As medicine matures, the same inevitable questions pop up, time and again: What’s next? How do we extend life expectancy? How do we make treatments more comfortable to administer? How do we undo any disease burden remaining and create a life for patients that is “more normal” than ever before?
These questions are ubiquitous, no matter which stage we are in with regards to a particular illness. We always want more. And that is a positive thing because it is that thirst for the undefined better that causes medical researchers to keep putting on their lab coats to work for the benefit of patients and their loved ones.
Hemophilia stands tall as a disease that medical researchers have “mastered” to some degree; it has gone from being a life-threatening illness to something that can be managed fairly well on an outpatient basis. The discovery of replacement therapy has saved countless lives and prevented many unnecessary crises that hemophilia used to be well known for.
However, dig a little deeper first and you will discover much more room for improvement. Okaygoun and colleagues wrote a paper on the current advancements in hemophilia treatment and published their work in the Journal of Biomedical Sciences. In their review, the team eloquently summarized these current problems with standard hemophilia treatment:
- The frequent need for factor administration is disruptive and can cause vein damage and scarring, which might discourage compliance.
- Prophylaxis requires physicians to plan in advance if the patient chooses to take part in high-risk activities such as contact sports, thus putting a lid on the types of activities they can participate in freely.
- Despite adequate prophylaxis, research demonstrates that long-term sequelae may still occur, such as joint arthropathy. This represents a massive source of morbidity or reduced quality of life.
Read more about hemophilia prognosis
It seems that once the immediate threat of death has been removed, there is always a myriad of changes that can be made to improve the quality of life for patients. Some suggest that patients should just be thankful for the availability of any treatment at all, but what is medicine without the restless and shifting space between the good and the great? In order to push forward in the discovery of new therapies not seen yet in the market, we must acknowledge what is lacking and be determined to fill it.
One of the simpler ways to start is to make our recombinant FVIII and FIX products possess a longer half-life, which means that they will require less frequent administration. But can this be done safely and effectively?
Okaygoun et al proposed 2 methods for this to become a possibility. The first is to fuse FVIII or FIX with albumin, which has a long half-life. So far, scientific attempts to do this have been met with success. For example, the terminal half-lives of these products have indeed improved (the primary goal), and they also have an excellent safety profile and achieved lower annualized bleeding rates (ABRs) when used prophylactically.
Read more about hemophilia therapies
Another method for extending half-life is by a process known as PEGylation, otherwise known as the procedure in which 1 or more polyethylene glycol (PEG) chains are covalently linked to rFVIII or rFIX. How does this work? “PEG chains interfere with the recombinant factors binding to their clearance receptors, thereby prolonging circulating half-life,” the British authors explained.
Some of these products are already licensed for use, and they have an exceedingly high half-life (PEGylated rFIX has a 5-fold increase in half-life compared to FIX). In addition, these products are well-tolerated, reduce ABRs, and do not result in inhibitor development.
Gene Therapy and Meeting the Challenge
Batty and Lilicarp have written an entire study solely dedicated to the idea of using gene therapy for future hemophilia treatments.
“Hemophilia became one of the early targets for gene therapy studies, due to the monogenic nature, with easily measurable laboratory (FVIII/FIX) and clinical (bleed rate) endpoints,” they said. “Small amounts of transgene expression that might be obtained from gene therapy have the potential to provide substantial clinical benefit, as seen in patients on prophylaxis (>1%) or with non-severe hemophilia (1–40%).”
The mainstay of gene therapy in hemophilia is to utilize recombinant adeno-associated viral (AAV) vectors for FVIII and FIX transduction. The most important benefit of this form of therapy is the clinical benefits seen in patients with hemophilia.
“Recent clinical data have presented normalization of factor levels in some patients with improvements in bleed rate and quality of life,” Batty and Lilicarp wrote.
The main toxicity of this treatment option is a transient elevation of liver enzymes, a phenomenon also reported by Okayguon et al. “Gene therapy was generally well-tolerated, although ALT increases were widely observed, with occasional associated decreases in factor activity,” they commented. “These increases were transient following glucocorticoid treatment and were not consistently associated with an anti-capsid T cell response, raising inquiries as to the etiology of the raised ALT.”
This article detailed 2 types of experimental hemophilia treatments that have received wide acclaim as research confirmed their clinical usefulness. However, if we look back at the current problems with hemophilia management listed earlier, the permanent normalizing of clotting factors in the body is recommended to be the holy grail. This is with little to no negative impact from normal bleeds. With the proverbial sharks closing in on this grand prize, it won’t come as a surprise if we continue to achieve major breakthroughs in the decades ahead.
Okaygoun D, Oliveira DD, Soman S, et al. Advances in the management of haemophilia: emerging treatments and their mechanisms. J Biomed Sci. Published online September 14, 2021. doi:10.1186/s12929-021-00760-4
Batty B, Lillicrap D. Advances and challenges for hemophilia gene therapy. Hum Mol Genet. Published online July 23, 2019. doi:10.1093/hmg/ddz157