genetic testing

The treatment landscape of hemophilia is undergoing a profound shift, moving from a factor replacement therapy paradigm to gene editing. In other words, we are moving from management toward a cure. 

The current standard of hemophilia treatment is still factor replacement therapy. Croteau et al, in their study on innovations in hemophilia therapy, sum up the role of replacement therapy today: “Prophylactic infusion of factor concentrate is the standard of care for adult and pediatric patients with severe hemophilia A and B, as well as those with a clinically severe bleeding phenotype despite moderate or mild deficiency by laboratory assessment, to prevent life-threatening bleeding and reduce chronic disability from recurrent intramuscular bleeding and hemarthrosis.” 

Mancuso and colleagues wrote a study on how the treatment landscape of hemophilia is moving from a replacement framework to a nonreplacement one. What is the significance of such a shift in strategy? “The rationale behind the design of new non-replacement therapies is to overcome the difficulties of intravenous delivery and to improve the effectiveness of therapies in all patients, regardless of the presence or absence of inhibitors,” they wrote. 

Continue Reading

Read more about hemophilia treatment 

The transition in treatment strategy is all about reducing the substantial disease burden that hemophilia patients carry, since administering drugs intravenously is uncomfortable.

“To administer IV injections frequently, central venous devices are often required, with associated risks from the surgical procedures and possible complications, such as infection or thrombosis,” Mancuso and colleagues wrote. ”This risk is particularly high in infants but can be an issue across all ages.”

Uniquely Positioned to Benefit

Hemophilia is a disease that is uniquely positioned to benefit from gene therapy. “Both hemophilia A and B are ideal candidates for gene therapy because they are monogenic diseases that might be treated effectively by delivering a substitute copy of the FVIII and FIX genes,” Mancuso et al explained.

The goal of gene therapy would be for the body to produce enough FVIII and FIX proteins to eliminate the need for exogenous factor replacement therapy. 

The main strategy for accomplishing this is the delivery of FVIII and FIX through the use of recombinant nonintegrating adeno-associated viral (AAV) vectors. Croteau et al explained how this would work: “AAV-mediated gene transfer is an in vivo gene therapy strategy whereby the modified AAV vector containing the therapeutic gene of interest is infused intravenously as a one-time therapy. Selection of the AAV serotype and engineering of the capsid facilitates delivery of the therapeutic gene to the cell type of interest for protein production.” 

So where are we in terms of the development of this therapy? Past and current clinical trials offer us clues.

“Early efficacy data from both hemophilia A and B gene therapy programs demonstrate encouraging results,” reported Croteau and colleagues, who conducted a review of clinical trials of gene therapy used in hemophilia patients. ”Both FVIII and FIX expression have significant inter-person variability within and among gene therapy programs.” 

Read more about hemophilia therapies

Data from multiple small phase 1 and 2 studies have demonstrated that the majority of patients treated with gene therapy have enough FVIII and FIX concentrations in the plasma to be able to stop regular prophylaxis and still maintain good control of bleeding. This means that gene therapy has shown promise in achieving the goal of eliminating the need for factor replacement therapy altogether. 

The caveat is that the study population of hemophilia gene therapy clinical trials is currently limited to patients over the age of 18 who have moderate to severe hemophilia A or B, representing only about 2% of patients with hemophilia. To participate in these studies, patients must not have a history of having FVIII or FIX neutralizing antibodies.

Indicators of Success 

The viability and success of gene therapy, if it becomes approved for use in the future, depends on a number of factors. The most important, of course, is whether this would provide a permanent cure for hemophilia. If gene therapy can result in the lifelong endogenous production of sufficient FVIII or FIX, it would change hemophilia treatment forever. 

In addition, we will need to have clearly defined eligibility criteria for this form of therapy. As mentioned earlier, current studies are performed on patients with moderate to severe hemophilia. In addition, patients with certain comorbidities, such as HIV and other hepatic diseases, are excluded from these trials. Will gene therapy therefore only be an option for a small, select group of patients with hemophilia? Further clinical studies will need to determine that. 

The affordability of gene therapy and equality in access are also important. It is reasonable to assume that gene therapy would be expensive, given that it theoretically eliminates the need for the constant IV administration of factor replacement therapy. Will the cost of gene therapy limit access to this game-changing treatment? Mancuso et al wrote, “Such a therapy has the potential to produce huge savings for direct and indirect costs related to hemophilia care; however, the cost is still likely to restrict access to patients in many countries worldwide.”


Croteau SE, Wang M, Wheeler AP. 2021 clinical trials update: innovations in hemophilia therapy. Am J Hematol. 2021;96(1):128-144. doi:10.1002/ajh.26018

Mancuso ME, Mahlangu JN, Pipe SW. The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editingLancet. 2021;397(10274):630-640. doi:10.1016/S0140-6736(20)32722-7