Gene Therapy for Hemophilia A: How Long Will It Last?

Schutgens, Roger E.G.

doi:10.1097/hs9.0000000000000720

Cited by 10 publications

(38 citation statements)

References 5 publications

(12 reference statements)

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“…37,38 We previously showed that a high-dose vector (1 × 10 13 vg/kg) could evade NAbs for liver transduction with AAV8 vector. 39 confirmed transduction with a lower vector dose (0.5 × 10 12 vg/kg) was inhibited by 1:1 Nab ratio even with an AAV5 vector (data not shown). Although NAbs induced by the first AAV5 abolished re-administration in this study, further investigation is required to determine whether the AAV5 capsid itself has the property to evade NAbs.…”

Section: Discussionmentioning

confidence: 60%

“…First, we assessed the transduction efficacy of AAV3B, AAV5, and AAV8 vectors harboring hFIX or secNanoLuc. We injected each AAV vector, intravenously, at the same dose (0.5 × 10 12 vg/kg) in C57Bl/6J mice, and transduction efficacy was determined by AAV genome in the liver. AAV8 vector enabled the transduction of AAV in the mouse liver when compared with AAV3B and AAV5 vectors (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

“…AAV3B, AAV5, or AAV8 vectors harboring human FIX or secNanoLuc were intravenously injected into mice (0.5 × 10 12 vg/kg). The serum and liver tissue were harvested 30 days after vector injection.…”

Section: Resultsmentioning

confidence: 99%

“…AAV5 and AAV8, which have been widely used in gene therapy with the liver as the target in clinical trials, and AAV3B, which reportedly possesses a high gene transfer efficiency to the human liver. 12,20,21…”

Section: Comparison Of the Capsid Amino Acid Sequence Among Aav Serot...mentioning

confidence: 99%

“…[9][10][11] Hence, most clinical trials of systemic administration of AAV vector have targeted only patients without NAbs against the AAV. [12][13][14] We have recently reported the prevalence of NAbs against several AAV serotypes in Japanese hemophiliacs and healthy individuals and found the prevalence to range from 20% to 30% in the parent population. 15 The administration of AAV vectors, in addition to natural infection with AAV, correspondingly induces a high titer of NAbs against the AAV vector.…”

Section: Introductionmentioning

confidence: 99%

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Successful Liver transduction by Re-administration of Different Adeno-Associated Virus Vector Serotypes in Mice

Baatartsogt

Kashiwakura

Hiramoto

et al. 2022

Preprint

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Intravenous administration of adeno-associated virus (AAV) vector is a promising gene therapy approach for monogenic diseases. However, re-administration of the same AAV serotype is impossible due to the induction of anti-AAV neutralizing antibodies (NAbs). Here we examined the feasibility of re-administration of AAV vectors to change the serotypes. We administered AAV3B, AAV5, or AAV8 vectors targeting the liver of C57BL/6 mice intravenously, and then assessed the emergence of NAbs and the transduction efficacy with a second administration. For all serotypes, we confirmed that re-administration with the same serotype was not possible. Although the highest neutralizing activity of NAb was induced by AAV5; however, the NAbs elicited by AAV5 did not react with any other serotypes, resulting in success in re-administration with the other serotypes. The re-administration of AAV5 was also successful in all mice treated with AAV3B and AAV8. The effective secondary administration of AAV3B and AAV8 was observed in most mice treated with AAV8 and AAV3B, respectively. However, few mice developed NAbs cross-reactive with the other serotypes, especially the serotypes with close sequence homology. In summary, AAV vector administration induced NAbs relatively specific to the serotype administrated. Secondary administration of AAVs targeting liver transduction could be successfully achieved by switching AAV serotypes in mice.

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Section: Discussionmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Comparison Of the Capsid Amino Acid Sequence Among Aav Serot...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Successful Liver transduction by Re-administration of Different Adeno-Associated Virus Vector Serotypes in Mice

Baatartsogt

Kashiwakura

Hiramoto

et al. 2022

Preprint

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Portal vein thrombosis in a patient with severe hemophilia B: A challenging balanced management

Benitez‐Hidalgo,

Suito Alcántara,

Martinez Garcia

et al. 2024

Clinical Case Reports

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Key Clinical MessageThe increased life expectancy in patients with hemophilia (PwH) over the last years has raised the incidence of comorbidities, including thromboembolic events. Thromboembolic events are rare in PwH and most of them occur in the presence of exogenous risk factors. There is still scarce scientific evidence on the optimal antithrombotic treatment and management approach in this population.AbstractIn the hemophilic population thromboembolic events are rare. Most of them are often multifactorial and occur in the presence of both exogenous (orthopedic surgery, intensive replacement therapy, use of central venous catheters…) and endogenous (cardiovascular diseases) risk factors. We describe the case of a 43‐year‐old patient with severe hemophilia B (sHB) receiving prophylaxis with eftrenonacog alfa (rFIXFc) and antithrombotic treatment due to portal vein thrombosis. The patient was treated with extended half‐ life factor IX (EHL‐FIX) prophylaxis maintaining higher trough levels to avoid new bleeding episodes associated to the underlying disease and the use of antithrombotic therapy with low molecular weight heparin. EHL‐FIX concentrates allow prolonged intervals between intravenous infusions and higher hemostatic protection thanks to increased factor trough levels. This current case report provides clinical evidence in antithrombotic management in a patient with severe hemophilia B.

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Successful liver transduction by re‐administration of different adeno‐associated virus vector serotypes in mice

Baatartsogt

Kashiwakura

Hiramoto

et al. 2023

The Journal of Gene Medicine

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Background Intravenous administration of adeno‐associated virus (AAV) vectors is a promising gene therapy approach for monogenic diseases. However, re‐administration of the same AAV serotype is impossible because of the induction of anti‐AAV neutralizing antibodies (NAbs). Here, we examined the feasibility of re‐administrating AAV vector serotypes different from the initial AAV vector serotype. Methods Liver‐targeting AAV3B, AAV5, and AAV8 vectors were intravenously injected in C57BL/6 mice, and the emergence of NAbs and the transduction efficacy following re‐administration were evaluated. Results For all serotypes, re‐administration of the same serotype was not possible. Although the highest neutralizing activity of NAb was induced by AAV5, anti‐AAV5 NAbs did not react with other serotypes, resulting in successful re‐administration with the other serotypes. AAV5 re‐administration was also successful in all mice treated with AAV3B and AAV8. Effective secondary administration of AAV3B and AAV8 was observed in most mice initially administrated AAV8 and AAV3B, respectively. However, few mice developed NAbs cross‐reacting with the other serotypes, especially those with close sequence homology. Conclusions In summary, AAV vector administration induced NAbs relatively specific to the administrated serotype. Secondary administration of AAVs targeting liver transduction could be successfully achieved by switching AAV serotypes in mice.

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Gene Therapy for Hemophilia A: How Long Will It Last?

Cited by 10 publications

References 5 publications

Successful Liver transduction by Re-administration of Different Adeno-Associated Virus Vector Serotypes in Mice

Successful Liver transduction by Re-administration of Different Adeno-Associated Virus Vector Serotypes in Mice

Portal vein thrombosis in a patient with severe hemophilia B: A challenging balanced management

Successful liver transduction by re‐administration of different adeno‐associated virus vector serotypes in mice

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