hemophilia a gene therapy

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. In this respect, several strategies have been described with a view to inhibiting TFPI by means of aptamers, fucoidan, monoclonal antibodies and peptide agents [10]. In the past decade, the advent of nonfactor therapies has improved hemostasis by simulating a missing coagulation protein or . 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. Congenital hemophilia A (factor VIII deficiency) is a bleeding disorder that results from pathologic variants in the gene F8 on the X chromosome. In vitro, the specific activity of recombinant FX-R338L is 510 times higher than that of wild-type recombinant FIX (FIX-WT). Hemophilia Guide: Causes, Symptoms and Treatment Options - Drugs.com b FVIII, factor VIII. Ertl H.C.J. Patients with severe hemophilia tend to experience bleeds into their joints, muscles or soft tissues following trauma or even without any apparent cause. 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. Gene therapy for hemophilias: The end of phenotypic testing or the start of a new era? Gene therapy for hemophilia has been pursued for over 20 years, but factor VIII presents more challenges than factor IX (associated with hemophilia B)this gene therapy, like most others of its . 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. 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]. Australian drugmaker CSL Ltd's CSL gene therapy Hemgenix offers a long-term solution for hemophilia B patients, but is among the world's most expensive treatments. Chapin J.C., Monahan P.E. Researchers have been working to develop a gene replacement treatment (gene therapy) for Hemophilia A. At the same time, the principle of healthcare equity should be upheld. Machin et al. Bacakova L., Zarubova J., Travnickova M., Musilkova J., Pajorova J., Slepicka P., Kasalkova N.S., Svorcik V., Kolska Z., Motarjemi H., et al. Entering the Modern Era of Gene Therapy. AAVs are currently the vectors of choice in gene therapy, particularly in the context of congenital coagulopathies. 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. Indeed, the use of AAV vectors has provided extraordinarily promising results in terms of the clotting factors concentrations and expression times. In clinical trials with FIX-R338L, they found that some patients showed an increase in liver transaminase levels, which was correlated with the loss of expression of FIX, even in immunosuppressed subjects. 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%). 1 For people with hemophilia A, this process is intended to deliver the functional F8 gene, which is required for the production of the protein Factor VIII. 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. Thus, dalcinonacog alpha, a new variant of R338L-Padua also known as CB 2679d-GT, containing three amino acid substitutions (R318Y, R338E, T343R), was shown to be more potent than R338L-Padua following AAV-based gene therapy in hemophilic mice. 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]. Pfizer is developing at least two other therapies for treating hemophilia. 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). ClinicalTrials.gov. The Cost of Hemophilia Treatment: The Importance of Minimizing It without Detriment to Its Quality. To evaluate the cost-effectiveness of gene therapy treatment of severe hemophilia A compared with prophylaxis with fac Hemophilia A and B are congenital bleeding disorders caused by a dysfunction or deficiency of coagulation factor (F) VIII or IX, respectively. 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]. Hemophilia Gene Therapy: Approaching the First Licensed Prod - LWW Multiyear Follow-up of AAV5-HFVIII-SQ Gene Therapy for Hemophilia A. U.S. National Library of Medicine Gene Therapy Study in Severe Hemophilia a Patients with Antibodies against AAV5 (270-203). Against the background of the imminent approval and release of gene therapy drugs addressed to patients with hemophilia, the WFH saw the need to carry out this initiative at a global scale. Sidonio R.F., Pipe S.W., Callaghan M.U., Valentino L.A., Monahan P.E., Croteau S.E. Nevertheless, this has not happened without significant controversy between its advocates and its critics regarding its promises, limits, possibilities and opportunities. Simioni P., Tormene D., Tognin G., Gavasso S., Bulato C., Iacobelli N.P., Finn J.D., Spiezia L., Radu C., Arruda V.R. When you come to Orlando Health Arnold Palmer, you and your child have . 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. The higher efficacy of viral vectors as compared with non-viral vectors has made them the better candidates for clinical application [20,23,24]. Rational Clinical Dose Selection of Adeno-Associated Virus-Mediated Gene Therapy Based on Allometric Principles. However, individuals with the same coagulation factor levels may exhibit varying bleeding phenotypes. Gene therapy - Mayo Clinic Miesbach W., OMahony B., Key N.S., Makris M. How to Discuss Gene Therapy for Haemophilia? 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. ClinicalTrials.gov Identifier: NCT03520712. [(accessed on 28 June 2021)]; Konkle B.A., Walsh C.E., Escobar M.A., Josephson N.C., Young G., von Drygalski A., McPhee S.W.J., Samulski R.J., Bilic I., de la Rosa M., et al. Towards a Global Multidisciplinary Consensus Framework on Haemophilia Gene Therapy: Report of the 2nd World Federation of Haemophilia Gene Therapy Round Table. This will definitely contribute to promoting a better understanding of the possibilities, potential risks, benefits and limitations of these new therapeutic protocols. At the Haley Center for Children's Cancer and Blood Disorders at Orlando Health Arnold Palmer Hospital for Children, our pediatric hematology team has years of experience providing the highest quality care to children with hemophilia, sickle cell anemia and other blood disorders.. George L.A., Sullivan S.K., Giermasz A., Rasko J.E.J., Samelson-Jones B.J., Ducore J., Cuker A., Sullivan L.M., Majumdar S., Teitel J., et al. 