Advanced therapy strategies. The company has started another two phase 3 trials with vector doses of 4 1013 and 6 1013 vg/kg [59,60]. Although HA and HB are considered clinically indistinguishable, several recent studies have questioned this idea, suggesting that patients with HB could be less prone to severe bleeds than those with HA with the same plasma levels of residual factor (identical disease phenotypes) [2]. Gene therapy is a suitable treatment of hemophilia for various reasons. Zhuang W.-Z., Lin Y.-H., Su L.-J., Wu M.-S., Jeng H.-Y., Chang H.-C., Huang Y.-H., Ling T.-Y. In this regard, Lombardi et al. Advanced therapies comprise a set of novel and innovative strategies such as cell therapy, gene therapy and regenerative medicine or tissue engineering. Generally, the results of the trials carried out so far on the use of AAVs in patients with HA and HB have yielded promising results. As far as gene therapy protocols are concerned, these can be defined as the transfer to one or more cells of a DNA fragment that encodes a protein and may be able to cure a certain disease. Gene therapy for hemophilia: a review on clinical benefit, limitations The narratives will represent a true sharing of experiences and offer an insight into how these patients and families have coped with hemophilia following the application of the new therapies. Indeed, the use of AAV vectors has provided extraordinarily promising results in terms of the clotting factors concentrations and expression times. Among persons with hemophilia, those with severe . At the same time, the principle of healthcare equity should be upheld. The information should be conveyed in the form of semi-structured informative sessions where patients should also be asked open-ended questions about their perceptions about the new treatments. Inhibitors are neutralizing antibodies that target exogenously administered coagulation factors. Olgasi C., Talmon M., Merlin S., Cucci A., Richaud-Patin Y., Ranaldo G., Colangelo D., Di Scipio F., Berta G.N., Borsotti C., et al. A clinical trial sponsored by the St. Jude Childrens Research Hospital in patients with HB, which used a scAAV2/8-LP1-hFIXco vector, was the first to confirm the long-term benefit of gene therapy with this kind of AAV vector [63,64]. The main adverse effect encountered was an increase in hepatic enzyme levels (ALT), which was treated with prednisolone. Received 2021 Jun 30; Accepted 2021 Jul 15. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. Factor concentrates account for 90% of all direct costs of treating hemophilia. Selecting the first doses of investigative drugs to be administered to humans on the basis of the results of preclinical studies has been, and still is in the context of advanced therapies, an important challenge for translational medicine. Hart D.P., Branchford B.R., Hendry S., Ledniczky R., Sidonio R.F., Ngrier C., Kim M., Rice M., Minshall M., Arc C., et al. This treatment concept makes it difficult for both doctors and patients to switch to a different alternative such as gene therapy, particularly given the uncertainties around its medium- and long-term adverse events. All authors have read and agreed to the published version of the manuscript. Smith E., Blomberg P. Gene therapyFrom idea to reality. This has prompted the development of new strategies aimed at eradicating the parts of the viral vector responsible for inducing the immune and inflammatory response or providing CD8+ lymphocytes with epitopes that enable them to bind to AAVs, thus attenuating the T-lymphocytes response [38]. U.S. National Library of Medicine The World Federation of Hemophilia Gene Therapy Registry (WFH GTR). Gene therapy protocols can be applied to somatic cells either in vivo, where correction of the gene, or its insertion into the cells, is performed in the body through a vector; or ex vivo, where correction of the gene, or its insertion, is carried out previously in a series of cells harvested from the patient then reimplanted following an expansion and selection process [20,22]. . Gene therapy for hemophilia A is a one-time infusion that uses a vector to deliver a functional gene to replace the hemophilia patient's own defective gene or a therapeutic gene to provide a missing protein. Hemophilia Gene Therapy: Approaching the First Licensed Prod - LWW Investments in investigating these new therapies are clearly justified as there are multiple chronic and severe conditions for which no treatment is currently available and others for which the existing treatment either results in severe side effects or is tedious and/or inconvenient, making adherence difficult. Concizumab, a humanized monoclonal antibody targeted against TFPI, is the most highly developed of these strategies. However, it must be said that retrovirus (RNA virus)-based vectors are practically absent from clinical practice despite their high transduction efficacy and their ability to maintain transgene