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Cited by 47Virus-based gene therapy researchRNA Interference and Gene DeliveryCRISPR and Genetic Engineering

The Future of In Utero Gene Therapy

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Peranteau, William H., Flake, Alan W.·2020·Molecular Diagnosis & Therapy
DOI 10.1007/s40291-020-00445-yPMC PMC9202471
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Abstract

Significant advances in the safety and efficacy of gene therapy have sparked a new frontier in therapeutics for genetic diseases as evidenced by the greater than 700 active gene therapy investigational new drug applications reported by the NIH and the US Food and Drug Association. Although postnatal gene therapy trials are encouraging, limitations to effective therapy including an immune barrier and initiation of treatment after disease onset can exist. Advances in prenatal diagnostics provide hope that many genetic abnormalities will be able to be diagnosed before birth. Prenatal gene therapy has the potential to take advantage of normal developmental properties of the fetus and overcome some of the current limitations to efficient postnatal gene therapy. The rationale for prenatal gene therapy includes the small fetal size, the tolerogenic fetal immune system, the presence of highly proliferative and accessible stem/progenitor cells of multiple organs, and, ultimately, the ability to treat diseases in which irreversible pathology begins prior to birth. This rationale is based on and supported by a number of published animal studies. Unique ethical considerations exist in the context of prenatal gene therapy, including the importance of rigorous evaluation of the effect of the therapy on fetal germ cells and developing organs as well as the mother. To date, animal studies have not demonstrated any significant germline or maternal effect of prenatal gene therapy. Finally, practical considerations of future clinical prenatal gene therapy will include, but not be limited to, determining the initial target disease characteristics and the importance of non-directive prenatal counseling of families carrying a fetus with a genetic diagnosis.

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  • For many genetic CNS diseases, pathology begins before birth and is difficult to reverse after onset, resulting in significant morbidity by the time of or shortly after birth.

    “Furthermore, the pathology of many genetic CNS diseases begins before birth and is difficult to reverse after onset resulting in significant morbidity by the time of or shortly after birth (3).”

    From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [3]

    The ‘In utero gene therapy: Rationale and supporting animal studies’ section says irreversible neurologic pathology begins before birth in neuronopathic Gaucher disease. The Conclusions also identify severe morbidity and irreversible early pathology as characteristics of potential target diseases. The paper does not establish that many genetic CNS diseases cause significant morbidity by birth or shortly afterward; it notes that a child can appear normal at birth despite fetal pathology. Page numbers were not available in our copy. (LLM, conf=0.84)

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  • Since congenital brain pathology often begins before birth, fetal intervention provides a therapeutic opportunity to mitigate irreversible disease burden.

    “Since congenital brain pathology often begins before birth, fetal intervention provides a therapeutic opportunity to mitigate irreversible disease burden (3).”

    From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [3]

    The ‘In utero gene therapy: Rationale and supporting animal studies’ section says irreversible neurologic pathology begins in utero in neuronopathic Gaucher disease and describes fetal gene therapy mitigating neuroinflammation and neurodegeneration in mice. This supports the therapeutic opportunity, but the paper does not establish that congenital brain pathology generally or often begins before birth. (LLM, conf=0.82)

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Research works printed but not linked: 36

