Trial reportThe New England journal of medicine2021
Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.
2 registry-linked trialsOpen access · bronzeAbstract readClinical Trial, Phase IClinical Trial, Phase IIMulticenter Study
In one paragraph
Trial report in The New England journal of medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 146 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
146citing papers in PubMed, 2 pooled it
26.6field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Gene-transfer, Open-label, Dose-escalation Study of SPK-8011 [Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene] in Individuals With Hemophilia A
A Multi-Center Evaluation of the Long-Term Safety and Efficacy of Spark-sponsored Gene Therapies in Males With Hemophilia A
Who cites it
146 citing papers in PubMed, 2 syntheses or guidelines pooled it, 240 citations in OpenAlex.
- Incidence, timing, and clinical significance of adverse immune events after gene replacement therapy: A systematic review and meta-analysis.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Pooled it
- Adeno-associated virus-based gene therapy for hemophilia A and B: a systematic review and meta-analysis.Blood advances · 2024Pooled it
- First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study.Gene therapy · 2026Trial
- Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials.Nature medicine · 2026Trial
- A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials.Haemophilia : the official journal of the World Federation of Hemophilia · 2025Trial
- Trial
- Article
- Defining the safety and efficacy of liver-directed AAV gene therapy using a human liver tissue-equivalent platform.Molecular therapy. Advances · 2026Article
- Laboratory Challenges in the Era of Novel Haemophilia Therapies.Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie · 2026Review
- Overview of Patient-Reported Outcomes in Haemophilia Gene Therapy.Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie · 2026Review
- AAV8-mediated mouse/human PROC expression rescues thrombophilia in hereditary protein C-deficient mice.Gene therapy · 2026Article
- AAV gene therapy for homozygous familial hypercholesterolemia: a phase 1 trial.Nature medicine · 2026Article
- Synthetic serum markers enable noninvasive monitoring of gene expression in primate brains.Neuron · 2026Article
- rAAV8 encapsidated HMR-001/z enables high efficiency hepatic transduction and restores hemostasis in hemophilic mice.Gene therapy · 2026Article
- Transforming Hemophilia Management: Lessons from Gene Therapy Clinical Trials.Molecular biotechnology · 2026Review
- Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- Phase 1 pilot study for hemophilia-A: AAV8 vector with prophylactic tacrolimus-glucocorticoid achieves therapeutic FVIII activity.Signal transduction and targeted therapy · 2026Article
- Review
- Gene Therapy for Heart Failure.Journal of cardiovascular translational research · 2026Review
- Immune Response Associated Hepatotoxicity in Hemophilia Gene Therapy: Mechanisms, Management, and Challenges.Journal of hematology · 2026Review
86 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 7 institutions in 2 countries.
Lindsey A GeorgeFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Paul E MonahanFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
M Elaine EysterFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Spencer K SullivanFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Margaret V RagniFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Stacy E CroteauFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
John E J RaskoFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Michael RechtFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Benjamin J Samelson-JonesFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Amy MacDougallFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Kristen JaworskiFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Robert NobleFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Marla CurranFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Klaudia KurandaFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Federico MingozziFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Tiffany ChangFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Kathleen Z ReapeFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Xavier M AnguelaFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Katherine A HighFrom the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), 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.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Spark Therapeutics (United States) · USChildren's Hospital of Philadelphia · USAmerican Thrombosis and Hemostasis Network · USHarvard University · USPenn State Milton S. Hershey Medical Center · USRoyal Prince Alfred Hospital · AUUniversity of Sydney · AU
Funding
Therapeutic Applications of Factor VIIIa Inactivation in Hemophilia AK08HL146991 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI GEORGE, LINDSEY ALLISON · 2019 to 2023
$698kRational Development of Bioengineered Factor IX Variants for Hemophilia B TherapyK08HL140078 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI SAMELSON-JONES, BEN J · 2018 to 2021
$638kNHLBI NIH HHS K08 HL140078NHLBI NIH HHS K08 HL 140078 (BJ Samelson-Jones)NHLBI NIH HHS K08 HL146991NHLBI NIH HHS K08 HL 146991 (LA George)
Abstract
backgroundThe 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.
methodsIn this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 10
resultsThe median safety observation period was 36.6 months (range, 5.5 to 50.3). 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. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration).
conclusionsSustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).
Indexed as
DependovirusGenetic TherapyGenetic VectorsAdolescentAdultFactor VIIIFollow-Up StudiesGenotypeGlucocorticoidsHemophilia AHepatocytesHumansImmunosuppression TherapyMaleMiddle AgedYoung AdultFactor VIIIGlucocorticoids
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Read underepoch 390
Registered trials
NCT03003533ClinicalTrials.gov
NCT03432520ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.