aav5 factor viii gene transfer in severe hemophilia a

This decline in transgenic protein coincided with a transient tenfold increase in liver transaminases (serum alanine aminotransferase [ALT] > aspartate transaminase [AST]), which spontaneously returned to baseline values over the subsequent weeks, consistent with a self-limiting process. doi: 10.1093/hmg/ddz157. Introduction. Adeno-associated virus (AAV)-based gene therapies can restore endogenous factor VIII (FVIII) expression in hemophilia A (HA). Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A, A first-in-human four-year follow-up study of durable therapeutic efficacy and safety of AAV gene therapy with valoctocogene roxaparvovec for severe haemophilia A. Nathwani AC, Reiss UM, Tuddenham EGD, et al. Wilhelm AR, Parsons NA, Samelson-Jones BJ, et al. HHS Vulnerability Disclosure, Help No major safety concerns were identified after the administration of SPK-8011. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J. The authors designed the trial. The first participant was enrolled on January 26, 2017, and the data cutoff date for the analysis was May 3, 2021. Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. 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. [6] Multiple ongoing clinical trials of gene therapy for Hemophilia A involve different serotypes of recombinant adeno-associated viral vectors targeting hepatocytes. We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic. S8). These novel therapies are beginning to change the clinical management of the hemophilias in countries with developed economies by decreasing infusion frequency, thus improving compliance with prophylaxis, offering alternatives to inhibitor patients, and easing the route of administration. Five participants did not receive glucocorticoids. N Engl J Med. Bleeding Cut: CSL Behring Plans H1 Filings for Hemophilia B Gene Therapy AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. Methods & clinical development. Semantic Scholar is a free, AI-powered research tool for scientific literature, based at the Allen Institute for AI. 2023 Apr 7;32:454-467. doi: 10.1016/j.omtn.2023.04.004. Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Miesbach WMK, Coppens M, Kamp-mann P, et al. Patient data support that sustained endogenous production of clotting factor as a result of gene therapy eliminates the need for infusion of coagulation factors, and may therefore also reduce treatment costs, but mild liver toxicities have been observed in some patients receiving high vector doses. 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. HHS Vulnerability Disclosure, Help Following administration, the vector must undergo a number of genome-processing, assembly, and repair steps to form full-length circularized episomes that mediate long-term FVIII expression in target tissues. Implantation of genetically altered fibroblasts that produce factor VIII is safe and well tolerated, and this form of gene therapy is feasible in patients with severe hemophilia A. N Engl J Med. 2023 Apr 7;32:454-467. doi: 10.1016/j.omtn.2023.04.004. 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. cDNA, complementary DNA; IM, intramuscular. Results: The same goal can be achieved by using zinc-finger nucleases and CRISPR/Cas9 to mediate targeted integration of the FVIII or FIX gene in a safe harbor using nonhomologous end joining.48 Recently, Sangamo Therapeutics, together with Georgetown University, announced the treatment of the first hemophilia B patient (SB-FIX; NCT02695160) with a gene-editing approach in which the targeted integration of the FIX cDNA into an intron of the host cell albumin gene is promoted by zinc-finger nucleases following systemic administration of 3 separate AAV vectors. These findings are consistent with the results of previous trials of AAV-mediated gene therapy for hemophilia B15,16 and contrast with the elevated alanine aminotransferase levels of unclear cause lasting for multiple months that were observed in a previous trial of AAV5-hFVIII-SQ gene therapy for hemophilia A.7,8 Although the suspected immune response against SPK200 did not arouse major safety concerns, it limited the efficacy of SPK-8011 in some participants. 3). An official website of the United States government. In 2011, the St. Jude/UCL phase 1/2 trial was the first to provide clear evidence of a stable dose-dependent increase in FIX levels in patients with severe hemophilia B following a single administration of adeno-associated viral (AAV) vectors. The https:// ensures that you are connecting to the 2017; 377: 2519-2530 . Advances in gene therapy for hemophilia: basis, current status, and future perspectives. Early treatment is needed for people with severe hemophilia A, but gene therapies have only been tested clinically in adults. 