AAV-based neonatal gene therapy for hemophilia A: long-term correction and avoidance of immune responses in mice
Open accessAbstract
Hemophilia A gene therapy has been hampered by immune responses to vector-associated antigens and by neutralizing antibodies or inhibitors against the factor VIII (FVIII) protein; these 'inhibitors' more commonly affect hemophilia A patients than those with hemophilia B. A gene replacement strategy beginning in the neonatal period may avoid the development of these immune responses and lead to prolonged expression with correction of phenotype, thereby avoiding long-term consequences. A serotype rh10 adeno-associated virus (AAV) was developed splitting the FVIII coding sequence into heavy and light chains with the chicken β-actin promoter/CMV enhancer for dual recombinant adeno-associated viral vector delivery. Virions of each FVIII chain were co-injected intravenously into mice on the second day of life. Mice express sustained levels of FVIII antigen ≥5% up to 22 months of life without development of antibodies against FVIII. Phenotypic correction was manifest in all AAV-FVIII-treated mice as demonstrated by functional assay and reduction in bleeding time. This study demonstrates the use of AAV in a gene replacement strategy in neonatal mice that establishes both long-term phenotypic correction of hemophilia A and lack of antibody development against FVIII in this disease model where AAV is administered shortly after birth. These studies support the consideration of gene replacement therapy for diseases that are diagnosed in utero or in the early neonatal period.
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A similar dual-vector strategy demonstrated phenotypic correction of FVIII deficiency in a mouse model of hemophilia A.
“Hu and Lipshutz used a similar dual-vector strategy to demonstrate phenotypic correction of FVIII deficiency in a mouse model of hemophilia A. 39”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [39]
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“10 vectors have been highly efficient in delivering coagulation factor (F) VIII at either lower doses (FVIII levels ∼5% at 2 × 1012 vg/kg) or higher doses (FVIII levels ∼19% at 7 × 1012 vg/kg) without any evidence of immuno-toxicity until ∼22 months after gene transfer (Hu and Lipshutz, 2012).”
BackgroundMethodCantero, G., Liu, X.-B., Mervis, R., Lázaro, M., Cederbaum, S., Golshani, P., & Lipshutz, G. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0897-16.2016 · Cited by 18 · see citing works
“, 2015a) and therapeutic genes (Hu et al., 2011, 2014; Hu and Lipshutz, 2012; Lee et al., 2012, 2013) shows that such neonatal interventions in mice can lead to both long-term expression and alteration of phenotype.”
BackgroundSelf-citationHu, C.-H., Tai, D. S., Park, H., Cantero-Nieto, G., Chan, E., Yudkoff, M., Cederbaum, S., & Lipshutz, G. (2014) · Gene Therapy · doi:10.1038/gt.2014.106 · Cited by 17 · see citing works
Self-citationCurrent and Emerging Issues in Adeno-Associated Virus Vector-Mediated Liver-Directed Gene Therapy
Piccolo, P., & Brunetti‐Pierri, N. (2024) · Human Gene Therapy · doi:10.1089/hum.2024.179 · Cited by 14 · see citing works
“76,77 81 At one and fi ve weeks post-injection into 1-week-old rhesus macaques, hepatic AAV vector genome content and transduced cells decreased by 20-and 100-fold, respectively.”
