An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia

Sehgal, Alfica; Barros, Scott; Ivanciu, Lacramioara; Cooley, Brian C.; Qin, June; Racie, Tim; Hettinger, Julia; Carioto, Mary; Jiang, Yongfeng; Brodsky, Joshua; Prabhala, Harsha; Zhang, Xuemei; Attarwala, Husain; Hutabarat, Renta; Foster, Don; Milstein, Stuart; Charissé, Klaus; Kuchimanchi, Satya; Maier, Martin A.; Nechev, Lubo; Pachamuthu, Kandasamy; Kel’in, Alexander V.; Nair, Jayaprakash K.; Rajeev, Kallanthottathil G.; Manoharan, Muthiah; Meyers, Rachel; Sørensen, Benny; Simon, Amy; Dargaud, Yesim; Négrier, Claude; Camire, Rodney M.; Akinc, Akin

doi:10.1038/nm.3847

Cited by 248 publications

(238 citation statements)

References 41 publications

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“…The utility of this GalNAc conjugate approach for efficient and potent hepatocellular siRNA delivery has provided a robust platform for the development of RNAi-based therapies in liver-based diseases, with GalNAc-siRNA conjugates in development for the treatment of hemophilia, 23 acute hepatic porphyria, 24 and hepatic infectious diseases, 25 among others. Indeed, GalNAc-mediated delivery has been deployed with other oligonucleotide-based therapeutic agents, including ASOs 26 and anti-microRNAs (miRNAs), 27 as demonstrated in preclinical studies and their advancement into clinical development.…”

Section: Discussionmentioning

confidence: 99%

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

et al. 2017

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Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25-10 mg/kg in the single and 2.5-10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5-10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p < 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.

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Section: Discussionmentioning

confidence: 99%

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

et al. 2017

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“…78 The promise of genetic therapies for improved management of coagulation disorders is now beginning to be realized. Although gene replacement strategies are the most prominent of these approaches, the application of inhibitory oligonucleotides 79 and small inhibitory RNA molecules 80 to alter the hemostatic balance has demonstrated how other nucleic acid-based strategies have shown considerable potential in recent clinical trials. With enhanced access to genome editing technologies, this momentum toward translational benefits is likely to continue.…”

Section: Future Considerations For the Application Of Gene Therapy Fomentioning

confidence: 99%

Gene Therapy for Coagulation Disorders

Swystun

Lillicrap

2016

Circulation Research

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Molecular genetic details of the human coagulation system were among the first successes of the genetic revolution in the 1980s. This information led to new molecular diagnostic strategies for inherited disorders of hemostasis and the development of recombinant clotting factors for the treatment of the common inherited bleeding disorders. A longer term goal of this knowledge has been the establishment of gene transfer to provide continuing access to missing or defective hemostatic proteins. Because of the relative infrequency of inherited coagulation factor disorders and the availability of safe and effective alternative means of management, the application of gene therapy for these conditions has been slow to realize clinical application. Nevertheless, the tools for effective and safe gene transfer are now much improved, and we have started to see examples of clinical gene therapy successes. Leading the way has been the use of adeno-associated virus-based strategies for factor IX gene transfer in hemophilia B. Several small phase 1/2 clinical studies using this approach have shown prolonged expression of therapeutically beneficial levels of factor IX. Nevertheless, before the application of gene therapy for coagulation disorders becomes widespread, several obstacles need to be overcome. Immunologic responses to the vector and transgenic protein need to be mitigated, and production strategies for clinical grade vectors require enhancements. There is little doubt that with the development of more efficient and facile strategies for genome editing and the application of other nucleic acid-based approaches to influence the coagulation system, the future of genetic therapies for hemostasis is bright. (Circ Res.

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“…The antithrombin anticoagulant pathway has been suppressed by administration of a RNA interference agent (ALN-AT3) in mice and in nonhuman primates 8 : hemostasis in mouse models of hemophilia was improved. A phase 1 study of this agent in normal patients and in patients with hemophilia is currently underway.…”

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confidence: 99%

Correcting the hemophilic imbalance

Lane

2017

Blood

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In this issue of Blood, Polderdijk et al design and evaluate a therapeutic inhibitor of activated protein C.1 They have produced a recombinant variant of a1- antitrypsin (a1AT) incorporating 3 residue changes within the P2-P19 sequence of its reactive loop. This variant (termed KRK a1AT) exhibits high specificity and inhibitory efficiency toward activated protein C. It is able to restore thrombin generation in normal and in hemophilia plasmas, when these are supplemented with soluble thrombomodulin. It is able to restore hemostasis in challenged hemophilia mice. KRK a1AT is therefore a potentially valuable future therapeutic agent for the human hemophilias

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An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia

Cited by 248 publications

References 41 publications

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

Gene Therapy for Coagulation Disorders

Correcting the hemophilic imbalance

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