What is the name of the study?

a combined phase 1 and 2 study that involved serotype 2–based AAV vectors (AAV2) showed only transient expression of FIX and suggested that stable expression of therapeutic levels of FIX may be limited by a capsid-specific cytotoxic T-cell response against the transduced hepatocytes.

What is the name of the vector?

These self-complementary AAV (scAAV) vectors mediate transgene expression at substantially higher levels than do single-stranded AAV vectors.

What is the cost of FIX treatment?

this treatment is prophylactic rather than curative, is extremely expensive, and is associated with inhibitor formation.

What is the name of the FIXco expression cassette?

the authors developed a codon-optimized FIX (FIXco) expression cassette that is packaged as complementary dimers within a single virion.

Open AccessJournal Article10.1056/NEJMOA1108046

Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

Q: What have the authors contributed in "Adenovirus-associated virus vector–mediated gene transfer in hemophilia b" ?

In this paper, the authors proposed a new approach to treat severe hemophilia B using AAV trans-optimization.

Q: What are the future works mentioned in the paper "Adenovirus-associated virus vector–mediated gene transfer in hemophilia b" ?

6,10 Second, to circumvent the possibility of humoral immunity to AAV, the authors pseudotyped these vectors with a capsid of serotype 8 ( AAV8 ), which has a lower seroprevalence in humans than does AAV2.

Q: What is the name of the article?

Somatic gene therapy for hemophilia B offers the potential for a cure through continuous endogenous production of FIX after a single administration of vector, especially since a small rise in circulating FIX to at least 1% of normal levels can substantially ameliorate the bleeding phenotype.

Q: What is the name of the author?

Persons with severe hemophilia B have functional FIX levels that are less than 1% of normal values and have frequent bleeding episodes, which are associated with crippling arthropathy and early death.

Q: What was the effect of the vector on the blood?

Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.

Q: How many participants were enrolled in each cohort?

Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group.

Q: What was the dose of vector in the peripheral blood of the patients with severe hemophilia?

The authors infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values).

Amit C. Nathwani, +31 more

- 21 Dec 2011

- The New England Journal of Medicine

- Vol. 365, Iss: 25, pp 2357-2365

1.8K

TL;DR: Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects.

Abstract: Background Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. Methods We infused a single dose of a serotype-8–pseudotyped, self-complementary adeno virus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. Results AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. Conclusions Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.)

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Most frequently asked questions

1. What have the authors contributed in "Adenovirus-associated virus vector–mediated gene transfer in hemophilia b" ?

In this paper, the authors proposed a new approach to treat severe hemophilia B using AAV trans-optimization.

2. What are the future works mentioned in the paper "Adenovirus-associated virus vector–mediated gene transfer in hemophilia b" ?

6,10 Second, to circumvent the possibility of humoral immunity to AAV, the authors pseudotyped these vectors with a capsid of serotype 8 ( AAV8 ), which has a lower seroprevalence in humans than does AAV2.

3. What is the name of the article?

Somatic gene therapy for hemophilia B offers the potential for a cure through continuous endogenous production of FIX after a single administration of vector, especially since a small rise in circulating FIX to at least 1% of normal levels can substantially ameliorate the bleeding phenotype.

4. What is the name of the author?

Persons with severe hemophilia B have functional FIX levels that are less than 1% of normal values and have frequent bleeding episodes, which are associated with crippling arthropathy and early death.

Citations

•Journal Article•10.1208/s12248-023-00814-5

Evaluation of Cellular Immune Response to Adeno-Associated Virus-Based Gene Therapy

Boris Gorovits, +14 more

- 26 Apr 2023

- Aaps Journal

TL;DR: In this paper , the authors provide recommendations and guidance to the industry sponsors, academic laboratories, and regulatory agencies working on AAV-based GTx viral vector modalities with the goal of achieving a more consistent approach to anti-AAV cellular immune response assessment.

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•Journal Article•10.1002/RTH2.12586

The intersection of vector biology, gene therapy, and hemophilia

Leszek Lisowski, +4 more

- 01 Aug 2021

TL;DR: A review of vector biology in the context of recombinant adeno-associated viral (rAAV)-based liver-directed gene therapy for hemophilia is presented in this article.