Khoja, S., Lambert, J., Nitzahn, M., Eliav, A., Zhang, Y.-C., Tamboline, M., Le, C., Nasser, E., Li, Y.-F., Patel, P., et al. (2022) · Molecular Therapy: Methods & Clinical Development · doi:10.1016/j.omtm.2022.03.015 · Cited by 13
Self-citationTai, D. S., Hu, C., Kim, E. H., & Lipshutz, G. S. (2015) · Pediatric Research · doi:10.1038/pr.2015.109 · Cited by 10 · see citing works
“muscle (8)) may determine whether substantial persistent expression remains as cells and tissues grow and divide in this period of rapid cellular proliferation of the neonate; hepatic loss of episomal AAV results in a substantial expression decline in mice during the first several weeks of life (6) and this loss can a…”
BackgroundMethodInfluentialSelf-citationUltrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in mice
Song, S., Lyle, M. J., Noble-Vranish, M. L., Tran, D. M., Harrang, J., Xiao, W., Unger, E. C., & Miao, C. H. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.01.006 · Cited by 17 · see citing works
Li, M., Chen, J.-S., Liu, Y., Zhao, J., Li, Y.-J., Hu, Y., Chen, Y., Sun, L.-T., Shu, Y., Feng, F., et al. (2022) · Antiviral Research · doi:10.1016/j.antiviral.2022.105383 · Cited by 10 · see citing works
“Compared with other viral vectors, recombinant AAV has been shown as one of the most promising vectors for therapeutic gene delivery, and its efficacy has been demonstrated in extensive clinical trials, ranging from hemophilia B38 to Parkinson’s disease (Hu and Lipshutz, 2012; Colella et al., 2018; Ferreira et al., 20…”
Tai, D. S., Hu, C., Lee, C. C. I., Martinez, M. L., Cantero, G., Kim, E. H., Tarantal, A. F., & Lipshutz, G. S. (2015) · Gene Therapy · doi:10.1038/gt.2015.65 · Cited by 11 · see citing works
Self-citationEscape or Fight: Inhibitors in Hemophilia A
Merlin, S., & Follenzi, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00476 · Cited by 12 · see citing works
Lundgren, T. S., Denning, G., Stowell, S. R., Spencer, H. T., & Doering, C. B. (2022) · Blood Advances · doi:10.1182/bloodadvances.2021006359 · Cited by 10 · see citing works
Zhu, Y., Li, C., Wan, X., Yang, Q., Xie, G. S., & Huang, J. (2019) · Journal of Invertebrate Pathology · doi:10.1016/j.jip.2019.107231 · Cited by 12 · see citing works
Iizuka, S., Sakurai, F., Tachibana, M., Ohashi, K., & Mizuguchi, H. (2017) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2017.07.001 · Cited by 8 · see citing works
“Among the various viral vectors used in the clinical and preclinical studies, AAV vectors are often used for in vivo gene therapy for hemophilia B and other inherited genetic disorders because of their superior transduction profiles.(2,10,11,28,29) Although AAV vectors are favorable for in vivo gene therapy, they poss…”
BackgroundGene Therapy for Hemophilia A: Where We Stand
Zhou, M., Hu, Z., Zhang, C., Wu, L., Li, Z., & Liang, D. (2020) · Current Gene Therapy · doi:10.2174/1566523220666200806110849 · Cited by 8 · see citing works
Evaluation of Transduction Properties of an Adenovirus Vector in Neonatal Mice
Iizuka, S., Sakurai, F., Shimizu, K., Ohashi, K., Nakamura, S.-I., Tachibana, M., & Mizuguchi, H. (2015) · BioMed Research International · doi:10.1155/2015/685374 · Cited by 7
“Numerous gene therapy trials have been conducted using animal model of neonatal disease and viral vectors, such as adeno-associated virus [3], retrovirus [4], and a lentivirus vectors [5].”
Sharma, S., Joshi, V., & Kumar, V. (2025) · Clinical and Translational Neuroscience · doi:10.3390/ctn9030032 · Cited by 7 · see citing works
“While lentiviral vectors have primarily been used for ex vivo gene transfer [6], AAV vectors have demonstrated substantial success in in-vivo gene therapy applications [7,8].”
Lyu, P., Yadav, M. K., Yoo, K., Jiang, C., Li, Q.-Q., Atala, A., & Lu, B. (2024) · Gene Therapy · doi:10.1038/s41434-024-00490-w · Cited by 5 · see citing works
New technologies in gene therapy for inducing immune tolerance in hemophilia A
Borsotti, C., & Follenzi, A. (2018) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2018.1539667 · Cited by 5 · see citing works
“For testing the feasibility of this therapeutic approach in pediatric patients, newborn hemophilic mice were treated with AAV carrying FVIII on day two after birth [35].”
