Improved treatment feasibility in children with hemophilia using arteriovenous fistulae: the results after seven years of follow-up

Mancuso, Maria Elisa; Berardinelli, L; Beretta, Claudio; Raiteri, M.; Pozzoli, E; Santagostino, Elena

doi:10.3324/haematol.2008.001594

Cited by 26 publications

(56 citation statements)

References 18 publications

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“…For the purpose of this analysis, we have included only the 115 patients enrolled and randomized who had actually started ITI (58 LD; 57 HD). The median age of subjects at start of ITI was 15.5 months (IQR [11][12][13][14][15][16][17][18][19][20][21][22][23][24]. The demographics of this group of patients are described in the primary report [19].…”

Section: Resultsmentioning

confidence: 99%

Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study

et al. 2015

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Section: Resultsmentioning

confidence: 99%

Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study

et al. 2015

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“…Current standard of care requires frequent (two to three times per week) i.v. dosing with plasma-derived or recombinant FIX protein and carries significant risk of side effects, including allergic and anaphylactic responses, infection, and sepsis (7,9,11). Whereas the recombinant purified protein is safer than the plasma-derived concentrates or cryoprecipitates in terms of the risk of blood-borne infections, and so forth, it is expensive and often in limited supply.…”

Section: Discussionmentioning

confidence: 99%

“…This means that patients on prophylactic treatment plans require indwelling venous ports and are at risk for developing infection, sepsis, and thrombosis. Patients may also experience an anaphylactic reaction to recombinant or plasma-derived FIX and can commonly develop antibodies that prevent the injected FIX proteins from forming clots (7,11).…”

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confidence: 99%

Systemic delivery of factor IX messenger RNA for protein replacement therapy

Ramaswamy

Tonnu

Tachikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

249

209

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Safe and efficient delivery of messenger RNAs for protein replacement therapies offers great promise but remains challenging. In this report, we demonstrate systemic, in vivo, nonviral mRNA delivery through lipid nanoparticles (LNPs) to treat a Factor IX (FIX)-deficient mouse model of hemophilia B. Delivery of human FIX (hFIX) mRNA encapsulated in our LUNAR LNPs results in a rapid pulse of FIX protein (within 4-6 h) that remains stable for up to 4-6 d and is therapeutically effective, like the recombinant human factor IX protein (rhFIX) that is the current standard of care. Extensive cytokine and liver enzyme profiling showed that repeated administration of the mRNA-LUNAR complex does not cause any adverse innate or adaptive immune responses in immune-competent, hemophilic mice. The levels of hFIX protein that were produced also remained consistent during repeated administrations. These results suggest that delivery of long mRNAs is a viable therapeutic alternative for many clotting disorders and for other hepatic diseases where recombinant proteins may be unaffordable or unsuitable.lipid nanoparticles | nonviral mRNA delivery | hemophilia B therapy | systemic delivery | hepatic diseases A berrant gene expression is the underlying cause for many pathologies and restoring the normal state by targeting genes through expression or knockdown is conceptually a simple solution (1). RNA-based therapeutics have some inherent advantages over DNA and viral vectors but their therapeutic use has been plagued by problems of poor translatability, lack of stability, inefficient delivery, and adverse immune reactions. Incremental improvements (5′ caps, codon optimization, use of optimized 5′ and 3′ UTRs, poly(A) modifications, modified nucleosides like 5-methyl cytosine (5MC), pseudouridine and 2 thio-UTP, etc.) have substantially improved the stability and translatability of RNAs while also making them immunologically silent. Furthermore, lipid nanoparticles (LNPs) have been developed as a nonviral option to encapsulate and deliver nucleic acids in vivo.Efficient in vivo delivery, however, has long been a major challenge because currently available LNPs can induce liver damage and stimulate an immune response (2). Lipid nanoparticles typically comprise four different lipids-an ionizable lipid, a neutral helper lipid, cholesterol, and a diffusible polyethylene glycol (PEG) lipid. When formulated into LNPs, these amine-containing ionizable lipids electrostatically complex with the negatively charged RNA to facilitate cellular uptake. These improvements have resulted in increasing use of small interfering RNA (siRNAs) as a potential therapeutic for systemic in vivo delivery to treat diseases like transthyretin amyloidosis, hepatitis B virus, hypercholesterolemia, cancer, and so forth (Arbutus, Alnylam Pharmaceuticals, Quark Pharmaceuticals, Allergan, Calando Pharmaceuticals, and others) (3). However, obvious differences between mRNAs and siRNAs in terms of length, stability, charge density, and so forth, make the synthesis, packa...

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“…14 As a result, such treatments are not readily available worldwide, and without treatment the median life expectancy of a hemophilia B patient drops to 11 years. 3 Therefore, a non-invasive alternative is highly desirable to overcome such limitations and promote the global availability of hemophilia treatment.…”

Section: Introductionmentioning

confidence: 99%

Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX

Horava

Peppas

2016

Ann Biomed Eng

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The oral administration of hematological factor IX can offer a convenient prophylactic treatment for hemophilia B patients. pH-Responsive hydrogels based on poly(methacrylic acid)-grafted-poly(ethylene glycol) (P(MAA-g-EG)) have been engineered as delivery vehicles for factor IX. In oral delivery, such hydrogel carriers protected factor IX from the gastric environment and released it under intestinal conditions as demonstrated by evaluation of the loading and release of factor IX. Tailoring of the hydrogel networks improved the loading of factor IX within the microcarriers, which is critical for minimizing protein degradation. Optimizing the loading conditions by increasing the incubation time and using a reduced ionic strength buffer further improved the delivery potential of the microcarriers. The presence of the microcarriers significantly enhanced the oral absorption of factor IX in vitro. As shown in this work, P(MAA-g-EG) microcarriers are promising candidates for the oral delivery of factor IX.

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Improved treatment feasibility in children with hemophilia using arteriovenous fistulae: the results after seven years of follow-up

Cited by 26 publications

References 18 publications

Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study

Central venous access device (CVAD) complications in Haemophilia with inhibitors undergoing immune tolerance induction: Lessons from the international immune tolerance study

Systemic delivery of factor IX messenger RNA for protein replacement therapy

Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX

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