Gene Therapy for Hemophilia: Progress, Challenges, and Future Directions

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Introduction

Hemophilia is an inherited disorder producing a deficiency of clotting factors, either factor VIII or factor IX, and has been a problem in the healthcare arena for many years. This is an inherited coagulation disorder that causes abnormally long, delayed bleeding that may lead to severe joint disorders and life-threatening bleeding episodes. The usual treatment approaches have therefore involved routine prophylactic dosing of clotting factor concentrates despite the cost and the potential development of inhibitors. In the previous years, though, the new advancement of gene therapy has brought new hope wherever it is found in individuals with hemophilia. This approach can be expected to reverse the source of the disease at a genetic level by supplementing functional genes in the patient’s genetic structure, thus having the potential to offer the patient a long-term cure and change the course of treatment for hemophilia. In this review, the author provides an overview of the studies on gene therapy for hemophilia, the hurdles for this new technique, and possible developments in this therapeutic approach.

The Evolution of Gene Therapy for Hemophilia

The historical course of the experimental gene therapy treatments for hemophilia started with the understanding that the nature of this pathology is the absence of a gene, so the prospects for gene replacement therapy are promising. The first historic step towards gene therapy was made with adeno-associated viral (AAV) vectors because they are used as therapeutic gene delivery vehicles because of their capacity to target specific tissues, for instance, the liver, which is required for the synthesis of clotting factors.

The advancement in gene therapy has fared well in the past decade, especially in liver-directed gene therapy by AAV. The first clinical applications were carried out in the treatment of hemophilia B by using AAV vectors and delivering the FIX gene. These trials proved to be successful as there was sustained FIX expression and reduction of bleeding episodes; subsequent strategies have been made similar in hemophilia A due to the improvements derived in vectors and gene constructs, which made it possible to express FIX/FVIII enough to ameliorate severe clinical manifestations of hemophilia.

The first papers devoted to such an approach have shown that stable FIX expression is possible in hemophilia B patients over multiple years, which proves the long-term perspective of gene therapy. More improvements have been made where genes are codon optimized for liver expression and liver-specific promoters are incorporated, which has improved the effectiveness of these treatments, thereby limiting the need for prophylactic infusions of the clotting factors.

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The Present Section Refers to Success Stories and Clinical Benefits

Clinical outcomes of gene therapy for hemophilia have been positive in terms of its obvious clinical utility. In patients with severe hemophilia B, gene therapy has been associated with an immense reduction of the baseline bleeding rates and the usage of exogenous factor replacement. Hitherto, many of the patients who were on steady infusions of clotting factors have been able to stop the prophylactic measures altogether, hence leading to enhanced quality of life.

For example, one study in the AMT-060 gene therapy showed that the FIX activity was maintained in the cases for as many as five years following the therapy. Most patients in this study reported a lowering of their annualized bleeding rates, and some had almost normal FIX levels. It is such a long-term stability of the clotting factor production that witnesses the capability of gene therapy to change hemophilia from a disease that requires lifetime management to one that may need only one treatment.

A more recent development is the investigation of better vectors like etranacogene dezaparvovec (AMT-061) which encodes a highly effective form of FIX. This vector has proven even more effective: the patients have reached the FIX activity level, which does not result in or considerably minimizes the bleeding episodes. The replication of outcomes to different studies shows a possibility of increasing the usage of gene therapy to a wider population of patients.

Challenges and Limitations

However, the development of gene therapy for hemophilia, which, as it has been seen, has made great strides, is facing some problems. Arguably the greatest challenge is what is known as immune responses to AAV vectors: biochemical responses that the body throws at the AAV vectors. Originally induced immunity to AAV serotypes, mainly due to previous natural infections, can significantly affect gene transfer. Due to this, researchers have turned to other types of serotypes and ways of reducing immune responses.

The other problem is the differences in the reactions of patients to a particular medication. A significant proportion of patients with such disorders attain adequate therapeutic levels of clotting factors, although some of them do not obtain these therapeutic goals, hence the need for further studies on factors that influence gene expression. A lot of variations exist in genomics due to the elaborate mechanism of gene regulation, biodistribution of vectors, or the nature of different patient populations.

However, some long-term effects of gene therapy are still unknown, and this makes it a subject of study to date. Despite few randomized control trials reporting serious side effects, most of them being mild to moderate and improving with time, there is always the possibility of late sequelae such as liver toxicity or insertional mutagenesis. Long-term care examination of patients who have undergone gene therapy is paramount to determining the efficacy of the therapy against the possible adverse effects.

Another hindrance to the use of gene therapy is the high cost involved in undertaking the therapy. Even though the treatment decreases the total costs related to hemophilia care, the production and administration of AAV vectors are costly. Research is being directed to the development of new strategies that will reduce the cost of gene therapy and new modes of funding the process.

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Future Directions

The prospects of gene therapy for the treatment of hemophilia appear rather optimistic, with several directions for additional development. The improvement of the vector design is one of the most motivating aspects of research. Future improvements in capsid engineering to develop efficient vectors mean that a higher transduction efficiency and lower immunogenicity are expected, along with the capacity to transduce many patients without exposure to the virus.

Another possible line of development is the study of nonviral gene delivery systems. Though the AAV vectors have proven instrumental in gene therapy for hemophilia, new strategies, such as the lipid nanoparticles or CRISPR/Cas9 system, may offer safer and more effective delivery systems for genes. Each of these technologies might circumvent some of the difficulties related to the use of viral vectors, including immunogenicity and viral recombination.

This review highlighted that it’s possible to expect further advances in gene editing techniques or CRISPR/Cas9 systems in the future of hemophilia treatment. Gene editing is different from gene therapy in that instead of inserting a new copy of the gene, the technique tries to repair the error. It could also be more long-lasting and accurate as compared to other treatments, and if the roots of the hair could be handled, then such treatments could be done only once.

Further, there is more attention paid to the question of expanding the potentialities of gene therapy for patients with inhibitors, which are present in a considerable number of hemophilia cases. The existing approaches are aimed at escaping the immune reaction to the introduced clotting factors: either changing the vectors or changing the recipient’s immune response to the desired gene products.

Conclusion

Gene therapy for hemophilia could very well be one of the most profound advances in treating genetic disorders. The progress made in the recent past brought the medical fraternity closer to finding a cure for hemophilia, and now patients may be able to enjoy long-term alleviation from the burden of their condition. However, immune responses against the vector, variability in the outcome of the patients, apprehensions regarding the long-term safety, and the high cost of treatment remain to be overcome. Further challenges will lie in the additional finding of gene therapy techniques by the investigators during the next few decades, if not beyond, by developing alternative delivery methods and exploring new therapeutic targets. Gene therapy leads toward a bright future in the treatment of hemophilia.

References

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  6. Wang, L., Calcedo, R., Bell, P., Lin, J., Grant, R.L., Siegel, D.L. and Wilson, J.M., 2011. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Human gene therapy, 22(11), pp.1389-1401.
  7. Soucie, J.M., Monahan, P.E., Kulkarni, R., Konkle, B.A. and Mazepa, M.A., 2018. The frequency of joint hemorrhages and procedures in nonsevere hemophilia A vs B. Blood advances, 2(16), pp.2136-2144.
  8. Jourdy, Y., Frétigny, M., Lassalle, F., Lillicrap, D., Négrier, C. and Vinciguerra, C., 2020. The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events. Journal of Thrombosis and Haemostasis, 18(5), pp.1087-1093.

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