expression over time. the contents by NLM or the National Institutes of Health. Another alternative is to correct the defective genes responsible for the disease. Ertl H.C.J. Samelson-Jones B.J., Finn J.D., George L.A., Camire R.M., Arruda V.R. Another important aspect will be reaching a consensus on the use of a multidisciplinary approach to the application of the new gene therapy protocols in hemophilia [46]. This replacement therapy can be given to treat a bleeding episode in progress. As regards the CRISPR/Cas9 tool, the variable part is nucleotide-based (RNA) rather than protein-based. Trinchero A., Sholzberg M., Matino D. The Evolution of Hemophilia Care: Clinical and Laboratory Advances, Opportunities, and Challenges. This guidance provides recommendations to sponsors developing human gene therapy (GT) products for the treatment of hemophilia including clinical trial design and related development of . MSCs, mesenchymal stem cells. UniQure Biopharma B.V. recently published the results of a series of clinical trials on HB using an AAV5 vector that uses the same FIX expression cassette as the Jude Childrens Research Hospital (AMT-060) but with the Padua variant of FIX [66,67]. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. ClinicalTrials.gov Identifier: NCT02576795. Hemophilia A and B are congenital bleeding disorders caused by a dysfunction or deficiency of coagulation factor (F) VIII or IX, respectively. Recombinant FVIII/FIX concentrates are obtained by fusion to polyethylene glycol, IgG1-Fc or albumin [4]. The authors evaluated the stability and long-term safety of the expression of the transgene in 10 patients with severe HB, all of whom were infused with a single dose of AAV8 vector. Pfizer is developing at least . However, individuals with the same coagulation factor levels may exhibit varying bleeding phenotypes. We are already well into the 21st century, an era in which precision and personalized medicine [87] are gaining huge momentum in the realm of pharmacology. Certain strategies have been implemented to reduce the economic impact of hemophilia, such as disease management programs and programs to control the price of drugs. The investment and dedication required by these procedures is fully justified as many of the conditions they are meant to treat are chronic and/or severe and either lack a curative treatment or are associated with tedious or inconvenient treatments or therapies, leading to significant side effects which hinder patient adherence. A rigorous economic evaluation of the new therapies requires a careful comparison between the costs and benefits of gene therapy and the standard of care without adverse events throughout the patients lifetime, including the relevant adjustments for price distortions. Preclinical and clinical studies have found that AT suppression leads to a dose-dependent reduction in AT levels which results in a decreased severity of the bleeding phenotypes in patients with hemophilia [7,8]. Evolutionary Insights into Coagulation Factor IX Padua and Other High-Specific-Activity Variants. [(accessed on 28 June 2021)]; U.S. National Library of Medicine Single-Arm Study to Evaluate the Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia a Patients at a Dose of 4E13 vg/kg (BMN270-302). [(accessed on 28 June 2021)]; U.S. National Library of Medicine A Factor IX Gene Therapy Study (FIX-GT) (FIX-GT). Current replacement. Several phase 1 and phase 2 studies have tested the effectiveness of Fitusiran in patients with hemophilia with or without inhibitors; phase 3 trials are now underway with the same goal in mind. This simple definition has opened up a whole new dimension in the treatment of a large variety of conditions, ranging from hereditary diseases to cancer and infectious, cardiovascular, hepatic and neurodegenerative conditions [20]. Gene therapy, however, represents a possible cure for hemophilia A. The incidence of hemophilia A is ~1 in 5000 and that of hemophilia B is 1 in 25 000 live male births. ClinicalTrials.gov Identifier: NCT04883710. Hemophilia | ASGCT - American Society of Gene & Cell Therapy [41], the majority of patients with hemophilia showed a positive attitude toward gene therapy and claimed to be keen to receive this treatment (40%; n = 8) o (35%; n = 7). ClinicalTrials.gov. Lastly, lentiviral vectors (LVs), based on single-stranded RNA lentiviruses, are integrative and not very likely to result in insertional mutagenesis, nor do they induce a significant immune response or produce a hepatotoxic effect. These findings helped dispel the fears associated with the unregulated clotting pattern of FIX-R338L and support its use in gene therapy protocols addressed at HB. Main clinical trials underway in the field of hemophilia A (HA) and hemophilia B (HB). Sidonio R.F., Pipe S.W., Callaghan M.U., Valentino L.A., Monahan P.E., Croteau S.E. A second hurdle to their implementation is related to the uncertainties around their