2C), and the cumulative percentage was 39% over the entire follow-up period (Fig. J Blood Med. The .gov means its official. Hemophilia B gene therapy with a high-specific-activity factor IX variant, BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression, Selection and evaluation of clinically relevant AAV variants in a xenograft liver model, CpG reduced factor VIII variants, compositions and methods and uses for treatment of hemostasis disorders. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. 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. Federal government websites often end in .gov or .mil. Chandler RJ, LaFave MC, Varshney GK, et al. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. George LA, Sullivan SK, Giermasz A, et al. The percentage of participants with no bleeding events ranged from 60 to 100% at years 1 through 4 of follow-up (Fig. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. 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. Rangarajan S, Walsh L, Lester W, et al. Thereafter, the participants received a single, intravenous infusion of SPK-8011 on an outpatient basis. Understand progress with gene therapy for hemophilia, Hemophilia A and B are X-linked recessive disorders resulting from mutations in the gene for blood clotting factor VIII (FVIII) and factor IX (FIX), respectively. AAV3 uses the human hepatocyte growth factor . 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. Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. 1 View large Download PPT Our phase 12 trial data showed that SPK-8011 imparted multiyear durable factor VIII expression that significantly reduced bleeding. For instance, AAV5 serotype pseudotyped vectors (AMT-060; UniQure Therapeutics, Amsterdam, The Netherlands) made using the insect cellbaculovirus method, but containing the same FIX gene cassette as that used in the St. Jude/UCL trial, resulted in mean FIX activity levels of 6.9%, despite using a log higher vector dose of 2e13 vg/kg.25 Increased ALT levels were observed in 3 of 10 patients recruited to AMT-060, requiring treatment with corticosteroids. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. SPK-9001 consists of bioengineered capsid pseudotyped AAV vector containing the FIX-R338L transgene with a lower number of CpG.29 Transaminitis occurred in only 2 of 10 subjects who responded well to steroids. These data provide support for our hypothesis that hepatocyte expression of factor VIII after AAV gene transfer is a viable approach for long-term stable phenotypic amelioration of hemophilia A. Updated follow-up of the Alta study, a phase 1/2, open-label, adaptive, dose-ranging study to assess the safety and tolerability of SB-525 gene therapy. Inclusion in an NLM database does not imply endorsement of, or agreement with, Fahs SA, Hille MT, Shi Q, Weiler H, Montgomery RR. The site is secure. 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. (PDF) Global Seroprevalence of Pre-existing Immunity Against AAV5 and We tested UK people with hemophilia B for immunity against AAV6. Participants in the cohorts that received 5 1011 vg per kilogram or 1 1012 vg per kilogram reached plateau factor VIII activity by 12 weeks; these kinetics of expression are consistent with previous observations in trials of AAV gene therapy for hemophilia B.16 In contrast, participants in the cohorts that received 1.5 1012 vg per kilogram or 2 1012 vg per kilogram (except Participant 6) had decreases in peak expression from week 6 to 12 to plateau expression by 26 to 52 weeks after vector administration. Valoctocogene roxaparvovec (BMN 270) is an AAV type 5 (AAV5)-mediated gene therapy developed for the treatment of HA, and it encodes a codon-optimized, B-domain-deleted human FVIII protein (hFVIII-SQ) under control of a hybrid liver-specific promoter. S3). In this study, the low and intermediate vector doses were safe but did not result in a detectable increase in plasma FIX levels, whereas the mixed results were noted in the 2 subjects treated using the high dose (2e12 vg/kg). Hemophilia A (HA) is an X-linked bleeding disorder caused by mutations in the coagulation factor VIII (FVIII) gene. A Bayesian negative binomial regression analysis showed that the mean spontaneous bleeding rates were less than 1 event per year, with a posterior probability of 0.99 when transgene-derived factor VIII activity was more than 10% of the normal value at least 50% of the time in a one-stage factor VIII assay (Fig. Gene transfer using adeno-associated virus (AAV) viral vectors carrying BDD-FVIII could achieve long-term correction of the phenotype. 