  1. [1]Collins FS, Gottlieb S. The Next Phase of Human Gene-Therapy Oversight. N Engl J Med. 2018; 379(15): 1393– 5. 30110242 PMC6688383
  2. [2]Friszer S, Maisonneuve E, Mace G, Castaigne V, Cortey A, Mailloux A, Determination of optimal timing of serial in-utero transfusions in red-cell alloimmunization. Ultrasound Obstet Gynecol. 2015; 46(5): 600– 5. 25523966
  3. [3]McGovern N, Shin A, Low G, Low D, Duan K, Yao LJ, Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2. Nature. 2017; 546(7660): 662– 6. 28614294 PMC6588541
  4. [4]Calcedo R, Griesenbach U, Dorgan DJ, Soussi S, Boyd AC, Davies JC, Self-reactive CFTR T cells in humans: implications for gene therapy. Hum Gene Ther Clin Dev. 2013; 24(3): 108– 15. 23790242 PMC4003469
  5. [6]Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE, CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007; 13(4): 419– 22. 17369837
  6. [7]Flotte TR, Trapnell BC, Humphries M, Carey B, Calcedo R, Rouhani F, Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. Hum Gene Ther. 2011; 22(10): 1239– 47. 21609134 PMC3205788
  7. [8]Flotte TR, Zeitlin PL, Reynolds TC, Heald AE, Pedersen P, Beck S, Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum Gene Ther. 2003; 14(11): 1079– 88. 12885347
  8. [9]Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP, Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther. 2007; 18(8): 726– 32. 17685853
  9. [10]Riley JS, McClain LE, Stratigis JD, Coons BE, Li H, Hartman HA, Pre-Existing Maternal Antibodies Cause Rapid Prenatal Rejection of Allotransplants in the Mouse Model of In Utero Hematopoietic Cell Transplantation. J Immunol. 2018; 201(5): 1549– 57. 30021770 PMC6103848
  10. [11]Simister NE. Placental transport of immunoglobulin G. Vaccine. 2003; 21(24): 3365– 9. 12850341
  11. [13]Chan JKY, Gil-Farina I, Johana N, Rosales C, Tan YW, Ceiler J, Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques. FASEB J. 2019; 33(3): 3954– 67. 30517034 PMC6404563
  12. [14]Davey MG, Riley JS, Andrews A, Tyminski A, Limberis M, Pogoriler JE, Induction of Immune Tolerance to Foreign Protein via Adeno-Associated Viral Vector Gene Transfer in Mid-Gestation Fetal Sheep. PLoS One. 2017; 12(1): e0171132. 28141818 PMC5283730
  13. [15]Sabatino DE, Mackenzie TC, Peranteau W, Edmonson S, Campagnoli C, Liu YL, Persistent expression of hF.IX After tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice. Mol Ther. 2007; 15(9): 1677– 85. 17565352
  14. [16]Endo M, Henriques-Coelho T, Zoltick PW, Stitelman DH, Peranteau WH, Radu A, The developmental stage determines the distribution and duration of gene expression after early intra-amniotic gene transfer using lentiviral vectors. Gene Ther. 2010; 17(1): 61– 71. 19727133
  15. [17]Joyeux L, Danzer E, Limberis MP, Zoltick PW, Radu A, Flake AW, In utero lung gene transfer using adeno-associated viral and lentiviral vectors in mice. Hum Gene Ther Methods. 2014; 25(3): 197– 205. 24660751 PMC4060818
  16. [18]Stitelman DH, Brazelton T, Bora A, Traas J, Merianos D, Limberis M, Developmental stage determines efficiency of gene transfer to muscle satellite cells by in utero delivery of adeno-associated virus vector serotype 2/9. Mol Ther Methods Clin Dev. 2014; 1: 14040. 26015979 PMC4362369
  17. [19]Rahim AA, Wong AM, Ahmadi S, Hoefer K, Buckley SM, Hughes DA, In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression. Gene Ther. 2012; 19(9): 936– 46. 22071970
  18. [20]Mattar CN, Wong AM, Hoefer K, Alonso-Ferrero ME, Buckley SM, Howe SJ, Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates. FASEB J. 2015; 29(9): 3876– 88. 26062602 PMC4560173
  19. [21]Buckley SM, Waddington SN, Jezzard S, Lawrence L, Schneider H, Holder MV, Factors influencing adenovirus-mediated airway transduction in fetal mice. Mol Ther. 2005; 12(3): 484– 92. 16099411
  20. [23]Endo M, Zoltick PW, Radu A, Jiang Q, Matsui C, Marinkovich PM, Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa. Gene Ther. 2012; 19(5): 561– 9. 21938019 PMC6541916