potential adverse events, mainly derived from transfection vectors (unknown risks and long-term outcomes, persistence of the therapeutic effect, need to readminister the vector). Tang et al. Human Gene Therapy for Hemophilia; Guidance for Industry As a potential cure for hemophilia, the new advanced therapies are also associated with a high cost, which limits their applicability and raises doubts about their cost-effectiveness and their equitable administration to patients with hemophilia worldwide, ensuring what the WHO has called the absence of avoidable and remediable differences between groups of people [51]. [(accessed on 28 June 2021)]; Pasi K.J., Rangarajan S., Mitchell N., Lester W., Symington E., Madan B., Laffan M., Russell C.B., Li M., Pierce G.F., et al. Some people receive continuous replacement therapy. Earlier clinical trials reported some success using benign adeno-associated viruses (AAVs) as the vector to deliver the therapeutic FVIII gene to cells in the liver, where the clotting protein is made. Reduction in the vector dose should also be avoided as it is often associated with a less efficient expression of the protein. SerpinPC is currently in the early stages of clinical investigation. A third alternative is to modify the transgene to boost the efficacy of the clotting factor once it has been expressed. Gene Therapy for Hemophilia A and Hemophilia B - Everyday Health Protocols are currently highly variable on account of the wide range of target cell types and gene transfection vectors available and the possibility of modifying the transgene to boost its expression efficacy. The gene therapy inserts a functional version of the defective genethe factor VIII gene in hemophilia A or the factor IX gene in hemophilia Binto the liver, which triggers clotting factor production. At the same time, every effort should be made to address the current inequalities in access to treatment by promoting social access and ensuring that patients receive the treatments they need regardless of geographical or economic factors. Verdera H.C., Kuranda K., Mingozzi F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Many of the patients participating in the trial (88.8%) experienced a slight increase in their alanine aminotransferase (ALT) levels, which was accompanied by a reduction in the activity of FVIII in one of the subjects. The cassette used in this study was the same wild-type human FIX gene cassette tested previously [68], also with the AAV5 serotype. Current Treatments | National Hemophilia Foundation Treatments are about as close to approval as they've ever been. Gene Therapy for Hemophilia | Hemaware Mesenchymal Stem Cells, Sources of Cells and Differentiation Potential. [36] reported two AAV serotypes (NP40 and NP59) capable of improving in vivo transduction of human hepatocytes in murine models. Modified autologous stem cells (YUVA-GT-F901). Hemophilia Guide: Causes, Symptoms and Treatment Options - Drugs.com sharing sensitive information, make sure youre on a federal Gene therapy in hemophilia A: a cost-effectiveness analysis Currently, gene therapies for Hemophilia A and Hemophilia B work differently in the body and have different results. Konkle B.A., Coffin D., Pierce G.F., Clark C., George L., Iorio A., Mahlangu J., Naccache M., OMahony B., Peyvandi F., et al. Hemophilia A is the most common type of hemophilia. [(accessed on 28 June 2021)]; {"type":"clinical-trial","attrs":{"text":"NCT04883710","term_id":"NCT04883710"}}. In vivo gene therapy where the (typically organ-specific) adeno-associated viral (AAVs) or lentiviral (LVs) vectors carried by the therapeutic gene are administered systemically to the patient. One of these clinical trials, sponsored by the Oxford University Hospitals NHS Foundation Trust, will analyze the potential impact of gene therapy on the lives of persons with hemophilia and their family members [57]. ClinicalTrials.gov Identifier: NCT04723680. In sum, a great deal of research is still needed into the optimization of AAV vectors, along two different paths. One alternative to reduce hepatotoxicity is to reduce the vector dose, but this usually results in a decreased expression efficacy. Immunosuppression using drugs such as corticosteroids is nowadays necessary to ensure the clinical benefits of AAV-mediated gene transfer. For that reason, transient immunosuppressive techniques have been developed to blunt the cells immune response against the virus. Treatment of hemophilia [3] has evolved very rapidly in the last few decades since the advent of plasma and cryoprecipitates; human plasma-derived clotting factor concentrates, and more recently recombinant factors, characterized by a high degree of purity and a longer half-life. Gene Therapy for Hemophilia A, ASC618, Set to Enter Phase 1/2 Trial However, further work will be necessary to address the side effects related to the immunogenicity and hepatotoxicity of these therapies, which usually make