...read moreread less

•Journal Article•10.1089/HUM.2018.233

Optimization of Dexamethasone Administration for Maintaining Global Transduction Efficacy of Adeno-Associated Virus Serotype 9

Zheng Chai, +6 more

- 16 Jul 2019

- Human Gene Therapy

TL;DR: Investigation of the impact of dexamethasone on AAV vascular permeability after systemic injection and kinetics of AAV virus clearance indicate that dexamETHasone is able to inhibit the vascular permeable of Aav and compromise the therapeutic effect after systemic administration of A AV vector.

...read moreread less

•Journal Article•10.1038/CTI.2016.53

The CD8 T-cell response during tolerance induction in liver transplantation.

Yik Chun Wong, +3 more

- 01 Oct 2016

- Clinical And Translational Immunology

TL;DR: This work discusses how alloreactive cytotoxic T‐cell responses are generated against allografts, before reviewing how the liver parenchyma, donor passenger leucocytes and the host immune system function together to attenuate allore active CD8 T‐ cell responses to promote the long‐term survival of liver transplants.

...read moreread less

•Journal Article•10.2147/JBM.S84597

Once-weekly prophylactic dosing of recombinant factor IX improves adherence in hemophilia B.

Claudia Djambas Khayat

- 30 Nov 2016

- Journal of Blood Medicine

TL;DR: Data indicate that the distribution of FIX into an extravascular FIX compartment may contribute to hemostasis independently of circulating plasma FIX levels, and it would be of interest to investigate the efficacy of lower doses of the drug administered once a week.

...read moreread less

...

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References

Journal Article•10.1038/NM1358

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

Catherine S. Manno, +32 more

- 12 Feb 2006

- Nature Medicine

TL;DR: In this article, a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B.

...read moreread less

2.1K

•Journal Article•10.1073/PNAS.182412299

Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy

Guangping Gao, +5 more

- 03 Sep 2002

- Proceedings of the National Academy of S...

TL;DR: Vectors based on AAV7 and AAV8 should be considered for human gene therapy because of low reactivity to antibodies directed to human AAVs and because gene transfer efficiency in muscle was similar to that obtained with the best known serotype, whereas, in liver, gene transfer was substantially higher than previously described.

...read moreread less

1.7K

•Journal Article•10.1086/595830

Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses

Roberto Calcedo, +4 more

- 01 Feb 2009

- The Journal of Infectious Diseases

TL;DR: The data indicate a strong linkage of seroreactivity between apparently distinct serotypes that has not been predicted previously in animal models and a strong link between neutralizing antibodies to AAV and AAVrh32.

...read moreread less

803

Journal Article•10.1038/NM1549

CD8(+) T-cell responses to adeno-associated virus capsid in humans.

Federico Mingozzi, +17 more

- 01 Apr 2007

- Nature Medicine

TL;DR: It is shown that healthy subjects carry AAV capsid–specific CD8+ T cells and that AAV-mediated gene transfer results in their expansion, and that no such expansion occurs in mice after A AV- mediated gene transfer.

...read moreread less

730

•Journal Article•10.1056/NEJMOA1000228

Dystrophin Immunity in Duchenne's Muscular Dystrophy

Jerry R. Mendell, +22 more

- 07 Oct 2010

- The New England Journal of Medicine

TL;DR: The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for Duchenne's muscular dystrophy.

...read moreread less

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Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

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Most frequently asked questions

1. What have the authors contributed in "Adenovirus-associated virus vector–mediated gene transfer in hemophilia b" ?

2. What are the future works mentioned in the paper "Adenovirus-associated virus vector–mediated gene transfer in hemophilia b" ?

3. What is the name of the article?

4. What is the name of the author?

5. What is the way to treat hemophilia B?

6. What was the effect of the vector on the blood?

7. What is the name of the study?

8. How many participants were enrolled in each cohort?

9. What is the name of the vector?

10. What was the dose of vector in the peripheral blood of the patients with severe hemophilia?

11. What was the cause of the increase in serum aminotransferase levels?

12. What is the cost of FIX treatment?

13. What is the name of the FIXco expression cassette?

Citations

Evaluation of Cellular Immune Response to Adeno-Associated Virus-Based Gene Therapy

The intersection of vector biology, gene therapy, and hemophilia

Optimization of Dexamethasone Administration for Maintaining Global Transduction Efficacy of Adeno-Associated Virus Serotype 9

The CD8 T-cell response during tolerance induction in liver transplantation.

Once-weekly prophylactic dosing of recombinant factor IX improves adherence in hemophilia B.

References

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy

Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses

CD8(+) T-cell responses to adeno-associated virus capsid in humans.

Dystrophin Immunity in Duchenne's Muscular Dystrophy

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