The DNA sequences transported by AAV vectors are stabilized in an episomal form, so that long-term expression is only possible through delivery into long-living postmitotic cells. At the same time, the gastroenterology and hepatology departments will have to monitor the hepatic function of recipients of gene therapy, especially during the first few months of treatment.
Pfizer Announces Positive Marstacimab Results from Pivotal Phase 3 (Created with Biorender.com). Milwaukee, June 16, 2020 - Patients are now able to participate in a phase I, first-in-human FDA approved clinical trial seeking a potential long-term treatment for Severe Hemophilia A, using a gene therapy that targets synthesis of coagulation Factor Eight (FVIII), which is stored and released from blood platelets at the site of an injured blood vessel. Another alternative is to correct the defective genes responsible for the disease. To this should be added the lack of experience of healthcare providers in managing the adverse events derived from the new advanced therapies and their lack of experience in calculating the cost-effectiveness of gene therapy (eligibility criteria, predictability of response, unknown risks, long-term complications). AAV vectors are currently the ones presenting with the highest potential for clinical use given their partial integration capacity and their low insertional mutagenesis risk. As a result, switching the therapeutic strategy from the current optimized and safe standard-of-care treatment based on recombinant products to a gene therapy strategy is not easy, especially considering the uncertainties around the medium- and long-term effects of gene therapy protocols, the lack of experience with these new procedures and the potentially unfavorable cost-effectiveness ratio associated with them. They are often based on an information handbook that includes information on AAV-mediated gene transfer, the eligibility criteria for participation in clinical trials, the possibility of anticipating the adverse events that could occur in the course of a clinical trial following gene therapy, the parameters that should be monitored during the clinical trial and the long-term effects of the therapy. 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"}}.
Hemophilia as a blueprint for gene therapy | Science A significant (five to eight-fold) reduction in bleeding time and of the total amount of blood lost (approximately four-fold) was obtained compared to R338L-Padua, which allows a faster and more robust hemostatic correction. 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. [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). The ultimate goal of the treatment of hemophilia should be a functional cure, but also healthcare equity. ClinicalTrials.gov Identifier: NCT04883710. The vectors DNA integrates at a very low rate and is typically lost from replicating cells. This is important to determine the primary eligibility of patients for AAV-based gene therapy clinical trials. Protocols based on gene therapy have gone from being potentially applicable ideas to becoming tangible realities [84], and they are bound to herald a new era where analyzing the specific phenotype of a monogenic hereditary disease such as hemophilia may not be needed anymore [85]. [(accessed on 28 June 2021)]; EU Clinical Trials Register. Hemophilia therapy in the United States has progressed from replacement therapies for on-demand treatment of bleeding to prophylaxis to reduce the frequency of bleeding. U.S. National Library of Medicine A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy with PF-06838435 in Adult Males with Moderately Severe to Severe Hemophilia B (BENEGENE-2). Konkle B.A., Coffin D., Pierce G.F., Clark C., George L., Iorio A., Mahlangu J., Naccache M., OMahony B., Peyvandi F., et al. One of these is emicizumab (Hemlibra), a subcutaneously administered bispecific monoclonal antibody recently approved for treatment of HA with or without inhibitors against FVIII. Subsequently, the cell repair system induces the potential correction into the DNA when repairing the break. Hemophilia B is also known as Christmas disease. Pierce G.F., Pasi K.J., Coffin D., Kaczmarek R., Lillicrap D., Mahlangu J., Rottellini D., Sanni T., Srivastava A., VandenDriessche T., et al. Although the results of AAV-based gene therapy using FIX as a transgene have been encouraging in the context of HB, increases in hepatotoxicity resulting from the loss of expression of the transgene are not uncommon, possibly due to adaptative or innate immune responses against the vectors capsid.
Innovative Gene Therapy in Hemophilia-A Clinical Trial | Press Release Bolt M.W., Brady J.T., Whiteley L.O., Khan K.N.