MethodDemasi, M. A. A., Molina, E. D. S., Bowman-Colin, C., Lojudice, F. H., Muras, A. G., & Sogayar, M. C. (2016) · Molecular Biotechnology · doi:10.1007/s12033-016-9939-9 · Cited by 6 · see citing works
Outcomes of progranulin gene therapy in the retina are dependent on time and route of delivery
Zin, E. A., Han, D., Tran, J., Morrison‐Welch, N., Visel, M., Kuronen, M., & Flannery, J. G. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.05.009 · Cited by 5 · see citing works
“While it has been shown that systemic injections with AAV9 in neonatal mice leads to the production of anti-AAV9 antibodies, another study has reported that systemic delivery to neonatal mice (P2) does not lead to the production of antibodies against their transduced protein of interest (factor VIII protein expressed…”
BackgroundSobhanimonfared, F., Bamdad, T., Sadigh, Z., Nikoo, H. R., & Choobin, H. (2018) · Acta virologica · doi:10.4149/av_2018_407 · Cited by 4
“…sense RNA virus belonging to the Rabdoviridae family, that quickly replicates and shows an effective oncolytic potential in a variety of tumors in pre-clinical models (Hastie and Grdzelishvili, 2012; Hu and Lipshutz, 2012; Shinozaki et al., 2005; Stan- ford et al., 2010; Yamaki et al., 2013).”
BackgroundRecent Advances in In Vivo Somatic Cell Gene Modification in Newborn Pups
Nakamura, S., Morohoshi, K., Inada, E., Sato, Y., Watanabe, S., Saitoh, I., & Sato, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015301 · Cited by 3 · see citing works
“To date, numerous gene therapy trials have been conducted using neonates and viral vectors such as AAV-[66,70,77], RV-[67,68], LV-[71,95], and AD-based vectors [69], as well as non-viral vectors [58], via the facial veins of neonatal mice.”
BackgroundNeonatal Gene Therapy for Inherited Disorders
Miyake, K., Miyake, N., & Shimada, T. (2018) · InTech eBooks · doi:10.5772/intechopen.69218 · Cited by 1 · see citing works
In Vivo Selection of S/MAR Sequences to Favour AAV Episomal Maintenance in Dividing Cells
Llanos-Ardaiz, A., Lantero, A., Neri, L., Mauleón, I., de Galarreta, M. R., Trigueros‐Motos, L., Weber, N. D., Ferrer, V., Aldabe, R., & González‐Aseguinolaza, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312734 · Cited by 1 · see citing works
“However, one of the main limitations for the therapeutic use of AAV vectors for the treatment of genetic disorders at an early age is that due to their episomal nature, the genomes are lost upon cell division [2,43].”
Sustained Correction of Hereditary Antithrombin Deficiency in Mice by AAV8-Mediated Gene Delivery.
Tao, Y.-Y., Lu, H., Wu, T., Cai, Y.-H., Guo, J., Corral, J., Hu, Y., & Tang, L. V. (2026) · Arteriosclerosis, Thrombosis and Vascular Biology · doi:10.1161/atvbaha.126.324442
Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy
Geard, A. F., Massaro, G., Hughes, M. P., Arbuthnot, P. B., Waddington, S. N., & Rahim, A. A. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17050650
“Reports indicate that perinatal gene transfer has shown a reduced, or absent, immune response to the transgene protein or viral capsid following AAV administration [43,49–51]; however, this may depend on the capsid used and organ system of interest [52].”
- Authors
- Hu, C., & Lipshutz, G. S.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Lipshutz, G S
- ORCID
- Lipshutz, G S
- Venue
- Gene Therapy
- Published
- 2012-01-12
- Volume
- 19
- Issue
- 12
- Pages
- 1166-1176
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC3432168
- OpenAlex
- W2004480433
- Cited by
- 48
- References
- 69
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 4 · 2012: 3
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS071076)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (3KO8HD057555-03S1, K08HD057555)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- 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
- Keywords
- hemophilia A, neonatal gene therapy, factor VIII, gene replacement, factor VIII inhibitors, neutralizing antibodies, bleeding time, mouse model
- MeSH terms
- Dependovirus, Animals, Animals, Newborn, Antibodies, Viral, Factor VIII, Genetic Vectors, Hemophilia A, Genetic Therapy, Mice, Antibodies, Neutralizing
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