Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A

Pasi, K. J.; Laffan, Michael; Rangarajan, Savita; Robinson, Tara M.; Mitchell, Nina; Lester, Will; Symington, Emily; Madan, Bella; Yang, Xinqun; Kim, Benjamin; Pierce, Glenn F.; Wong, Wing Yen

doi:10.1111/hae.14391

Cited by 76 publications

(122 citation statements)

References 25 publications

(102 reference statements)

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“… 3 – 5 A single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) given at a dose of 6 × 10 13 vector genomes (vg) per kilogram body weight or 4 × 10 13 vg per kilogram body weight in 13 adults with severe hemophilia A produced clinically relevant FVIII levels and reductions in bleeding and exogenous FVIII usage 4 , with effects lasting for at least 5 or 4 years of follow-up, respectively. 5 , 6 The most common adverse event was transient, asymptomatic alanine aminotransferase (ALT) increases that resolved without clinical sequelae. 4 , 5 While multiyear expression of FVIII following a single infusion represents a substantial clinical leap forward, there are gaps in our understanding of the biological mechanisms that enable such expression.…”

Section: Mainmentioning

confidence: 99%

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A

Fong

Yates

Sihn

et al. 2022

Nat Med

Self Cite

View full text Add to dashboard Cite

Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial (NCT02576795), liver biopsy samples were collected 2.6–4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.

show abstract

Section: Mainmentioning

confidence: 99%

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A

Fong

Yates

Sihn

et al. 2022

Nat Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hepatic gene transfer of codon-optimized SQ-BDD-FVIII cDNA using AAV vectors has emerged as a promising therapeutic approach for HA (13,14). Substantial improvement in hemostasis was documented at a 5-yr follow-up (28). However, this gene therapy approach has encountered two major hurdles: 1) A requirement for very high vector doses to drive FVIII expression in hepatocytes; and 2) Declining therapeutic transgene expression over time accompanied with signs of liver damage, both of which may be directly linked to the fact that FVIII is retained and prone to misfolding in the ER during therapy (29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

“…Initial results appeared to be very successful, with correction of FVIII levels into the normal range during the first year (13,14). Substantial improvement in hemostasis was documented at a 5-yr follow-up (28). Unfortunately, elevated liver enzyme levels were observed in the first year, and FVIII expression levels gradually declined to the lower end of the therapeutic range, starting in the second year (29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Deng

Kapelanski-Lamoureux

Gao

et al. 2021

Preprint

View full text Add to dashboard Cite

Clotting Factor VIII (FVIII) is the protein deficient in hemophilia A (HA), an X chromosome-linked bleeding disorder affecting 24.6 per 100,000 males at birth. Scientists and clinical physicians have been striving hard to find a cure for this disease. Presently, HA therapy involves prophylactic infusion of plasma-derived or recombinant-derived FVIII. Recent clinical studies have reported success using recent adeno-associated-virus (AAV) vector mediated delivery of a FVIII gene. FVIII is a 330 kDa glycoprotein comprised of three domains (A1-A2-B-A3-C1-C2). The B domain is dispensable and B domain-deleted (BDD) FVIII is used in the clinic as an effective protein replacement therapy for HA. Previously, we observed that hydrodynamic tail vein injection of the BDD-FVIII vector resulted in FVIII aggregation and endoplasmic reticulum (ER) stress in murine livers. Additionally, mice that were exposed to transient ER stress and then fed a high fat diet (HFD) for 9 months developed hepatocellular carcinoma (HCC). Therefore, we deduced that ectopic transient expression of FVIII in hepatocytes of mice with subsequent HFD feeding may also develop HCC. Here, we tested hepatocyte expression of two BDD-FVIII variants in vivo. BDD-FVIII aggregates in the ER and induces hepatocyte apoptosis, and N6-FVIII is more efficiently folded and secreted from the ER and causes less hepatocyte apoptosis. We performed tail vein injections of vectors directing expression of BDD-FVIII or N6-BDD to hepatocytes of 6-week old mice. One week after injection, mice were fed 60% HFD for 65 weeks. We found that 50% of mice that received N6-BDD developed liver tumors; in contrast, 90% of mice given BDD-FVIII developed liver tumors. Of the mice injected with BDD-FVIII, 30% developed carcinomas and 60% developed adenomas. Similar masses were not observed in mice that received empty vector. These findings raise concerns about the safety of long-term ectopic expression of FVIII in hepatocytes during FVIII gene therapy

show abstract

“…While QoL has improved considerably with the advent of new therapies for PwH, including gene therapy for both haemophilia A and B, 11,12 the burden for patients and their families remains significant, and constant vigilance is required. O'Mahony et al indicate that the ultimate goal is to support a person's ability to 'forget' about their disease and focus on their life goals: education, family, career, and overall contribution to society.…”

Section: What Is the Value Of Innovation In Gene Therapy?mentioning

confidence: 99%

Section: What Is the Value Of Innovation In Gene Therapy?mentioning

confidence: 99%

Is the world ready for gene therapy?

Garrison

Kleinermans

2022

Haemophilia

View full text Add to dashboard Cite

KEY POINTS OF CONSIDERATION To prepare for the introduction of gene therapies in haemophilia care, healthcare frameworks for evaluation and valuation will need to evolve to address the unique requirements of current and future innovations for treating this rare disease. The papers in this supplement provide an insightful and comprehensive state‐of‐the‐art assessment of these requirements and challenges. In terms of evaluation, the definition of a patient‐defined value framework that captures multi‐dimensional, patient‐centered outcomes is an important first step for determining the full benefit of gene therapy for persons with haemophilia. In terms of valuation and rewards for innovation, health systems will need to develop alternative payment models for risk‐sharing that will allow payers and society to address uncertainties about the ultimate clinical and economic value of these innovations. And health technology assessment authorities will need to exercise greater flexibility in evidence requirements given the unique features of data collection for a potentially curative therapy for a rare disease with long‐term uncertainties about durability of impact. Collaboration among stakeholders will be essential for developing the critical evidence requirements and providing the incentives needed to achieve sustainable budgets and broad access for persons with haemophilia worldwide.

show abstract

Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A

Cited by 76 publications

References 25 publications

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A

Ectopic FVIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma

Is the world ready for gene therapy?

Contact Info

Product

Resources

About