aav5 factor viii gene transfer in severe hemophilia a

Gene therapy for hemophilia cannot be given to patients with anti-AAV capsid-neutralizing antibodies, and cellular immunity with CD8 + T cells should be controlled for sustained expression, and long-term therapeutic effects should be closely observed because of the failure of the AAV vector genome to replicate during cell division. The critical impact of adeno-associated virus (AAV) gene transfer in hemophilia care is discussed, including the recent clinical outcomes, changes in disease perceptions, and its treatment burden. One subject had higher levels of neutralizing anti-AAV2 antibodies prior to gene transfer, which appeared to block successful transduction and resulted in a lack of transgenic FIX expression. 1 and Figs. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. Rangarajan S et al. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, Yu H, Vettermann C, Pierce GF, Wong WY, Pasi KJ. Alternatively, NAbs could be overcome by using immunosuppression or plasmapheresis or by simply increasing vector dose or adding empty capsids.45. Amit C. Nathwani, UCL Cancer Institute, Department of Haematology, Katharine Dormandy Haemophilia and Thrombosis Unit, Royal Free Hospital, Pond St, London NW3 2QG, United Kingdom; e-mail: amit.nathwani@ucl.ac.uk. Descriptive statistics were used to analyze data from all the enrolled participants. Stable FIX expression and durable reductions in bleeding and factor IX consumption for up to 4 years following AMT-060 gene therapy in adults with severe or moderate-severe hemophilia B, Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps, The unfolded protein response: from stress pathway to homeostatic regulation, Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. All the participants had vector shedding that was below the quantification limit in saliva, serum, urine, and semen by 3 weeks after vector infusion and in PBMCs by 12 weeks after vector infusion (Fig. Hum Mol Genet. Despite this widening therapeutic choice for the treatment of the hemophilia, gene therapy has great appeal because it offers the potential for a cure through endogenous production of FVIII or FIX following transfer of a normal copy of the respective gene. This is the first report demonstrating multiyear therapeutic efficacy and safety of multiple AAV-cFVIII vectors in hemophilia A dogs and provides the basis for human clinical studies. Panel B shows the posterior density of the mean annualized rate of spontaneous bleeding among participants with factor VIII activity of more than 10% of the normal value at least half the time; among these participants, there was a 99% probability of an annualized rate of spontaneous bleeding of less than 1 event. N Engl J Med. Factor VIII activity was determined with the use of a one-stage factor VIII assay. The planned phase 3 trial utilizing this vector is sponsored by Pfizer (New York, NY). 1, 2 However, some people with severe haemophilia A on prophylaxis still experience bleeding. government site. Additionally, the lower seroprevalence of AAV8 in humans (25% compared with >70% for AAV2) enabled exclusion of fewer subjects with preexisting humoral immunity to AAV8.23. National Library of Medicine The development of a new generation of lentiviral vectors designed for efficient delivery of the transgene to the liver following systemic delivery of vectors carrying FVIII and FIX shows great promise and supports the further evaluation of this approach in the clinic.49. 2C), and the cumulative percentage was 39% over the entire follow-up period (Fig. . Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia . Rangarajan S, Walsh L, Lester W, et al. Semantic Scholar is a free, AI-powered research tool for scientific literature, based at the Allen Institute for AI. MeSH Transgenic FIX expression has remained stable at 5% of normal in the high-dose cohort over a 7-year follow-up period, resulting in a substantial reduction in spontaneous bleeding and FIX protein usage without toxicity. Furthermore, both SPK-8011 and AAV5-hFVIII-SQ have cassette sizes of approximately 5 kb, so the length of DNA packaged is not different; whether other factors (e.g., charge differences in the capsid sequence) affect DNA packaging, inverted terminal repeatdependent formation of stable concatemers, or both is unclear.24 Although both vectors used promoters targeting hepatocyte expression of factor VIII, cell-specific expression was not confirmed, which leaves open the possibility that expression from heterogeneous cell sources may account for differences in durability. Immunity to AAV6 may make people with hemophilia B ineligible for gene therapy using this vector. Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 41013 vg per kilogram or 61013 vg per kilogram of the gene therapy. In addition, among these 12 men, the combined mean factor VIII activity when the participants were not receiving glucocorticoids for 26 to 52 weeks (12.96.9% of the normal value) was analogous to the combined mean factor VIII activity after more than 52 weeks (12.07.1%). In this issue of Blood, Miesbach et al show that adeno-associated virus-5 (AAV5) liver-directed gene therapy in severe and moderate hemophilia B was clinically effective, with patients achieving stable factor IX (FIX) expression. Interindividual variability in transgene mRNA and protein - PubMed Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. As a library, NLM provides access to scientific literature. Thus, AAV gene therapies are likely to alter the treatment paradigm for hemophilia A and B. Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following transfer of a functional gene to replace the hemophilic patient's own defective gene. official website and that any information you provide is encrypted In preclinical studies in mice and nonhuman primates, scAAV vectors mediated a 10-fold increase in transduction efficiency compared with ssAAV vectors.19,20 Subsequently, we realized that the covalently closed hairpin structure of scAAV vector inhibited polymerase chain reaction amplification of vector genomes, resulting in an underestimation of vector titer. These vectors have the best safety profile among gene transfer vectors of viral origin, because wild-type AAV has not been associated with human disease. An official website of the United States government. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A government site. Recent hemophilia B gene therapy trial using AAV. Methods: All these elevations were mild except in Participant 12, who was hospitalized on an elective basis to receive intravenous methylprednisolone for a grade 2 elevation in the alanine aminotransferase level (3.0 to 4.9 times the upper limit of the normal range); this elevated level constituted the only serious adverse event in the trial (Table 2). S6 though S8). 6e13 vg/kg: FVIII expression in the normal range for 6 of 7 patients. Bleeding in target joints resolved in five of six participants. Mol Ther. Unlike FVIII, emicizumab is active in plasma all of the time and is associated with microangiopathy and thrombosis, particularly when used in combination with activated prothrombin complex concentrates.8 Other novel approaches entail the lowering of endogenous anticoagulants, such as antithrombin or tissue factor pathway inhibitor, with antisense RNA technology (fitusiran)9 or a monoclonal antibody (eg, concizumab),10 respectively. Miesbach WMK, Coppens M, Kamp-mann P, et al. It is unlikely to be related to the AAV5 capsid, because stable FIX levels for 3.5 years have been observed in AMT-060, which also used AAV5 pseudotyped vector. 2017; 377: 2519 . The enrolled participants met all screening criteria outlined in the Supplementary Appendix. There was no evidence of inhibitor formation to FIX-Padua. Zhang K, Wu N, Cen J, Li J, Wang Z, Xia Q, Hui L. Cell Prolif. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med. This confidence interval was used to describe the multiyear durability of factor VIII expression. 2022 Mar 17;386(11):1013-1025. doi: 10.1056/NEJMoa2113708. N Engl J Med. 8600 Rockville Pike The limited packaging capacity of AAV vectors (4680 nucleotides) and the poor expression profile of FVIII have hindered the use of these vectors for gene therapy of hemophilia A. Therefore, hemophilia patients have to carefully plan periods of increased physical activities, such as sports, which people living without hemophilia can hardly imagine. doi: 10.1093/hmg/ddz157. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy, AAV vector integration sites in mouse hepatocellular carcinoma. This reaction resolved within 72 hours with outpatient antipyretic therapy. Prophylaxis is associated with a sawtooth pattern of factor levels in plasma: high immediately after infusion and falling rapidly to near baseline, leading to breakthrough bleeding. Activity of transgene-produced B-domain-deleted factor VIII in human Serologic and imaging studies were performed as outlined in the trial protocol. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .). Bethesda, MD 20894, Web Policies The percentage of participants with no bleeding events ranged from 60 to 100% at years 1 through 4 of follow-up (Fig. ), and Spark Therapeutics (P.E.M., A.M., K.J., R.N., M.C., K.K., F.M., T.C., K.Z.R., X.M.A., K.A.H. Stable long-term FIX expression at 1% to 8% of normal was established in all 10 subjects. All the trial participants provided written informed consent for enrollment into one of four dose cohorts, which ranged from a low dose of vector to a high dose (i.e., from 5 1011 vector genomes [vg] per kilogram of body weight to 2 1012 vg per kilogram). Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. One strategy to overcome NAbs, which works well in animal models, is to switch AAV serotype20; however, this may not be applicable in humans because of the cross-reactivity of NAbs. These approaches have shown efficacy in reducing the rate of bleeding in hemophilia A and B patients, including those with inhibitors, but their use may be limited by a risk for thrombogenicity. Clipboard, Search History, and several other advanced features are temporarily unavailable. More than half of patients with hemophilia A or B have factor levels < 1% of normal.1 These individuals have a severe bleeding phenotype consisting of frequent spontaneous musculoskeletal and soft tissue bleeding. In this phase 12 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Ongoing monitoring of the liver does not show any evidence of long-lasting damage.24 Therefore, the key factors that led to the success of the St. Jude/UCL trial were exclusion of patients with preexisting antibodies to AAV serotype and early use of corticosteroids upon detecting an increase in ALT, potentially suppressing an immune response directed against transduced hepatocytes. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N. Engl. 2017 Dec 28;377(26):2519-2530. doi: 10.1056/NEJMoa1708483. Copyright 2020 Massachusetts Medical Society. This site needs JavaScript to work properly. Drug-Related Adverse Events and Drug-Related Serious Adverse Events. Preclinical studies around this time suggested that, for a given dose of AAV, expression was significantly higher following liver-targeted delivery of AAV compared with intramuscular injections, perhaps because the liver is the natural site of FIX synthesis.18 Therefore, in the second study, AAV2 vectors were infused into the hepatic artery using 3 doses ranging from 0.08 to 2e12 vg/kg in patients with severe hemophilia B. Becker S, Simpson JC, Pepperkok R, et al. Hemophilia provides an attractive target for gene therapy studies, due to the monogenic nature of these disorders and easily measurable endpoints (factor levels and bleed rates), and AAV based gene therapy is one of a number of novel approaches for treatment of hemophilia progressing through clinical trials. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A | NEJM Conclusions: AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. This led to the hypothesis that an excess of unmethylated CpG motifs, which are common in bacterial, but not mammalian, DNA, triggered a Toll-like receptor 9 response, leading to loss of transduced hepatocytes with an associated transaminitis that is not responsive to corticosteroids.28. This decline in transgene expression occurred in the absence of transaminitis, with the greatest decrease in FVIII activity occurring in those patients with the highest level of FVIII expression. National Library of Medicine Additional objectives were to characterize expression pharmacokinetics and the immune response to SPK200 and expressed factor VIII-SQ protein. The site is secure. Unable to load your collection due to an error, Unable to load your delegates due to an error. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. In addition, AAV5-hFVIII-SQ differs from SPK-8011 with respect to codon optimization of the expression cassette, AAV capsid serotype, vector dose (30 to 120 times as high with AAV5-hFVIII-SQ), and the promoter.7,8. This open-label, multicenter, nonrandomized, dose-escalation, phase 12 trial evaluated SPK-8011 for hemophilia A. Conflict-of-interest disclosure: A.C.N. 4e13 vg/kg: FVIII expression in the mild range for 6 of 6 patients. (PDF) Global Seroprevalence of Pre-existing Immunity Against AAV5 and This review explores recent progress and the remaining limitations that need to be overcome for wider availability of this novel treatment of inherited bleeding disorders. Potential for cellular stress response to hepatic factor VIII expression from AAV vector, Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses, Protein-engineered coagulation factors for hemophilia gene therapy. Efficacy end points included factor VIII activity determined by a central laboratory on the basis of a steady-state one-stage factor VIII assay and the number of factor VIII infusions and bleeding events after vector administration. ), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E. and transmitted securely. One of the 2 patients treated at the 3e13-vg/kg dose level had ALT elevation requiring a tapering course of oral corticosteroids. Thirtyone percent of people with hemophilia B had neutralizing factors against AAV6. Zolotukhin I, Markusic DM, Palaschak B, Hoffman BE, Srikanthan MA, Herzog RW. Epub 2023 May 17. The authors designed the trial. Education Program. Both studies were associated with loss of transgenic FIX despite administration of prednisolone. The first author wrote the first draft of the manuscript with subsequent input from the other authors and without editorial assistance. The gray vertical line indicates an annualized rate of spontaneous bleeding of 1 event. Amit C. Nathwani; Gene therapy for hemophilia. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A | NEJM Sangamo Therapeutics (SB-525) announced results of their ongoing phase 1/2 trial in 8 patients with severe hemophilia A treated in 4 dose cohorts (9e11, 2e12, 1e13, and 3e13 vg/kg; n = 2 per cohort.36 At 6 weeks postinfusion, the 2 patients at the highest tested dose (3e13 vg/kg) reached between 94% and 140% of normal levels. Thereafter, the participants received a single, intravenous infusion of SPK-8011 on an outpatient basis. The availability of convincing evidence for long-term expression of transgenic FVIII and FIX at therapeutic levels, resulting in amelioration of the bleeding diathesis following AAV-mediated gene transfer, is an important step toward development of curative gene therapy. Spiral, Imperial College Digital Repository. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med 2017;377:2519-30. Repeated episodes of intra-articular bleeding cause severe progressive destructive arthropathy, with deformity leading to complete loss of joint function and attendant disability. All the participants had factor VIII expression after vector administration. Of the 7 patients treated using 6e13 vg/kg, 6 achieved an FVIII level > 50% (Table 2), using a 1-stage clotting assay, at 1 year. Thirteen of the 18 participants were receiving factor prophylaxis before vector administration; the remainder received factor VIII on demand. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose,.

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