Hemophilia Gene Therapy: Key Principles | Pfizer Entering the Modern Era of Gene Therapy. [(accessed on 28 June 2021)]; U.S. National Library of Medicine A Factor IX Gene Therapy Study (FIX-GT) (FIX-GT). The novel gene efficiency factor (GEF) concept was developed to describe the efficiency of the in vivo AAV-mediated gene transfer system.
Hemophilia | ASGCT - American Society of Gene & Cell Therapy This is not an issue in HB as the FIX gene is smaller than the FVIII gene. All the patients, however, developed capsid-specific antibodies. The analysis made in this article is based on some of the clinical trials in progress on HA or HB reported in the ClinicalTrials.gov repository [55] and the European Union Clinical Trials Register [56]. Hemophilia A and B are caused by a single gene mutation. Research of gene therapy for hemophilia A is now taking place. Top-line results are expected in 2023, and the trial is anticipated to end in July 2026. ClinicalTrials.gov Identifier: NCT03520712. Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. Von Drygalski A., Giermasz A., Castaman G., Key N.S., Lattimore S., Leebeek F.W.G., Miesbach W., Recht M., Long A., Gut R., et al.
Corinna L. Schultz, MD - Nemours 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]. HAVEN 1, a non-interventional phase 3 trial involving patients with severe HA and inhibitors, demonstrated that patients on emicizumab had 87% less bleeding episodes than those without prophylaxis, and 79% less bleeding episodes than those on previous prophylaxis [5]. This is due to their good safety profile and their capability for partial integration, which ensures long-term expression of the transgene. According to the US Centers for Disease Control and Prevention . According to international medicine agencies, the products used in the context of advanced therapies are drugs for human use that are based on genes, tissues or cells and that offer innovative solutions for the treatment of some diseases [11] (Figure 1). However, as the mechanism underlying R338Ls clotting hyperactivity remains unknown, the potential adverse events associated with a random coagulation pattern and the possibility of developing thrombotic complications cannot be ascertained. The lessons learned from treating hemophilia will inform advances in gene therapy of other inherited disorders. Gene Therapy for Inherited Bleeding Disorders. Nair et al. 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.
Gene therapy for hemophilia A shows promise in phase 3 clinical trial Gene therapy is a suitable treatment of hemophilia for various reasons. To evaluate the cost-effectiveness of gene therapy treatment of severe hemophilia A compared with prophylaxis with fac Marstacimab is a laboratory-engineered monoclonal antibody developed to treat hemophilia A and B . Shima M., Hanabusa H., Taki M., Matsushita T., Sato T., Fukutake K., Fukazawa N., Yoneyama K., Yoshida H., Nogami K. Factor VIIIMimetic Function of Humanized Bispecific Antibody in Hemophilia A. Shetty S., Vora S., Kulkarni B., Mota L., Vijapurkar M., Quadros L., Ghosh K. Contribution of Natural Anticoagulant and Fibrinolytic Factors in Modulating the Clinical Severity of Haemophilia Patients. Despite the substantial advances made in AAV optimization, significant limitations still exist to the use of preclinical data to guide dose selection in clinical trials. In the United States, the annual cost exceeds USD 300,000 per adult patient. It indicates the number of molecules of the therapeutic protein produced per day by each genome of the administered vector (vg). 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). 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. Gene Therapy for Hemophilia A Patients with severe hemophilia A were treated with an adeno-associated virus construct containing coagulation factor VIII cDNA and followed for 1 to 3 years.. The main problem in the case of FVIII is related to the packaging in the vector as the gene of this protein is much larger (7 kb) and exceeds the packaging capacity of AAVs, which is around 5 kb. Here's where things stand: How is hemophilia treated now? All authors have read and agreed to the published version of the manuscript. Milken Institute School of Public Health. [52] carried out a study to evaluate the economics of gene therapy in patients with severe HA as compared with prophylaxis with exogenous FVIII using a Markov state-transition model to estimate the costs and efficacy of treatment of severe HA in the United States.
