Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

George, Lindsey A.; Monahan, Paul E.; Eyster, M. Elaine; Sullivan, Spencer K.; Ragni, Margaret V.; Croteau, Stacy E.; Rasko, John E.J.; Recht, Michael; Samelson-Jones, Ben; MacDougall, Amy; Jaworski, Kristen; Noble, Robert; Curran, Marla; Kuranda, Klaudia; Mingozzi, Federico; Chang, Tiffany; Reape, Kathleen Z.; Anguela, Xavier M.; High, Katherine A.

doi:10.1056/nejmoa2104205

Cited by 141 publications

(103 citation statements)

References 34 publications

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“…Of note, the safety and efficacy results generated with this novel AAV vector, SPK-8011 , constitute the proof of concept to support our ongoing phase 1/2 clinical study (NCT03003533) that represents the first use of a bioengineered AAV capsid in a clinical study for the treatment of hemophilia A. 16 …”

Section: Discussionmentioning

confidence: 88%

“…Importantly, preliminary results from our phase 1/2 dose escalation trial appear consistent with the notion that clinically relevant levels of FVIII are achieved at doses ranging from 5 × 10 11 to 2 × 10 12 vg/kg, with no evidence of a cellular immune response to transduced hepatocytes. 16 The ability to achieve therapeutic levels of FVIII expression at AAV vector doses that are comparable with those used in the context of AAV trials for the treatment of hemophilia B represents a significant departure from the previously held notion that AAV gene therapy for hemophilia A would require significantly higher doses. As a point of comparison, results from two gene therapy studies in severe hemophilia A subjects showed that the threshold level above which clinically relevant expression level is detected is at least 10-fold higher than for other investigational AAV vectors.…”

Section: Discussionmentioning

confidence: 99%

“…The studies presented here identified investigational SPK-8011 , an AAV vector that contains the first bioengineered capsid to be evaluated clinically in a phase 1/2 study for the treatment of hemophilia A (NCT03003533). 16 …”

Section: Introductionmentioning

confidence: 99%

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Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A

Elkouby

Armour

Toso

et al. 2022

Molecular Therapy - Methods & Clinical Development

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Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011 , currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 10 12 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A

Elkouby

Armour

Toso

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…Gene therapy and gene editing have been rapidly evolving in cancer over the past decades and might soon expand the armory of cancer therapeutics in clinical use [61][62][63][64] . However, compared to the recent success of gene therapy in monogenic hereditary diseases such as hemophilia, cancer gene therapy lags behind due to difficulties regarding safety and delivery 65 .…”

Section: Discussionmentioning

confidence: 99%

Neomorphic DNA-binding enables tumor-specific therapeutic gene expression in fusion-addicted childhood sarcoma

Hölting¹,

Cidre‐Aranaz

Matzek

et al. 2022

Preprint

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Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer types including pediatric sarcomas, such as Ewing sarcoma (EwS) and alveolar rhabdomyosarcoma (ARMS). Despite their exquisite specificity, these driver oncogenes have been considered largely undruggable due to their lack of enzymatic activity. Here, we show in the EwS model that - capitalizing on neomorphic DNA-binding preferences - the addiction to the respective fusion transcription factor EWSR1-FLI1 can be leveraged to express therapeutic genes. We genetically engineered a de novo enhancer-based, synthetic and highly potent expression cassette that can elicit EWSR1-FLI1-dependent expression of a therapeutic payload as evidenced by episomal and CRISPR-edited genomic reporter assays. Combining in silico screens and immunohistochemistry, we identified GPR64 as a highly specific cell surface antigen for targeted transduction strategies in EwS. Functional experiments demonstrated that anti-GPR64-pseudotyped lentivirus harboring our expression cassette can specifically transduce EwS cells to promote the expression of viral thymidine kinase sensitizing EwS for treatment to the otherwise relatively non-toxic (Val)ganciclovir and leading to strong anti-tumorigenic, but no adverse effects in vivo. Further, we prove that similar vector designs can be applied in PAX3-FOXO1-driven ARMS, and to express immunomodulatory cytokines, such as IL-15 and XCL1, in tumor types typically considered to be immunologically cold. Collectively, these results generated in pediatric sarcomas indicate that exploiting, rather than suppressing, the neomorphic functions of chimeric transcription factors may open inroads to innovative and personalized therapies, and that our highly versatile approach may be translatable to other cancers addicted to oncogenic transcription factors with unique DNA-binding properties.

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“…Despite these difficulties, gene therapy for haemophilia is now possible as demonstrated by the results of several ongoing or completed clinical trials [ 5 – 7 ]. These trials show that after gene therapy, people with haemophilia can achieve normal levels of FVIII or FIX, no longer develop bleeding complications and not require replacement therapy.…”

mentioning

confidence: 99%

Haemophilia gene therapy: experiences and lessons from treated patients

Hermans

2022

Orphanet J Rare Dis

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Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A

Cited by 141 publications

References 34 publications

Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A

Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A

Neomorphic DNA-binding enables tumor-specific therapeutic gene expression in fusion-addicted childhood sarcoma

Haemophilia gene therapy: experiences and lessons from treated patients

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