2023 Apr 17;14:20406207231165857. doi: 10.1177/20406207231165857. Unable to load your collection due to an error, Unable to load your delegates due to an error. Epub 2018 Aug 6. Each of the 4 patients with increased liver enzymes received a short tapering course of prednisolone, leading to normalization of ALT and AST levels with preservation of FIX transgene expression in the range of 2% to 5% of normal. Zancanella V, Valls A, Liefhebber JMP, Paerels L, Tornero CV, Wattimury H, van der Zon T, van Rooijen K, Golinska M, Grevelink T, Ehlert E, Pieterman EJ, Keijzer N, Gerardus Princen HM, Stokman G, Liu YP. 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. Notably, 2 subjects treated at the high-dose level had no evidence of transaminitis and did not require treatment with steroids. Transaminitis can be readily controlled with a short course of prednisolone in some circumstances, and it appears to be a self-limiting phenomenon with no evidence of late reoccurrence or persistent hepatocellular damage. Freeline Therapeutics has coupled a synthetic capsid (AAVS3), adapted for more efficient transduction of human hepatocytes, with a modified FIX expression cassette containing the R338L mutation. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. Rangarajan S1, Walsh L1, Lester W1, Perry D1, Madan B1, Laffan M1, Yu H1, Vettermann C1, Pierce GF1, Wong WY1, Pasi KJ1 Author information Affiliations 11 authors 1. Epub 2017 Apr 11. The site is secure. 8600 Rockville Pike Close monitoring of participants to determine safety and efficacy and to confirm initial multiyear observations of durable expression are ongoing. Finally, on average, AAV5-hFVIII-SQ was associated with factor VIII activity that was 10 times as high at 1 year after vector administration as that of SPK-8011.8,9 This outcome was not unexpected given that vector doses of AAV5-hFVIIISQ were orders of magnitude higher than those of SPK-8011. Between 20% and 70% of patients have preexisting neutralizing anti-AAV antibodies (NAbs) to specific AAV serotypes, which can block efficient gene transfer. sharing sensitive information, make sure youre on a federal 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. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). No other uses without permission. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med 2017;377:2519-30. Endogenous factor VIII activity greater than 10% of the normal value is associated with a low risk of spontaneous joint bleeding.3,4 Either recurrent intravenous infusion of exogenous factor or sub-cutaneous administration of a factor VIIImimetic bispecific monoclonal antibody, emicizumab, is currently used to confer a moderate or mild hemophilia phenotype in patients with hemophilia A.3,5,6, Multiple ongoing clinical trials of gene therapy for hemophilia A involve the use of recombinant adeno-associated viral (AAV) vectors to target hepatocyte factor VIII expression with the goal of a one-time disease-altering therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .). the contents by NLM or the National Institutes of Health. Although successful gene trans - fer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. 2019 by The American Society of Hematology. No new findings were noted on ultrasonographic assessment of the liver; these assessments were performed to screen for hepatocellular carcinoma, which was identified in preclinical studies as a concern with respect to the long-term safety of systemic administration of AAV.20,21. All rights reserved. The https:// ensures that you are connecting to the Prophylaxis was discontinued in the 16 participants who had sustained factor VIII expression. Gene therapy for hemophilia - American Society of Hematology The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. Conflict-of-interest disclosure: A.C.N. Additional objectives were to characterize expression pharmacokinetics and the immune response to SPK200 and expressed factor VIII-SQ protein. Among the 15 participants in whom factor VIII expression was maintained and who were followed for more than 52 weeks, the mean factor VIII activity more than 52 weeks after vector administration was 11.06.8% of the normal value (range, 3.2 to 24.8) in a one-stage factor VIII assay and 6.93.8% of the normal value (range, 3.0 to 14.3) in a chromogenic factor VIII assay. Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang JD, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, Kim B; GENEr8-1 Trial Group. Achievement of Normal Circulating Factor VIII Activity Following Bmn 270 AAV5-FVIII Gene Transfer: Interim, Long-Term Efficacy and Safety Results from a Phase 1/2 Study in Patients with Severe Hemophilia a - ScienceDirect Volume 130, Supplement 1, 8 December 2017, Page 603 801. Standard of care for people with severe haemophilia A is prophylactic administration of exogenous factor VIII (FVIII) or emicizumab to reduce frequency of bleeding. ), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E. Nathwani AC, Tuddenham EGD, Rangarajan S, et al. 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. RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection. Int J Mol Sci. Consistent with the presence of a glucocorticoid response element in the promoter, factor VIII expression increased in all the participants while they were receiving glucocorticoids. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in. 2023 May;56(5):e13467. FOIA Interindividual variability in transgene mRNA and protein - Nature Clinical pharmacology is a central field for AAV gene therapy, represented by the pillars of pharmacokinetics, pharmacodynamics/efficacy, and safety. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A The New England Journal of Medicine TAKE-HOME MESSAGE In this phase I/II study, 9 patients with severe hemophilia A were infused with a single dose of recombinant adeno-associated virus vector encoding modified factor VIII. . PDF AAV5 Factor VIII Gene Transfer in Severe Hemophilia A Panel B shows the annualized number of exogenous factor VIII infusions before and after vector infusion. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. Participants 5 and 12 lost transgene expression. No major safety concerns were reported. Preliminary data, reported at the 60th American Society of Hematology Annual Meeting and Exposition (1-4 December 2018, San Diego, CA), from 2 patients treated at a dose of 4.5e12 vg/kg show promise, with steady-state expression at 45% 5% and no evidence of transaminitis or neutralizing anti-FIX antibodies.31. Once in the target cell nucleus, the FIX transgene is integrated at a specific site that matches with the guide DNA arms within the patients genome using the host cells homologous recombination machinery.47 This approach has been successful in mice but remains to be tested in humans. This open-label, multicenter, nonrandomized, dose-escalation, phase 12 trial evaluated SPK-8011 for hemophilia A. with a decline in FVIII activity from a mean of 31% at 1 year to 23% at 2 years postgene transfer. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. Seven participants (who had received 61013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. 2017; 377: 2519 . Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A This site needs JavaScript to work properly. *, Four participants had adverse events related to glucocorticoids (Table 2). The safety and efficacy of AAV8 serotype pseudotyped HLP-hFVIII-V3, manufactured in mammalian HEK-293 cells, have been assessed in 3 adult men with severe hemophilia A with a short follow-up period of 13 to 47 weeks; FVIII levels of 69% were achieved in 1 of the patients treated at a dose of 2e12 vg/kg. Consistent with findings in other trials of therapy for hemophilia A,7,22 factor VIII activity that was determined with the use of a one-stage factor VIII assay was 1.5 times as high as that determined with the use of a chromogenic factor VIII assay (Fig. Disclaimer. 2021 Nov 18;385(21):1961-1973. doi: 10.1056/NEJMoa2104205. This confidence interval was used to describe the multiyear durability of factor VIII expression. Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an Immunity to AAV6 may make people with hemophilia B ineligible for gene therapy using this vector. Descriptive statistics were used to analyze data from all the enrolled participants. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A | NEJM 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. DOI: 10.1056/NEJMoa1708483 Data from an ongoing trial of gene therapy for hemophilia A showed an average decrease of approximately half of transgene expression from year 1 to year 2 after vector administration; the most recently presented 4-year follow-up data showed that this decrease continued.79 The results of this trial suggested that long-term, stable factor VIII activity may not be achieved with hepatocyte-directed AAV gene transfer in humans. Methods: Collectively, they are among the most common inherited bleeding disorders in the world. Therefore, hemophilia patients have to carefully plan periods of increased physical activities, such as sports, which people living without hemophilia can hardly imagine.
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