Pfizer's hemophilia therapy reduces bleeding in late-stage study U.S. National Library of Medicine Ascending Dose Study of Genome Editing by Zinc Finger Nuclease Therapeutic SB-FIX in Subjects with Severe Hemophilia B. ClinicalTrials.gov Identifier: NCT02695160. 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. ClinicalTrials.gov Identifier: NCT03369444. Substitution of R338L leads to a gain-of-function mutation, which in turn results in a hyperfunctional FIX. 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. 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. Several gene-editing tools are currently in use, such as transcription activator-like effector nucleases (TALENs), zinc finger nucleases (ZFNs) and CRISPR/Cas9 [26,27]. These are based on recombinant DNA techniques that offer high levels of safety against emerging pathogens, as well as high efficacy and long half-lives, allowing administration of one single dose every 10 days in the case of FIX and two doses every 10 days in the case of FVIII. Treatment of hemophilia based on plasma-derived products can be very costly, especially if such products are of a recombinant nature [49]. There are several other gene therapy approaches in earlier stages of development. After the first encouraging results of intravenously administered adeno-associated virus (AAV)-based liver-directed gene therapy in patients with severe hemophilia B were reported in 2011, many gene therapy studies have been initiated. Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve your body's ability to fight disease. University College London has started a new phase 1/2 clinical trial focused on HB, using the AAV-F9, FLT180a vector [65]. Fitusiran is an RNA interference (RNAi) therapy that targets antithrombin (AT) in the liver and interferes with the translation of its messenger RNA, preventing AT synthesis and promoting hemostasis. Providing patients with hemophilia with adequate information is now more necessary than ever. The purpose of the Registry is to gain a comprehensive insight into the conditions under which gene therapy is administered; the expected, unexpected and unknown safety issues; and the duration of the efficacy of therapy over the long term. Every patient will be monitored for 15 years, and any adverse events occurring from the start of administration of therapy will be recorded at 3, 6, 9, 12, 18 and 24 months, and yearly thereafter. Gene therapy treatments based on siRNA (small interference RNA) are also being developed. [77] showed that the high specific activity of FIX-R338L requires FVIIIa as a cofactor. Equity vs. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy. As regards transfection vectors, gene therapy can be classified into viral and non-viral.
Gene Therapy for Hemophilia | Hemaware [(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. Gene therapy treatment for hemophilia A is currently available in Europe. Advanced (gene and cell) therapies could provide a cure for many hereditary conditions such as hemophilia. 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. Received 2021 Jun 30; Accepted 2021 Jul 15. Modified autologous stem cells (YUVAGT-F801), Lentiviral factor IX gene. Ma Q., Liao J., Cai X. government site. Treatments are about as close to approval as they've ever been. Machin et al. One alternative to therapeutic gene-based gene therapy is correction of the defective genes causing the condition through a wide range of gene-editing tools (TALENs, ZFNs and CRISPR/Cas9). 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). The cost of prophylaxis was USD 1.7 million and 6.62 QALYs. As regards the CRISPR/Cas9 tool, the variable part is nucleotide-based (RNA) rather than protein-based. Anguela X.M., High K.A. The advances made in the last few years by gene therapy for the treatment of congenital coagulopathies have caused an unprecedented upheaval, specifically in the treatment of patients with HA and HB. Pfizer is developing at least . About Hemophilia Hemophilia is a genetic disease that prevents blood from clotting properly leading to prolonged internal and external bleeding. Tomeo F., Mariz S., Brunetta A.L., Stoyanova-Beninska V., Penttila K., Magrelli A. Haemophilia, State of the Art and New Therapeutic Opportunities, a Regulatory Perspective. On the other hand, recent studies have shown that the natural anticoagulation pathway (antithrombin and tissue factor pathway inhibitors, protein S and protein C) is capable of restoring hemostasis in patients with a bleeding disorder [6]. A total of over 40 active gene therapy clinical trials were found on the subject of hemophilia, with an approximate 50/50 split between HA and HB.
