Fetal and neonatal gene therapy: benefits and pitfalls

Waddington, Simon N.; Kennea, Nigel; Buckley, Smk; Gregory, Lisa G.; Themis, Michael; Coutelle, Charles

doi:10.1038/sj.gt.3302375

Cited by 42 publications

(31 citation statements)

References 67 publications

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“…Together, these data suggest that neonatal treatment offers many unique advantages, and that both early detection and treatment are essential for effective genetic therapy with this type of disease. Also, in the context that LINCL is not included in routine newborn genetic screens (Fletcher, 2006;Meikle et al, 2006;NNSGRC, 2008), together with observations from other investigators of the success of neonatal gene transfer (Bostick et al, 2007;Broekman et al, 2007;Daly et al, 1999;Griffey et al, 2006;Li and Daly2002;Passini et al, 2003;Passini and Wolfe2001;Rafi et al, 2005;Shen et al, 2001;Waddington et al, 2004), the studies presented here have social implications in that they suggest that to achieve maximal therapeutic impact of currently available gene transfer vectors, newborn screening with early identification and therapy of this disorder will achieve better results than waiting until the disease manifests clinically.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence suggest that earlier administration offers several unique advantages to treating lysosomal storage disorders (Kohn and Parkman1997;Waddington et al, 2004). Foremost among these is that, treating individuals before disease onset prevents the occurrence of irreversible damage.…”

Section: Disease Progression In Lysosomal Storage Diseasesmentioning

confidence: 99%

“…The benefit of treatment as neonates may arise from a combination of factors, including, but not limited to: (1) therapeutically relevant levels of the deficient TPP-I enzyme can be achieved early in life, which may prevent the development of disease as opposed to reversing the established disease; and (2) earlier administration leads to a higher density and more widespread distribution of vector within the much smaller, and immature neonatal brain (Kohn and Parkman1997;Waddington et al, 2004).…”

Section: Time Of Therapymentioning

confidence: 99%

“…Based on these observations, and studies of several groups showing that administration of gene transfer vectors to the newborn CNS provides significant advantage to administration later in life (Bostick et al, 2007;Broekman et al, 2007;Daly et al, 1999;Griffey et al, 2006;Li and Daly2002;Passini et al, 2003;Passini and Wolfe2001;Rafi et al, 2005;Shen et al, 2001;Waddington et al, 2004), we hypothesized that if an AAVrh.10 vector coding for the wild type CLN2 cDNA were administered to the CNS of newborn CLN2-/-mice, we would achieve significant improvement in survival over administration to older animals. Compared to parallel administration in 3 or 7 wk old mice, administration at postnatal day 2 demonstrated remarkable persistent, widespread expression of the CLN2 gene product, with concomitant improvement of a number of tests of CNS function as well as significant survival advantage.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, corrective gene therapies for neurodegenerative diseases are not restorative but rather halt disease progression, making delivery prior to disease onset an important objective. With these limitations in mind, three basic strategies have been employed to achieve therapeutic levels of gene expression throughout the brain: identifying gene transfer vectors that will diffuse through the CNS more effectively (Cearley and Wolfe2006;Deglon and Hantraye2005;Shevtsova et al, 2005;Sondhi et al, 2007), optimizing the method of delivery and volume and rate of infusion (Chen et al, 1999;Hackett et al, 2005;Hsich et al, 2002), and administration at an earlier time point, when the brain is smaller and immature (Bostick et al, 2007;Broekman et al, 2007;Daly et al, 1999;Griffey et al, 2006;Li and Daly2002;Passini et al, 2003;Passini and Wolfe2001;Rafi et al, 2005;Shen et al, 2001;Waddington et al, 2004). Studies from our laboratory and others have identified several serotypes of adeno-associated virus (AAV) vectors that are more effective than the first generation vectors used for CNS gene transfer (Broekman et al, 2006;Burger et al, 2005;Cearley and Wolfe2006;Harding et al, 2006;Sondhi et al, 2007;Taymans et al, 2007), the parameters for optimal administration of vectors to the CNS have been established (Chen et al, 1999;Hackett et al, 2005;Hsich et al, 2002) and several studies have shown that administration earlier in life results in an advantage over therapy in older animals (Bostick et al, 2007;Broekman et al, 2007;Daly et al, 1999;Griffey et al, 2006;Li and Daly2002;Passini et al, 2003;Passini and Wolfe2001...…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

Sondhi

Peterson

Edelstein

et al. 2008

Experimental Neurology

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SummaryLate infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk treated mice, 168 days for 7 wk treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.

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Section: Discussionmentioning

confidence: 99%

Section: Disease Progression In Lysosomal Storage Diseasesmentioning

confidence: 99%

Section: Time Of Therapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

Sondhi

Peterson

Edelstein

et al. 2008

Experimental Neurology

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Fetal Endocrinology

Katugampola¹,

Gevers²,

Dattani³

2019

Brook's Clinical Pediatric Endocrinology

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Sperm‐mediated gene transfer: Applications and implications

2005

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Recent developments in studies of sperm-mediated gene transfer (SMGT) now provide solid ground for the notion that sperm cells can act as vectors for exogenous genetic sequences. A substantive body of evidence indicates that SMGT is potentially useable in animal transgenesis, but also suggests that the final fate of the exogenous sequences transferred by sperm is not always predictable. The analysis of SMGT-derived offspring has shown the existence of integrated foreign sequences in some cases, while in others stable modifications of the genome are difficult to detect. The appearance of SMGT-derived modified offspring on the one hand and, on the other hand, the rarity of actual modification of the genome, suggest inheritance as extrachromosomal structures. Several specific factors have been identified that mediate distinct steps in SMGT. Among those, a prominent role is played by an endogenous reverse transcriptase of retrotransposon origin. Mature spermatozoa are naturally protected against the intrusion of foreign nucleic acid molecules; however, particular environmental conditions, such as those occurring during human assisted reproduction, can abolish this protection. The possibility that sperm cells under these conditions carry genetic sequences affecting the integrity or identity of the host genome should be critically considered. These considerations further suggest the possibility that SMGT events may occasionally take place in nature, with profound implications for evolutionary processes.

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Fetal and neonatal gene therapy: benefits and pitfalls

Cited by 42 publications

References 67 publications

Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

Fetal Endocrinology

Sperm‐mediated gene transfer: Applications and implications

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