Cellular uptake and lysosomal delivery of galactocerebrosidase tagged with the HIV Tat protein transduction domain

Zhang, Xian Yang; Dinh, Annie; Cronin, James G.; Li, Su Chen; Reiser, Jakob

doi:10.1111/j.1471-4159.2007.05030.x

Cited by 29 publications

(31 citation statements)

References 45 publications

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“…Previously, Tat has been tested in mouse GALC. 20 Tat-fusion increased the secretion rate and M6P receptor–independent uptake of mouse GALC. Our study further confirmed these Tat effects in human GALC.…”

Section: Discussionmentioning

confidence: 90%

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HIV Tat Domain Improves Cross-correction of Human Galactocerebrosidase in a Gene- and Flanking Sequence-dependent Manner

Meng¹,

Eto

Schiffmann³

et al. 2013

Molecular Therapy - Nucleic Acids

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Krabbe disease is a devastating neurodegenerative lysosomal storage disorder caused by a deficiency of β-galactocerebrosidase (GALC). Gene therapy is a promising therapeutic approach for Krabbe disease. As the human brain is large and it is difficult to achieve global gene transduction, the efficacy of cross-correction is a critical determinant of the outcome of gene therapy for this disease. We investigated whether HIV Tat protein transduction domain (PTD) can improve the cross-correction of GALC. Tat-PTD significantly increased (~6-fold) cross-correction of GALC through enhanced secretion and uptake in a cell-culture model system. The effects of Tat-PTD were gene and flanking amino acids dependent. Tat-fusion increased the secretion of α-galactosidase A (α-gal A), but this did not improve its cross-correction. Tat-fusion did not change either secretion or uptake of β-glucocerebrosidase (GC). Tat-PTD increased GALC protein synthesis, abolished reactivity of GC to the 8E4 antibody, and likely reduced mannose phosphorylation in all these lysosomal enzymes. This study demonstrated that Tat-PTD can be useful for increasing cross-correction efficiency of lysosomal enzymes. However, Tat-PTD is not a mere adhesive motif but possesses a variety of biological functions. Therefore, the potential beneficial effect of Tat-PTD should be assessed individually on each lysosomal enzyme.

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Section: Discussionmentioning

confidence: 90%

“…This was not seen in other lysosomal enzymes with Tat-fusion in previous studies. 17,20 We therefore studied the potential mechanism for the increased expression of GALC-Tat.…”

Section: Resultsmentioning

confidence: 99%

HIV Tat Domain Improves Cross-correction of Human Galactocerebrosidase in a Gene- and Flanking Sequence-dependent Manner

Meng¹,

Eto

Schiffmann³

et al. 2013

Molecular Therapy - Nucleic Acids

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“…Research has reported that mimovirus vaccines with sizes similar to viruses can induce cellular immunity (Wu et al 2002, Yang et al 2008. Other studies also have indicated that mimovirus vaccines induce cellular and humoral immune responses (Zhang et al 2008). These studies demonstrate that mimovirus vaccines could be developed as an ideal contraceptive vaccine to induce immune responses and suppress fertility.…”

Section: Discussionmentioning

confidence: 99%

Induction of specific immune response and suppression of fertility by B-cell-epitope-based mimovirus vaccine

Shen¹,

Wang²,

Zhang³

et al. 2011

Reproduction

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SPINLW1 (previously known as eppin (epididymal protease inhibitor)) is a target under intense scrutiny in the study of male contraceptive vaccines. B-cell-dominant epitopes are now recognized as key parts of the induction of humoral immune responses against target antigens. The generation of robust humoral responses in vivo has become a crucial problem in the development of modern vaccines. In this study, we developed a completely novel B-cell-dominant-epitope-based mimovirus vaccine, which is a kind of virus-size particulate antigen delivery system. The mimovirus successfully self-assembled from a cationic peptide containing a cell-penetrating peptide of TAT 49-57 and a plasmid DNA encoding both three SPINLW1 (103-115) copies and adjuvant C3d3. The male mice were immunized with the epitope-based mimovirus vaccine, which resulted in a gradual elevation of specific serum IgG antibody levels. These reached a peak at week 4. Mating for the fertility assay showed that the mimovirus vaccine had accomplished a moderate fertility inhibition effect and investigation into the mechanism of action showed that it did so by interfering with the reproductive function of the sperm but that it did not damage the structures of the testes or cause serum testosterone to decline. Our results suggest an ideal protocol for suppressing fertility in mice by an engineered mimovirus vaccine.

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“…TAT has also been used for lysosomal delivery of PTs under the frame of ERT in some lysosomal disorders (159). Ohta's group (143) ligated the TAT domain to the super-antiapoptotic factor FNK to produce the PTD-FNK fusion protein.…”

Section: Organelle Targetingmentioning

confidence: 99%

Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

Papadopoulou

Tsiftsoglou

2011

Pharm Res

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Protein therapy is considered an alternative approach to gene therapy for treatment of genetic-metabolic disorders. Human protein therapeutics (PTs), developed via recombinant DNA technology and used for the treatment of these illnesses, act upon membrane-bound receptors to achieve their pharmacological response. On the contrary, proteins that normally act inside the cells cannot be developed as PTs in the conventional way, since they are not able to "cross" the plasma membrane. Furthermore, in mitochondrial disorders, attributed either to depleted or malfunctioned mitochondrial proteins, PTs should also have to reach the subcellular mitochondria to exert their therapeutic potential. Nowadays, there is no effective therapy for mitochondrial disorders. The development of PTs, however, via the Protein Transduction Domain (PTD) technology offered new opportunities for the deliberate delivery of human recombinant proteins inside eukaryotic subcellular organelles. To this end, mitochondrial disorders could be clinically encountered with the delivery of human mitochondrial proteins (engineered via recombinant DNA and PTD technologies) at specific intramitochondrial sites to exert their function. Overall, PTD-mediated Protein Replacement Therapy emerges as a suitable model system for the therapeutic approach for mitochondrial disorders.

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Cellular uptake and lysosomal delivery of galactocerebrosidase tagged with the HIV Tat protein transduction domain

Cited by 29 publications

References 45 publications

HIV Tat Domain Improves Cross-correction of Human Galactocerebrosidase in a Gene- and Flanking Sequence-dependent Manner

HIV Tat Domain Improves Cross-correction of Human Galactocerebrosidase in a Gene- and Flanking Sequence-dependent Manner

Induction of specific immune response and suppression of fertility by B-cell-epitope-based mimovirus vaccine

Transduction of Human Recombinant Proteins into Mitochondria as a Protein Therapeutic Approach for Mitochondrial Disorders

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