Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy

Verhenne, Sebastien; Vandeputte, Nele; Pareyn, Inge; Izsvák, Zsuzsanna; Rottensteiner, Hanspeter; Deckmyn, Hans; Meyer, Simon F. De; Vanhoorelbeke, Karen

doi:10.1161/atvbaha.116.308680

Cited by 19 publications

(12 citation statements)

References 49 publications

(52 reference statements)

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“…A single injection of AAV8‐hAAT‐mMDTCS vector at a dose > 2.6 × 10 11 vector genome per kilogram body weight resulted in a long‐term expression of functional ADAMTS‐13 at therapeutic levels, which prevented shigatoxin‐induced TTP in Adamts‐13 − / − mice . Other gene therapy approaches include the transplantation of hematopoietic progenitor cells transduced with lentiviral vector encoding a full‐length ADAMTS‐13 and the liver expression of a full‐length ADAMTS‐13 by the sleeping beauty transposon SBX100 system . In addition, ectopic expression of a full‐length recombinant ADAMTS‐13 in megakaryocytes and platelets in Adamts‐13 − / − mice also showed protection against TTP after VWF or shigatoxin challenge in the presence of anti‐ADAMTS‐13 antibody .…”

Section: Therapiesmentioning

confidence: 99%

Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

Saha

McDaniel

Zheng

2017

Journal of Thrombosis and Haemostasis

125

107

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Summary Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. In general, severe deficiency of plasma ADAMTS13 activity (<10 IU/dL) with or without detectable inhibitory autoantibodies against ADAMTS13 supports the diagnosis of TTP if a patient presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS13 activity (>20 IU/dL) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. While plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide, and splenectomy, etc. should be considered to eliminate autoantibodies for sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis, diagnosis, and current and potential novel therapies for hereditary and acquired TTP.

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Section: Therapiesmentioning

confidence: 99%

Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

Saha

McDaniel

Zheng

2017

Journal of Thrombosis and Haemostasis

125

107

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“…TTP is a rare but life-threatening disease with high morbidity and mortality rates in the absence of timely and appropriate treatment. The current standard of care is plasma exchange, however multiple therapeutic approaches such as anti-inflammatory antibodies, proteasome modulators, antioxidants, anti-VWF nanobodies and gene therapy have been explored 8 – 14 . Among these experimental therapeutic options, enzyme replacement therapy (ERT) has shown promise in preclinical models and ex vivo studies 6 , 15 .…”

Section: Discussionmentioning

confidence: 99%

“…Rituximab) 7 . Along with other experimental therapeutic options tested in preclinical models or clinical trials 8 – 14 , enzyme replacement with rhADAMTS13 has proved to be an effective and safe treatment for both inherited and acquired TTP 6 , 15 . In acquired TTP, there are high circulating levels of neutralizing antibodies to wild-type ADAMTS13 and physicians often must resort to immediate plasma exchange prior to addressing the underlying causality of TTP.…”

Section: Introductionmentioning

confidence: 99%

mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice

Liu-Chen

Connolly

Cheng

et al. 2018

Sci Rep

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Thrombotic thrombocytopenic purpura (TTP) is primarily caused by deficiency of ADAMTS13 within the blood stream due to either genetic defects or presence of inhibitory autoantibodies. Preclinical and clinical studies suggest that enzyme replacement therapy with recombinant human ADAMTS13 protein (rhADAMTS13) is effective and safe in treatment of TTP. However, frequent dosing would be required due to the relatively short half-life of rhADAMTS13 in circulation as well as the presence of inhibitory autoantibodies that collectively result in the poor pharmacological profile of rhADAMTS13. With technical breakthroughs in exploring mRNA as therapeutics, we hypothesized that restoration of ADAMTS13 activity for a prolonged duration of time can be achieved through systemic dosing of mRNA, wherein the dosed mRNA would utilize hepatic cells as bioreactors for continuous production of ADAMTS13. To test this hypothesis, mRNA encoding human ADAMTS13 WT or an ADAMTS13 variant, that had demonstrated resistance to predominant clinical TTP autoantibodies, was formulated in lipid nano-particles for liver-targeted delivery. In both ADAMTS13-sufficient and -deficient mice, a single dose of the formulated mRNAs at 1 mg/kg resulted in expression of hADAMTS13 at or above therapeutically relevant levels in mice for up to five days. This proof-of-concept study suggests that mRNA therapy could provide a novel approach for TTP treatment.

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“…Many novel gene therapeutic options have Review been investigated in preclinical studies. [99][100][101] In the recent work by Liu-Chen et al, 53 a full-length optimized ADAMTS13 mRNA was synthesized and encapsulated into LNPs. Upon a single i.v.…”

Section: Thrombotic Thrombocytopenic Purpuramentioning

confidence: 99%

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

et al. 2019

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Long-Term Prevention of Congenital Thrombotic Thrombocytopenic Purpura in ADAMTS13 Knockout Mice by Sleeping Beauty Transposon-Mediated Gene Therapy

Abstract: These data demonstrate the feasibility of using SB100X-mediated gene therapy to achieve sustained expression of transgene ADAMTS13 and long-term prophylaxis against TTP in mice.

Cited by 19 publications

References 49 publications

Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

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