it necessary to prescribe concomitant administration of immunosuppressive corticosteroids. This kind of vector derives from a native non-pathogenic and barely immunogenic AAV of the parvovirus family which, given its inability to replicate, requires an auxiliary virus to do so [33]. These results led to a change in strategy and to the use of non integrative recombinant viruses such as AAVs. Gene therapy for hemophilia - American Society of Hematology The study is intended to evaluate the efficacy and safety of PF-06838435 (rAAV-SPARK100-HFIX-PADUA) in male adult subjects with moderate or severe HB, with circulating FIX concentrations <2%. Handbooks also include easy-to-read infographic materials that physicians can use as visual aids during patient consultations. Mannucci P.M., Franchini M. Is Haemophilia B Less Severe than Haemophilia A? Pursuing this strategy will require a definition of variables (serotype/dose of the viral vector, manufacturing techniques) capable of controlling the integration capacity of the different vectors and/or the immune response against the AAV capsid, as well as an evaluation of the patients quality of life defined as an improvement in those outcomes that are most relevant for the patients (chronic pain, yearly infusion rate, mental health). This usually results in small sample sizes and low statistical significance levels. The ultimate goal of the treatment of hemophilia should be a functional cure, but also healthcare equity. U.S. National Library of Medicine Gene Therapy Study in Severe Haemophilia a Patients (270-201). This makes it possible to translate the biological efficacy observed in animal studies to clinical trials in humans, which provides a rational basis to determine the initial dose of the new in vivo virus-mediated gene therapy products. APC is a serine protease that can bind to the endothelial protein C receptor, which approximates it to thrombin for its activation. According to the US Centers for Disease Control and Prevention . "Gene therapy for hemophilia has been on the horizon for more than two decades. Iriart J.A.B. When you come to Orlando Health Arnold Palmer, you and your child have . Nonetheless, immunosuppressive drugs are associated with metabolic side effects and with an increased overinfection risk. The active substance in Roctavian, valoctocogene roxaparvovec, is based on a virus (adeno-associated virus or AAV) which has been modified to not cause disease in humans. FIX expression remained stable for at least 20 weeks, and no significant increases in immunogenicity were observed. Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B. U.S. National Library of Medicine Dose-Escalation Study of a Self Complementary Adeno-Associated Viral Vector for Gene Transfer in Hemophilia B. ClinicalTrials.gov Identifier: NCT00979238. Corinna L. Schultz, MD - Nemours Educational programs should be introduced to provide all stakeholders with the information they require about gene therapy as a therapeutic option, including the management of adverse events and the strategies conducive to ensuring the cost-effectiveness of the treatment. Gene therapy could cause a great upheaval in the treatment of patients with hemophilia and other congenital diseases. Pediatric Hematology - Orlando Health AAV-based gene therapies for the treatment of HA are at an earlier stage of development than those for HB. Over an 18-year period, gene therapy also showed itself to be more economically efficient than on demand or prophylactic treatment in patients with severe HB. U.S. National Library of Medicine HOPE-B: Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults with Hemophilia B. ClinicalTrials.gov Identifier: NCT01687608. [71] analyzed safety, pharmacokinetic profile, FIX activity and immune response in patients undergoing a gene therapy protocol based on the AAV virus serotype 8 (AskBio009) [72]. The clinical potential of hemophilia gene therapy has now been pursued for the past 30 years, and there is a realistic expectation that this goal will be achieved within the next couple of years with the licensing of a gene therapy product. Weyand A.C., Grzegorski S.J., Rost M.S., Lavik K.I., Ferguson A.C., Menegatti M., Richter C.E., Asselta R., Duga S., Peyvandi F., et al. Garrison L.P., Jiao B., Dabbous O. Gene Therapy May Not Be as Expensive as People Think: Challenges in Assessing the Value of Single and Short-Term Therapies. Different Sources of Stem Cells and Their Application in Cartilage Tissue Engineering. He Q., Wang H.-H., Cheng T., Yuan W.-P., Ma Y.-P., Jiang Y.-P., Ren Z.