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. Research of gene therapy for hemophilia A is now taking place. 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. The high cost of the new therapies could exacerbate existing inequalities and become a problem for the sustainability of healthcare systems, particularly in low- and medium-income countries. Current replacement. AAV-based gene therapies for the treatment of HA are at an earlier stage of development than those for HB. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. This is important to determine the primary eligibility of patients for AAV-based gene therapy clinical trials. ICER Publishes Final Report and Policy Recommendations for Hemophilia A 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. International Journal of Molecular Sciences, https://creativecommons.org/licenses/by/4.0/, https://onlinepublichealth.gwu.edu/resources/equity-vs-equality/, Adeno-associated virus serotype 5 vector containing a variant of B-domain deleted human FVIII, Recombinant adeno-associated virus serotype 6 vector encoding B-domain deleted human FVIII (known as SB-525), Adeno-associated virus serotype 8 vector containing a functional copy of the codon-optimized FVIIIs cDNA encoding B-domain deleted FVIII, Recombinant adeno-associated virus vector containing a bioengineered capsid and a codon-optimized expression cassette to drive the expression of the SQ form of a B-domain deleted human FVIII (known as SPK-8011), Non-replicating adeno-associated virus serotype 2 vector expressing the Padua variant (R338L) of human FIX, Adeno-associated virus serotype rh10 vector containing the human FIX gene, Recombinant adeno-associated virus serotype 3 vector containing a codon-optimized expression cassette encoding a variant of human FIX known as FLT180a, Recombinant adeno-associated virus vector containing codon-optimized FIX-Padua (known as AMT-061), Lentiviral vector encoding human FVIII or FIX, Gene therapy study in patients with severe HA with antibodies against AAV5, Adeno-associated virus serotype 5 vector containing a B-deleted variant of FVIII, Gene therapy study in patients with severe HA, Study evaluating the efficacy and safety of valoctocogene roxaparvovec in patients with HA, Study evaluating the efficacy and safety of volactocogene roxaparvovec combined with prophylactic administration of corticosteroids in HA, Single-arm study evaluating the efficacy and safety of a dose of 4 10, New adeno-associated virus serotype 8 capsid vector pseudotype encoding FVIII-V3 (AAV2/8-HLP-FVIII-V3), University College, London/Medical Research Council, Safety and dose-escalation study of an adeno-associated virus vector used as gene therapy in HA, Adeno-associated virus serotype 8 (AAV8) expressing FVIII Factor VIII (BDD-FVIII) (BAX 888), Study evaluating the efficacy and safety of PF-07055480 in adults with moderate or severe HA, Recombinant AAV2/6 encoding B-domain deleted FVIII cDNA, Gene therapy study of recombinant AAV2/6 with the FVIII gene (SB-525) in patients with severe HA, Recombinant adeno-associated virus serotype 6 (AAV6) encoding B-domain deleted human FVIII cDNA, AAV5 containing the human FIX gene (AAV5-hFIX), Dose confirmation trial of AAV5-hFIXco-Padua, Recombinant adeno-associated virus serotype 5 (AAV5) vector containing the Padua variant of a codon-optimized complementary human FIX under the control of a liver-specific promoter (AAV5-hFIXco-Padua, AMT-061), HOPE-B: Study of AMT-061 in patients with moderate or severe HB, Single ascending dose of adeno-associated virus serotype 8 of FIX in adults with HB, Adeno-associated virus serotype 8 for FIX gene therapy (AskBio009), Phase 12 study of SHP648, an adeno-associated virus vector for gene therapy in patients with HB, Adeno-associated virus serotype 8 (AAV8) vector expressing FIX Padua (SHP648), Dose-escalation study of a complementary adeno-associated virus gene therapy vector in patients with HB, Self-complementary adeno-associated virus serotype 8 (AAV8) vector expressing a transgene of codon-optimized FIX (scAAV2/8-LP1-hFIXco), St. Jude Childrens Research Hospital/National Heart, Lung, and Blood Institute (NHLBI)/Hemophilia of Georgia, Inc./Childrens Hospital of Philadelphia/University College, London, Long-term safety and efficacy study of SPK-9001 in patients with HB, Non-replicating adeno-associated virus serotype 2 (AAV2) vector expressing the Padua variant (R338L) of human FIX under the control of the liver-specific apolipoproten E (Apo E) enhancer (PF-06838435/fidanacogene elaparvovec), Study evaluating the efficacy and safety of gene therapy with PF-06838435 in adult males with moderate or severe HB, Lentiviral factor VIII gene. The criteria influencing patients decisions included the annual bleeding rate, the level of factor, uncertainty about long-term risks, the impact of treatment on their daily lives and the possibility that prophylaxis may be discontinued. As a library, NLM provides access to scientific literature. FIX expression persisted for at least 20 weeks and immunogenicity remained unchanged. Wagner H.J., Weber W., Fussenegger M. Synthetic Biology: Emerging Concepts to Design and Advance Adeno-Associated Viral Vectors for Gene Therapy. The main adverse effect encountered was an increase in hepatic enzyme levels (ALT), which was treated with prednisolone. 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.. 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]. Samelson-Jones B.J., Finn J.D., Raffini L.J., Merricks E.P., Camire R.M., Nichols T.C., Arruda V.R. Gene therapy for hemophilia: a review on clinical benefit, limitations 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. Multiple animal studies have shown that TFPI inhibition can reduce bleeding in the context of hemophilia [9]. 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].
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