About Hemophilia - National Human Genome Research Institute Accessibility Gene therapy for hemophilias: The end of phenotypic testing or the start of a new era? 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. U.S. National Library of Medicine The World Federation of Hemophilia Gene Therapy Registry (WFH GTR). The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Although more work is needed to increase treatment efficacy and reduce adverse events such as immunogenicity and hepatotoxicity, these protocols could allow curation of the disease, thereby increasing the patients quality of life, and a reduction in both direct and indirect costs throughout the lifetime of patients suffering from chronic lifelong diseases [54]. 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. This can be achieved thanks to the availability of a wide range of varieties and types of target cells and transfection vectors, and because it is now possible to regulate the gene expression and the characteristics of the transgene, and in the end, ensure its safety. BAX 335 Hemophilia B Gene Therapy Clinical Trial Results: Potential Impact of CpG Sequences on Gene Expression. In a study by Overbeeke et al. [(accessed on 28 June 2021)]; U.S. National Library of Medicine Dose Confirmation Trial of AAV5-hFIXco-Padua. The incidence of hemophilia A is ~1 in 5000 and that of hemophilia B is 1 in 25 000 live male births. 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]. Another possibility is to modify the transgene itself to boost the efficiency of the coagulation factor once it has expressed itself. ClinicalTrials.gov Identifier: NCT03489291. A vector dose-dependent increase in circulating FIX of 1% to 6% was observed over a mean 3-year period, which made it possible to reduce the frequency of prophylactic administration of FIX and, in some cases, even suspend it. Although gene therapy protocols are in general more efficient than cell therapy ones, they may be associated with a higher incidence of adverse events, derived mainly from the viral transfection vector used. Consistent use of specific and generally accepted terms and an optimized narrative (verbal, written and pictorial language) to convey the information could minimize confusion and facilitate the making of informed decisions on the potential offered by gene therapy [42]. In the past decade, the advent of nonfactor therapies has improved hemostasis by simulating a missing coagulation protein or . Robinson M.M., George L.A., Carr M.E., Samelson-Jones B.J., Arruda V.R., Murphy J.E., Rybin D., Rupon J., High K.A., Tiefenbacher S. Factor IX Assay Discrepancies in the Setting of Liver Gene Therapy Using a Hyperfunctional Variant Factor IX-Padua. An ideal transfer vector should be immunologically inert; highly tissue- and cell-specific; integrative; capable of sustainably producing the transgene and transducing genes to divided or undivided cells; easy to produce at large scale; and capable of maximum transgene loading. 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. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. As a library, NLM provides access to scientific literature. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed. Since May 2021, the World Federation of Hemophilia (WFH) has been working on a Gene Therapy Registry [44,45] intended to put together a worldwide database of patients with hemophilia receiving gene therapy. Appropriate multidisciplinary planning will also be necessary at the different stages of the procedure, including evaluation, informed consent, dosing and short- and long-term treatment and follow-up. Research is at present also focusing on the tissue factor pathway inhibitor (TFPI), the main inhibitor of the onset of the coagulation cascade, which has been shown to regulate the severity of a wide range of hemorrhagic and coagulation disorders. In the last decade, enormous progress has been made in the development of gene therapy for hemophilia A and B. They performed several unidirectional and probabilistic sensitivity analyses to determine the soundness of their results. 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. No clinical thromboses, inhibitors or immunity reactions were observed against the Padua variant of FIX. Ertl H.C.J. Miesbach W., OMahony B., Key N.S., Makris M. How to Discuss Gene Therapy for Haemophilia? The choice between a viral or non-viral vector, and between the different kinds of viral vectors available, must be based on a compromise between the phenotypic features of the disease and the therapeutic targets pursued. [(accessed on 28 June 2021)]; {"type":"clinical-trial","attrs":{"text":"NCT04723680","term_id":"NCT04723680"}}.
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