-H. Genetic Correction and Hepatic Differentiation of Hemophilia B-Specific Human Induced Pluripotent Stem Cells. Adenoviral (DNA virus) vectors are non-integrative and are able to efficiently package the therapeutic gene but present with a very high immunogenic capacity, which could trigger severe anaphylactic reactions. Toon K., Bentley E.M., Mattiuzzo G. More than Just Gene Therapy Vectors: Lentiviral Vector Pseudotypes for Serological Investigation. Clearly viable cell and gene therapy approaches exist both to address monogenic and polygenic conditions, and to increase the effective duration of therapeutic proteins and boost their level of expression. The molecular regulation of the activation, inactivation and FVIIIa-dependence of FIX-R338L and FIX-WT are similar, but the FVIIIa-dependent hyperactivity of FIX-R338L is the result of a faster activation rate of FX. AAV Liver Expression of FIX-Padua Prevents and Eradicates FIX Inhibitor without Increasing Thrombogenicity in Hemophilia B Dogs and Mice. Although huge strides have been made in our understanding of the molecular mechanisms behind diseases and in the development of drugs that have had a hugely positive impact on the treatment of some types of cancer, many of the promises of gene therapy remain unfulfilled for other diseases as a result of the hurdles to the therapys widespread use. Providing patients with hemophilia with adequate information is now more necessary than ever. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, hemophilia, advanced therapies, gene therapy, FVIII transgene, FIX transgene, adeno-associated virus, lentiviral vectors, {"type":"clinical-trial","attrs":{"text":"NCT02035605","term_id":"NCT02035605"}}, {"type":"clinical-trial","attrs":{"text":"NCT03520712","term_id":"NCT03520712"}}, {"type":"clinical-trial","attrs":{"text":"NCT02576795","term_id":"NCT02576795"}}, {"type":"clinical-trial","attrs":{"text":"NCT03370913","term_id":"NCT03370913"}}, {"type":"clinical-trial","attrs":{"text":"NCT04323098","term_id":"NCT04323098"}}, {"type":"clinical-trial","attrs":{"text":"NCT03001830","term_id":"NCT03001830"}}, {"type":"clinical-trial","attrs":{"text":"NCT03370172","term_id":"NCT03370172"}}, {"type":"clinical-trial","attrs":{"text":"NCT04370054","term_id":"NCT04370054"}}, {"type":"clinical-trial","attrs":{"text":"NCT03061201","term_id":"NCT03061201"}}, {"type":"clinical-trial","attrs":{"text":"NCT02396342","term_id":"NCT02396342"}}, {"type":"clinical-trial","attrs":{"text":"NCT03489291","term_id":"NCT03489291"}}, {"type":"clinical-trial","attrs":{"text":"NCT03569891","term_id":"NCT03569891"}}, {"type":"clinical-trial","attrs":{"text":"NCT01687608","term_id":"NCT01687608"}}, {"type":"clinical-trial","attrs":{"text":"NCT04394286","term_id":"NCT04394286"}}, {"type":"clinical-trial","attrs":{"text":"NCT00979238","term_id":"NCT00979238"}}, {"type":"clinical-trial","attrs":{"text":"NCT03307980","term_id":"NCT03307980"}}, {"type":"clinical-trial","attrs":{"text":"NCT03861273","term_id":"NCT03861273"}}, {"type":"clinical-trial","attrs":{"text":"NCT03217032","term_id":"NCT03217032"}}, {"type":"clinical-trial","attrs":{"text":"NCT03961243","term_id":"NCT03961243"}}. ClinicalTrials.gov Identifier: NCT03370913. This is not an issue in HB as the FIX gene is smaller than the FVIII gene. Swystun L.L., Lillicrap D. Gene Therapy for Coagulation Disorders. This means that it acts by decreasing the amplification of FXa generation and intrinsic thrombin generation by FVa and FVIIIa proteolysis. [(accessed on 28 June 2021)]; U.S. National Library of Medicine Dose Confirmation Trial of AAV5-hFIXco-Padua. It can also be given on a regular schedule at home to help prevent bleeding episodes. Indigenous Genetics and Rare Diseases: Harmony, Diversity and Equity. The cells used in cell therapy are generally stem cells equipped with a series of special characteristics, such as being undifferentiated, having the ability to self-renew and to differentiate to different cell lines or to different embryonic layers [12,13,14,15]. For that reason, it is of the essence for the international community to implement the advances made in an equitable way so as to reduce healthcare disparities [88]. Recombinant vectors display tropism for a series of target tissues, such as the liver, which makes them the most commonly used gene therapy viral vectors in hemophilia (90%), followed by in vivo and ex vivo LVs (10%). ClinicalTrials.gov Identifier: NCT03520712. This reduces the expectations regarding the target factor correction as it is not necessary to restore circulating factor levels to 100%. An official website of the United States government. Hemophilia A, also called factor VIII (8) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII (FVIII), a clotting protein. About Hemophilia Hemophilia is a genetic disease that prevents blood from clotting properly leading to prolonged internal and external bleeding. Australian drugmaker CSL Ltd's gene therapy Hemgenix offers a long-term solution for hemophilia B patients, but is among the world's most expensive treatments. Pfizer is developing at least two other therapies for treating hemophilia. Gene therapy is the delivery of a functional gene to specific target cells within a patient's body to either replace a missing gene or augment a gene that is not functioning properly.