Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B

George, Lindsey A.; Ragni, Margaret V.; Rasko, John E.J.; Raffini, Leslie; Samelson-Jones, Ben; Ozelo, Margareth C.; Hazbon, Maria; Runowski, Alexa R.; Wellman, Jennifer; Wachtel, Katie; Chen, Yifeng; Anguela, Xavier M.; Kuranda, Klaudia; Mingozzi, Federico; High, Katherine A.

doi:10.1016/j.ymthe.2020.06.001

Cited by 138 publications

(116 citation statements)

References 56 publications

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“…Of note, the long-term follow-up of subjects from the CHOP/Avigen rAAV2- F9 trial at 12–15 years did not show evidence of tumors via measurement of tumor markers or liver enzymes. 98 , 119 …”

Section: Aav-based Gene Therapy: the Quandariesmentioning

confidence: 99%

Guest Editor: G. Castaman GENE THERAPY FOR HEMOPHILIA: FACTS AND QUANDARIES IN THE 21ST CENTURY

Arruda

Doshi

2020

Mediterr J Hematol Infect Dis

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Therapy for hemophilia has evolved in the last 40 years from plasma-based concentrates to recombinant proteins and, more recently, to non-factor therapeutics. Along this same timeline, research in adeno-associated virus (AAV) based gene therapy vectors has provided the framework for successful early phase clinical trials initially for hemophilia B (HB) and now for hemophilia A. Successive lessons learned from these early pivotal HB trials have paved the way for current advanced phase trials. Nevertheless, questions linger regarding 1) the optimal balance of vector dose to transgene expression, 2) amount and durability of transgene expression required, and 3) long-term safety. Some trials have demonstrated unique findings not seen previously regarding transient elevation of liver enzymes, immunogenicity of the vector capsid, and loss of transgene expression. This review will provide an update on the clinical AAV gene therapy trials in hemophilia and address the questions above. A thoughtful and rationally approached expansion of gene therapy to the clinics would certainly be a welcome addition to the arsenal of options for hemophilia therapy. Further, the global impact of gene therapy could be vastly improved by expanding eligibility to different patient populations and to developing nations. With the advances made to date, it is possible to envision a shift from the early modest goal of simply increasing life expectancy to a significant improvement in quality of life by reduction in spontaneous bleeding episodes and disease complications.

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Section: Aav-based Gene Therapy: the Quandariesmentioning

confidence: 99%

Guest Editor: G. Castaman GENE THERAPY FOR HEMOPHILIA: FACTS AND QUANDARIES IN THE 21ST CENTURY

Arruda

Doshi

2020

Mediterr J Hematol Infect Dis

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“…Yet, the high immunogenicity of AAV draws concern to the potential for participants of viral-based gene therapy clinical trials to acquire AAV immunity, and for potential preexisting immunity in some patients (reviewed in ( Ronzitti et al, 2020 ). These are major concerns because immunity to AAV is likely to prevent repeat administration of AAV gene therapy to patients ( George et al, 2020 ), therefore risking their eligibility for future AAV-based therapies. In 2020, the imlifidase (IdeS) enzyme was tested in rodents and non-human primates and successfully demonstrated inhibition of the host immune response to AAV resulting from preexisting immunity and following AAV gene therapy ( Leborgne et al, 2020 ).…”

Section: Therapeutic Delivery Vectorsmentioning

confidence: 99%

Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies

et al. 2021

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Prognosis of patients with cystic fibrosis (CF) varies extensively despite recent advances in targeted therapies that improve CF transmembrane conductance regulator (CFTR) function. Despite being a multi-organ disease, extensive lung tissue destruction remains the major cause of morbidity and mortality. Progress towards a curative treatment strategy that implements a CFTR gene addition-technology to the patients’ lungs has been slow and not yet developed beyond clinical trials. Improved delivery vectors are needed to overcome the body’s defense system and ensure an efficient and consistent clinical response before gene therapy is suitable for clinical care. Cell-based therapy–which relies on functional modification of allogenic or autologous cells ex vivo, prior to transplantation into the patient–is now a therapeutic reality for various diseases. For CF, pioneering research has demonstrated proof-of-principle for allogenic transplantation of cultured human airway stem cells into mouse airways. However, applying a cell-based therapy to the human airways has distinct challenges. We review CF gene therapies using viral and non-viral delivery strategies and discuss current advances towards autologous cell-based therapies. Progress towards identification, correction, and expansion of a suitable regenerative cell, as well as refinement of pre-cell transplant lung conditioning protocols is discussed.

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“…Preclinical data in mouse models point to a long-lasting expression for all the animal’s life ( 20 ). Reports from clinical trials in humans have shown therapeutic levels of the transgene for up to 10 years in some patients ( 21 ), but other clinical trials have revealed silencing in humans ( 22 ). This silencing of AAV expression has also been reported in large animal models such as in woodchuck infected with the woodchuck hepatitis virus ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

“…This silencing of AAV expression has also been reported in large animal models such as in woodchuck infected with the woodchuck hepatitis virus ( 23 ). The immune response against viral capsids has been proposed as the primary mechanism of silencing operating in humans ( 22 , 24 ). However, AAV silencing remains poorly understood due to the lack of animal models that reproduce this phenomenon.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Liver Expression of an Apolipoprotein A-I Mimetic Peptide Attenuates Interferon-Alpha-Induced Inflammation and Promotes Antiviral Activity

et al. 2021

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Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.

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Long-Term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene Transfer: AAV2-hFIX16 for Severe Hemophilia B

Cited by 138 publications

References 56 publications

Guest Editor: G. Castaman GENE THERAPY FOR HEMOPHILIA: FACTS AND QUANDARIES IN THE 21ST CENTURY

Guest Editor: G. Castaman GENE THERAPY FOR HEMOPHILIA: FACTS AND QUANDARIES IN THE 21ST CENTURY

Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies

Long-Term Liver Expression of an Apolipoprotein A-I Mimetic Peptide Attenuates Interferon-Alpha-Induced Inflammation and Promotes Antiviral Activity

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