In Utero Gene Therapy Consensus Statement from the IFeTIS

Almeida-Porada, Graça; Waddington, Simon; Chan, Jerry Ky; Peranteau, William H.; MacKenzie, Tippi C.; Porada, Christopher D.

doi:10.1016/j.ymthe.2019.02.015

Cited by 34 publications

(50 citation statements)

References 11 publications

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“…Such analyses are particularly important when integrating vectors are used with the goal of achieving lifelong correction following a single intervention. For instance, prenatal treatment (PNTx) for HA 42,52 could induce lifelong tolerance to FVIII and thereby eliminate the risk of inhibitor formation, the most feared problem in treatment/management of HA. Although direct injection of viral vectors into prenatal recipients would likely be successful, numerous safety concerns need to be addressed before the direct injection of viral vectors into prenatal recipients is clinically possible.…”

Section: Discussionmentioning

confidence: 99%

Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A

El-Akabawy

Rodriguez

Ramamurthy

et al. 2020

Molecular Therapy - Methods & Clinical Development

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The delivery of factor VIII (FVIII) through gene and/or cellular platforms has emerged as a promising hemophilia A treatment. Herein, we investigated the suitability of human placental cells (PLCs) as delivery vehicles for FVIII and determined an optimal FVIII transgene to produce/secrete therapeutic FVIII levels from these cells. Using three PLC cell banks we demonstrated that PLCs constitutively secreted low levels of FVIII, suggesting their suitability as a transgenic FVIII production platform. Furthermore, PLCs significantly increased FVIII secretion after transduction with a lentiviral vector (LV) encoding a myeloid codon-optimized bioengineered FVIII containing high-expression elements from porcine FVIII. Importantly, transduced PLCs did not upregulate cellular stress or innate immunity molecules, demonstrating that after transduction and FVIII production/secretion, PLCs retained low immunogenicity and cell stress. When LV encoding five different bioengineered FVIII transgenes were compared for transduction efficiency, FVIII production, and secretion, data showed that PLCs transduced with LV encoding hybrid human/porcine FVIII transgenes secreted substantially higher levels of FVIII than did LV encoding B domain-deleted human FVIII. In addition, data showed that in PLCs, myeloid codon optimization is needed to increase FVIII secretion to therapeutic levels. These studies have identified an optimal combination of FVIII transgene and cell source to achieve clinically meaningful levels of secreted FVIII.

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Section: Discussionmentioning

confidence: 99%

Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A

El-Akabawy

Rodriguez

Ramamurthy

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…54,55 As with invasive fetal therapies, work in the field of fetal stem cell and gene therapies has progressed steadily, and gathered the necessary critical mass of investigators to initiate the creation of the International Fetal Transplantation and Immunology Society (IFeTIS). 56 Members of this group are now assessing the feasibility and effectiveness of fetal stem cell therapy in human phase I/II studies, including in utero transplantation with maternal haematopoetic stem cells for alpha thalassaemia major (NCT02986698) and mesenchymal stem cells for osteogenesis imperfecta (BOOSTB4, NCT03706482). First in human experiments with other minimally invasive or transplacental therapies, addressing directly the molecular basis of rare fetal disorders, have also been successfully applied in the past decade, including intra-amniotic injection of the recombinant receptor-binding domain of ectodysplasin A for X-linked hypohydrotic ectodermal dysplasia 57 or maternal administration of rapamycin which inhibits the upregulated m-Tor pathway in cardiac rhabdomyomas in fetal tuberous sclerosis.…”

Section: A Decade Of Fetal Therapymentioning

confidence: 99%

“…As with invasive fetal therapies, work in the field of fetal stem cell and gene therapies has progressed steadily, and gathered the necessary critical mass of investigators to initiate the creation of the International Fetal Transplantation and Immunology Society (IFeTIS) 56 . Members of this group are now assessing the feasibility and effectiveness of fetal stem cell therapy in human phase I/II studies, including in utero transplantation with maternal haematopoetic stem cells for alpha thalassaemia major (NCT02986698) and mesenchymal stem cells for osteogenesis imperfecta (BOOSTB4, NCT03706482).…”

Section: A Decade Of Fetal Therapymentioning

confidence: 99%

Right or wrong? Looking through the retrospectoscope to analyse predictions made a decade ago in prenatal diagnosis and fetal surgery

et al. 2020

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“…In this study, we aimed to assess the attitudes of an international cohort of patients and parents of patients with certain LSDs regarding fetal ERT. Since many groups are also performing preclinical studies of in utero gene therapy for LSDs [ 24 , 25 ], we also included questions on attitudes toward in utero gene therapy. We discuss our survey findings within the context of our phase 1 clinical trial for fetuses with certain LSDs and within the broader ELSI, including challenges around the extent to which in utero ERTs can offer socially inclusive treatment options in the context of the different healthcare systems around the world.…”

Section: Introductionmentioning

confidence: 99%

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

Schwab

Brown

Lianoglou

et al. 2022

Orphanet J Rare Dis

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Background Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood–brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies. Methods A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients’ demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression. Results The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13–9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43–6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18–5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27–6.46, p = 0.011). Conclusions Familiarity with postnatal ERT increased respondents’ likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT.

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In Utero Gene Therapy Consensus Statement from the IFeTIS

Cited by 34 publications

References 11 publications

Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A

Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A

Right or wrong? Looking through the retrospectoscope to analyse predictions made a decade ago in prenatal diagnosis and fetal surgery

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

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