Fetal gene therapy: recent advances and current challenges

Mattar, Citra Nurfarah Zaini; Choolani, Mahesh; Biswas, Arijit; Waddington, Simon N.; Chan, Jerry Kok Yen

doi:10.1517/14712598.2011.585153

Cited by 20 publications

(12 citation statements)

References 121 publications

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“…We have recently demonstrated that global nervous system transduction can be achieved after in utero intravenous administration of this vector in fetal mice and late‐gestation NHPs (8, 9). Considering the potential benefits of fetal therapy from the perspectives of the recipient and the burden on vector production, perinatal gene delivery is a suitable strategy for treating diseases when irreversible pathology begins in utero or at birth and for conditions affecting growth and development (10).…”

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confidence: 99%

Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates

et al. 2015

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Several acute monogenic diseases affect multiple body systems, causing death in childhood. The development of novel therapies for such conditions is challenging. However, improvements in gene delivery technology mean that gene therapy has the potential to treat such disorders. We evaluated the ability of the AAV9 vector to mediate systemic gene delivery after intravenous administration to perinatal mice and late-gestation nonhuman primates (NHPs). Titer-matched single-stranded (ss) and self-complementary (sc) AAV9 carrying the green fluorescent protein (GFP) reporter gene were intravenously administered to fetal and neonatal mice, with noninjected age-matched mice used as the control. Extensive GFP expression was observed in organs throughout the body, with the epithelial and muscle cells being particularly well transduced. ssAAV9 carrying the WPRE sequence mediated significantly more gene expression than its sc counterpart, which lacked the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) sequence. To examine a realistic scale-up to larger models or potentially patients for such an approach, AAV9 was intravenously administered to late-gestation NHPs by using a clinically relevant protocol. Widespread systemic gene expression was measured throughout the body, with cellular tropisms similar to those observed in the mouse studies and no observable adverse events. This study confirms that AAV9 can safely mediate systemic gene delivery in small and large animal models and supports its potential use in clinical systemic gene therapy protocols.—Mattar, C. N., Wong, A. M. S., Hoefer, K., Alonso-Ferrero, M. E., Buckley, S. M. K., Howe, S. J., Cooper, J. D., Waddington, S. N., Chan, J. K. Y., Rahim, A. A. Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates.

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confidence: 99%

Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates

et al. 2015

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“…Multiple outstanding reviews have been written over the last decade, discussing IUGT in detail. 2 , 16 , 25 , 89 , 147–155 For this reason, we will endeavor to highlight some of the key advantages and risks to this, as yet, experimental therapeutic approach, focusing on the utility of this treatment modality for correcting hemophilia A (HA). It is important to note that many genetic diseases exert a significant amount of irreversible damage during embryonic and fetal development.…”

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confidence: 99%

In utero stem cell transplantation and gene therapy: rationale, history, and recent advances toward clinical application

Almeida-Porada

Atala

Porada

2016

Molecular Therapy - Methods & Clinical Development

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Recent advances in high-throughput molecular testing have made it possible to diagnose most genetic disorders relatively early in gestation with minimal risk to the fetus. These advances should soon allow widespread prenatal screening for the majority of human genetic diseases, opening the door to the possibility of treatment/correction prior to birth. In addition to the obvious psychological and financial benefits of curing a disease in utero, and thereby enabling the birth of a healthy infant, there are multiple biological advantages unique to fetal development, which provide compelling rationale for performing potentially curative treatments, such as stem cell transplantation or gene therapy, prior to birth. Herein, we briefly review the fields of in utero transplantation (IUTx) and in utero gene therapy and discuss the biological hurdles that have thus far restricted success of IUTx to patients with immunodeficiencies. We then highlight several recent experimental breakthroughs in immunology, hematopoietic/marrow ontogeny, and in utero cell delivery, which have collectively provided means of overcoming these barriers, thus setting the stage for clinical application of these highly promising therapies in the near future.

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“…Fetal gene therapy is inherently flawed as the potential detrimental phenotypic effects of any genetic mutation, be it at the chromosomal or molecular level, have already occurred in the embryonic period. Albeit with some minor success, in utero treatment has been applied to fetuses at risk for a number of genetic and congenital anomalies, including congenital diaphragmatic hernia, cystadenomatoid malformation of the lung and saccrococygeal teratoma, shunts for uropathies and thoracic fluids, pharmacological therapies for congenital adrenal hyperplasia and neural tube defect as well as stem cell treatment of severe combined immunodeficiency disorder [ 26 , 27 , 28 , 29 , 30 ]. The insights gained over the past decade with regard to stem cell biology as well as the ability to manipulate genetic sequences are two of an increasing number of technologies whereby there now are opportunities to alter the course of abnormal development during the critical time of embryogenesis, as summarized next.…”

Section: Introductionmentioning

confidence: 99%

“…This will be an especially arduous scientific journey, requiring novel technologies involving embryonic visualization [ 37 ], gene manipulations [ 33 ] and/or transplantation of genetically-altered mesenchymal stem cells [ 27 ], all with the goal to ameliorate potential physical and functional damage. It is anticipated that the first effective therapies would be applied to a collective group of monogenic disorders for the purpose of achieving phenotypic cure early in the disease process and before the development of permanent organ damage [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

The Future of Prenatal Diagnosis and Screening

Pergament

2014

JCM

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Fetal gene therapy: recent advances and current challenges

Abstract: Although there are valid safety and ethical concerns, the authors argue that there may soon be enough convincing evidence from non-human primate models to take the next step towards clinical trials in the near future.

Cited by 20 publications

References 121 publications

Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates

Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates

In utero stem cell transplantation and gene therapy: rationale, history, and recent advances toward clinical application

The Future of Prenatal Diagnosis and Screening

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