Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles

Chen, Chun-Yu; Tran, Dominic M.; Cavedon, Alex; Cai, Xinghan; Rajendran, Raj; Lyle, Meghan J.; Martini, Paolo G.V.; Miao, Carol H.

doi:10.1016/j.omtn.2020.03.015

Cited by 55 publications

(44 citation statements)

References 62 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 231 ). In addition, mRNA-based protein replacement therapies have been applied to haematological diseases (for example, haemophilia A 232 , haemophilia B 91 , 104 , 233 and thrombotic thrombocytopaenic purpura 234 ), central nervous system disorders 67 , 152 (for example, Friedreich’s ataxia 67 ), skin diseases 235 , 236 (for example, elastin deficiency 235 ) and hearing loss 237 in preclinical studies.…”

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Lipid nanoparticles for mRNA delivery

et al. 2021

View full text Add to dashboard Cite

Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle–mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle–mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle–mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology.

show abstract

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Lipid nanoparticles for mRNA delivery

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Prolonged gene therapy by lipid-coated nanoparticle-encapsulated DNA or mRNA encoding human FVIII can solve this unmet medical need. A recent report showed that a single injection of BDD- FVIII mRNA-containing lipid nanoparticles at different dosages had a sufficient therapeutic efficacy [ 45 ]. However, the mRNA-lipid nanoparticle regimen rapidly decreased its therapeutic levels within 5–7 days post-treatment.…”

Section: Discussionmentioning

confidence: 99%

Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe3O4 Nanoparticles

et al. 2021

View full text Add to dashboard Cite

Hemophilia A is a bleeding disease caused by loss of coagulation factor VIII (FVIII) function. Although prophylactic FVIII infusion prevents abnormal bleeding, disability and joint damage in hemophilia patients are common. The cost of treatment is among the highest for a single disease, and the adverse effects of repeated infusion are still an issue that has not been addressed. In this study, we established a nonviral gene therapy strategy to treat FVIII knockout (FVIII KO) mice. A novel gene therapy approach was developed using dipalmitoylphosphatidylcholine formulated with iron oxide (DPPC-Fe3O4) to carry the B-domain-deleted (BDD)-FVIII plasmid, which was delivered into the FVIII KO mice via tail vein injection. Here, a liver-specific albumin promoter-driven BDD-FVIII plasmid was constructed, and the binding ability of circular DNA was confirmed to be more stable than that of linear DNA when combined with DPPC-Fe3O4 nanoparticles. The FVIII KO mice that received the DPPC-Fe3O4 plasmid complex were assessed by staining the ferric ion of DPPC-Fe3O4 nanoparticles with Prussian blue in liver tissue. The bleeding of the FVIII KO mice was improved in a few weeks, as shown by assessing the activated partial thromboplastin time (aPTT). Furthermore, no liver toxicity, thromboses, deaths, or persistent changes after nonviral gene therapy were found, as shown by serum liver indices and histopathology. The results suggest that this novel gene therapy can successfully improve hemostasis disorder in FVIII KO mice and might be a promising approach to treating hemophilia A patients in clinical settings.

show abstract

“…Moderna took a broader approach and targeted different genetic disease models including progressive familial intrahepactic cholestasis type 3 [98], citrin deficiency [99], hemophilia A [100], acute intermittent porphyria [101], Fabry disease [102], classic galactosemia [103], alpha 1-antitrypsin deficiency [104], and arginase deficiency [105]. From the several pre-clinical studies, Moderna advanced several programs into Phase 1 studies in 2019 through 2021, based on intravenous infusion of mRNA-LNP products, including mRNA-1944 (an LNP formulation of two mRNAs encoding the heavy and light chains of a human IgG antibody directed against Chikungunya virus) [106], mRNA-3927 (an LNP formulation of two mRNAs encoding the alpha and beta subunits of the mitochondrial enzyme propionyl-CoA carboxylase, a deficiency that leads to propionic acidemia characterized by recurring life-threatening metabolic decompensations and progressive multi-organ damage) [107], and mRNA-3705 (an LNP formulation of mRNA encoding methylmalonyl-CoA mutase, in which a deficiency leads to methylmalonic acidemia, a progressive and highly lethal disease characterized by episodes of metabolic decompensation) [108].…”

Section: Protein/enzyme Replacement Therapymentioning

confidence: 99%

Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

et al. 2022

View full text Add to dashboard Cite

The world raced to develop vaccines to protect against the rapid spread of SARS-CoV-2 infection upon the recognition of COVID-19 as a global pandemic. A broad spectrum of candidates was evaluated, with mRNA-based vaccines emerging as leaders due to how quickly they were available for emergency use while providing a high level of efficacy. As a modular technology, the mRNA-based vaccines benefitted from decades of advancements in both mRNA and delivery technology prior to the current global pandemic. The fundamental lessons of the utility of mRNA as a therapeutic were pioneered by Dr. Katalin Kariko and her colleagues, perhaps most notably in collaboration with Drew Weissman at University of Pennsylvania, and this foundational work paved the way for the development of the first ever mRNA-based therapeutic authorized for human use, COMIRNATY®. In this Special Issue of Pharmaceutics, we will be honoring Dr. Kariko for her great contributions to the mRNA technology to treat diseases with unmet needs. In this review article, we will focus on the delivery platform, the lipid nanoparticle (LNP) carrier, which allowed the potential of mRNA therapeutics to be realized. Similar to the mRNA technology, the development of LNP systems has been ongoing for decades before culminating in the success of the first clinically approved siRNA-LNP product, ONPATTRO®, a treatment for an otherwise fatal genetic disease called transthyretin amyloidosis. Lessons learned from the siRNA-LNP experience enabled the translation into the mRNA platform with the eventual authorization and approval of the mRNA-LNP vaccines against COVID-19. This marks the beginning of mRNA-LNP as a pharmaceutical option to treat genetic diseases.

show abstract

Treatment of Hemophilia A Using Factor VIII Messenger RNA Lipid Nanoparticles

Cited by 55 publications

References 62 publications

Lipid nanoparticles for mRNA delivery

Lipid nanoparticles for mRNA delivery

Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe3O4 Nanoparticles

Lipid Nanoparticle Delivery Systems to Enable mRNA-Based Therapeutics

Contact Info

Product

Resources

About