Gene therapy for hemophilia

Abstract

Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following transfer of a functional gene to replace the hemophilic patient’s own defective gene. The hemophilias are ideally suited for gene therapy because a small increment in blood factor levels (≥5% of normal) is associated with significant amelioration of bleeding phenotype in severely affected patients. In 2011, the St. Jude/UCL phase 1/2 trial was the first to provide clear evidence of a stable dose-dependent increase in FIX levels in patients with severe hemophilia B following a single administration of adeno-associated viral (AAV) vectors. Transgenic FIX expression has remained stable at ∼5% of normal in the high-dose cohort over a 7-year follow-up period, resulting in a substantial reduction in spontaneous bleeding and FIX protein usage without toxicity. This study has been followed by unparalleled advances in gene therapy for hemophilia A and B, leading to clotting factor activity approaching normal or near-normal levels associated with a “zero bleed rates” in previously severely affected patients following a single administration of AAV vectors. Thus, AAV gene therapies are likely to alter the treatment paradigm for hemophilia A and B. This review explores recent progress and the remaining limitations that need to be overcome for wider availability of this novel treatment of inherited bleeding disorders.

Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH

“…Additional approaches to gene therapy for hemophilia are under study in preclinical and early clinical models including use of gene-editing, lentiviral vector, and cellular therapies. 3,8,14 These will carry common and unique risks and benefits compared with AAV-mediated gene therapy and postmarketing surveillance will need to be adaptable to new safety signals and new endpoints as the field evolves. 15 Additionally, registration trials are being performed in a healthy subset of patients, and restrict use of comedications, thereby reducing the likelihood of detecting disease-drug and drug-drug interactions.…”

“…Current data on these emerging technologies suggest a potential "functional cure," with bleeding essentially eliminated in the majority of treated hemophilia patients. [1][2][3] Although the potential for these transformative gene therapies is great, emerging technologies by definition have unknown safety and efficacy risks. 4 Most of these gene therapies will be evaluated and approved based on small cohort trial enrollment with limited duration follow-up.…”

“…5 Current late-phase gene therapy trials for hemophilia A and B are using an adeno-associated viral (AAV) vector for targeted in vivo hepatocyte expression. [1][2][3] Naturally occurring AAV is a member of the Parvoviridae family and is generally considered nonpathogenic. 6 Although clinical trial data provide reassurance of short-term safety and efficacy of AAV-mediated gene therapy, we are entering this new treatment era with remaining questions of short-and long-term safety.…”

“…In terms of efficacy measured by bleeding events, overall, most trials have shown a remarkable decrease in bleeding and factor usage and improved quality of life. [1][2][3]7,8,13 However, only longer term data will answer the questions around efficacy and durability and identify differences should they exist by vector or transgene used.…”

Towards a global multidisciplinary consensus framework on haemophilia gene therapy: Report of the 2nd World Federation of Haemophilia Gene Therapy Round Table

“…Much progress has been made in the development of gene therapy treatment for haemophilia A and B over the past three decades 1,2 . Results from clinical trials have led to the first gene therapy treatment currently under review by health authorities, 2‐7 with several other FVIII and FIX gene therapies following close behind in late‐stage clinical trials, 8‐12 attention is now focusing on the still unresolved challenges of gene therapy 1‐2,10,13‐15 …”