalignant diseases that, as the researchers argue, otherwise do not require chemotherapy or irradiation as part of their standard treatment.
Results published in late September 2019 in Blood Advances, a publication published by the American Society of Hematology, researchers describe targeted nongenotoxic preconditioning for 2bF8 gene therapy utilizing a hematopoietic cell–specific antibody-drug conjugate or ADC, to potentially replace total body irradiation or chemotherapy.
The ADC consists of saporin, a so-called ribosome inactivating protein (RIP), conjugated to CD45.2- and CD117-targeting antibodies. CD117 (c-kit) is a transmembrane tyrosine kinase receptor. The protein is found on the surface of many different types of cells.
The scientists found that a combination of CD45.2- and CD117-targeting ADC preconditioning was effective for engrafting 2bF8-transduced hematopoietic stem cells and was favorable for platelet lineage reconstitution.
They observed that two thirds of hemophilia A mice that received 2bF8 lentivirus-transduced hematopoietic stem cells under (CD45.2+CD117)-targeting ADC conditioning maintained sustained therapeutic levels of platelet FVIII expression.
Furthermore, when CD8-targeting ADC was supplemented, chimerism and platelet FVIII expression were significantly increased, with long-term sustained platelet FVIII expression in all primary and secondary recipients.
Importantly, immune tolerance was induced and hemostasis was restored in a tail-bleeding test, and joint bleeding also was effectively prevented in a needle-induced knee joint injury model in hemophilia A mice after 2bF8 gene therapy.
In summary, the researchers demonstrated for the first time efficient engraftment of gene-modified hematopoietic stem cells without genotoxic conditioning. They concluded that the combined cocktail ADC-mediated hematopoietic cell–targeted nongenotoxic preconditioning that they developed is safe, highly effective and favorable for platelet-specific gene therapy in hemophilia A mice.
They also note that this is a promising rapidly translatable strategy for HSC-based gene therapy that could result in new treatment option of all genetic blood-based diseases and provide a platform for safe and sustained protein production for therapeutic purposes.
Such a treatment strategy could be especially meaningful for hemophilia A patients who are wary of standard preconditioning.
 Breakthroughs in Gene Therapy for Hemophilia – ASH Clinical News, October 1, 2018 [Article]
 Gao C, Schroeder JA, Xue F, Jing W, Cai Y, Scheck A, Subramaniam S, Rao S, et al. Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice. Blood Adv. 2019 Sep 24;3(18):2700-2711. doi: 10.1182/bloodadvances.2019000516.[Pubmed][Article]