  21. [24]Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis. 2017; 2(1-2): 1– 71. 29152458 PMC5685203
  22. [25]Massaro G, Mattar CNZ, Wong AMS, Sirka E, Buckley SMK, Herbert BR, Fetal gene therapy for neurodegenerative disease of infants. Nat Med. 2018; 24(9): 1317– 1323. 30013199 PMC6130799
  23. [26]Wert SE, Whitsett JA, Nogee LM. Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol. 2009; 12(4): 253– 74. 19220077 PMC2987676
  24. [27]Lin S, Staahl BT, Alla RK, Doudna JA. Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. Elife. 2014; 3: e04766. 25497837 PMC4383097
  25. [29]Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016; 533(7603): 420– 4. 27096365 PMC4873371
  26. [31]Huang TP, Zhao KT, Miller SM, Gaudelli NM, Oakes BL, Fellmann C, Circularly permuted and PAM-modified Cas9 variants broaden the targeting scope of base editors. Nat Biotechnol. 2019; 37(6): 626– 31. 31110355 PMC6551276
  27. [32]Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016; 351(6271): 400– 3. 26721683 PMC4760628
  28. [35]Yin H, Xue W, Chen S, Bogorad RL, Benedetti E, Grompe M, Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol. 2014; 32(6): 551– 3. 24681508 PMC4157757
  29. [36]Song CQ, Wang D, Jiang T, O’Connor K, Tang Q, Cai L, In vivo Genome Editing Partially Restores Alpha1-Antitrypsin in a Murine Model of AAT Deficiency. Hum Gene Ther. 2018; 29(8): 853– 860. 29597895 PMC6110121
  30. [37]Rossidis AC, Stratigis JD, Chadwick AC, Hartman HA, Ahn NJ, Li H, In utero CRISPR-mediated therapeutic editing of metabolic genes. Nat Med. 2018; 24(10): 1513– 8. 30297903 PMC6249685
  31. [38]Ricciardi AS, Bahal R, Farrelly JS, Quijano E, Bianchi AH, Luks VL, In utero nanoparticle delivery for site-specific genome editing. Nat Commun. 2018; 9(1): 2481. 29946143 PMC6018676
  32. [39]Bahal R, Ali McNeer N, Quijano E, Liu Y, Sulkowski P, Turchick A, In vivo correction of anaemia in beta-thalassemic mice by gammaPNA-mediated gene editing with nanoparticle delivery. Nat Commun. 2016; 7: 13304. 27782131 PMC5095181
  33. [40]Romero Z, DeWitt M, Walters MC. Promise of gene therapy to treat sickle cell disease. Expert Opin Biol Ther. 2018; 18(11): 1123– 36. 30324810
  34. [41]Loukogeorgakis SP, Shangaris P, Bertin E, Franzin C, Piccoli M, Pozzobon M, In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment. Stem Cells. 2019; 37(9): 1176– 88. 31116895 PMC6773206
  35. [42]Witt R, MacKenzie TC, Peranteau WH. Fetal stem cell and gene therapy. Semin Fetal Neonatal Med. 2017; 22(6): 410– 4. 28619624
  36. [45]Almeida-Porada G, Waddington SN, Chan JKY, Peranteau WH, MacKenzie T, Porada CD. In Utero Gene Therapy Consensus Statement from the IFeTIS. Mol Ther. 2019; 27(4): 705– 7. 30837116 PMC6453510

Cited by

Sorted by citations

Authors
Peranteau, W. H., & Flake, A. W.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Peranteau, William H.
ORCID
Venue
Molecular Diagnosis & Therapy
Publisher
Springer Science and Business Media LLC
Published
2020-02-04
Volume
24
Issue
2
Pages
135-142
ISSN
  • 1177-1062 (ISSN-L)
  • 1179-2000
DOI
10.1007/s40291-020-00445-y
PMC
PMC9202471
OpenAlex
W3004897733
Cited by
47
References
7
Citations by year
2026: 8 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 4
FWCI
0.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Diagnosis & Therapy (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (DP2HL152427)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
prenatal gene therapy, in utero gene therapy, fetal immune tolerance, maternal safety, prenatal diagnosis, genetic disorders, prenatal counseling
MeSH terms
Animals, Clinical Trials as Topic, Female, Fetal Diseases, Genetic Counseling, Humans, Pregnancy, Prenatal Diagnosis, Genetic Therapy, Genetic Predisposition to Disease, Biomedical Research

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