Enhanced brain distribution of modified aspartoacylase

Poddar, Nitesh Kumar; Zano, Stephen P.; Natarajan, Reka; Yamamoto, Bryan K.; Viola, Ronald E.

doi:10.1016/j.ymgme.2014.07.002

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…While immunological impairments and decreased macrophage survival have recently been reported in ASPA-null mice [ 3 , 28 ], the CD pathology is virtually exclusively confined to the CNS. Consequently efforts for development of an enzyme replacement therapy focussed on development of ASPA modification that would allow the recombinant enzyme to cross the blood–brain barrier [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

et al. 2017

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N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease—a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CNS pathology and lasting neurological benefits. This finding signifies the first successful post-symptomatic treatment of a white matter disorder using an adeno-associated virus vector tailored towards oligodendroglial-restricted transgene expression.Electronic supplementary materialThe online version of this article (10.1007/s00401-017-1784-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

et al. 2017

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“…In light of these limitations, nanoconjugation of these small-molecular-weight osmolytes is emerging as a potential strategy for not only enhancing their efficiency as protein folders but also modulating their bioavailability with enhanced specificity. Several studies have come up wherein nanoencapsulation of osmolytes endows them with varied beneficial properties such as high specificity, biocompatibility, biodegradability, water solubility, and low toxicity. ,, Moreover, nanocarrier systems can be exploited as an emerging delivery method to enhance the permeability of the BBB through various strategies such as PEGlylated liposomes, functionalized nanoparticles, and microcapsules and thereby releasing the therapeutic amount of nano-osmolytes with prolonged shelf life to the targeted site of the brain . Recently, researchers have shown that polylactide- co -glycolide (PLGA) NP conjugated glycopeptide can pass the BBB at the optimum level as a reference to the injected dose .…”

Section: Introductionmentioning

confidence: 99%

“…18 In this direction, PEGylated conjugated biomolecules or polymeric nanoparticles have been extensively used as nanocarriers against the disadvantages of using nanoparticles in terms of immunogenicity, cytotoxicity, drug leakage, reticuloendothelial system uptake, and hemolysis. 17 Therefore, the design of nano-osmolyte drugs that are nontoxic, biocompatible, and target-specific is an urgent need for better therapeutics of protein aggregation disorders. 19,20 Keeping in view the importance and emergence of nanoosmolyte conjugates as future therapeutic agents, the present review, for the first time, was designed to provide an overview of the current status of the nano-osmolyte conjugation as a promising strategy for tailoring osmolyte−protein interaction for enhanced chaperonic effects and efficient prevention against protein aggregation.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, researchers have shown that polylactide- co -glycolide (PLGA) NP conjugated glycopeptide can pass the BBB at the optimum level as a reference to the injected dose . In this direction, PEGylated conjugated biomolecules or polymeric nanoparticles have been extensively used as nanocarriers against the disadvantages of using nanoparticles in terms of immunogenicity, cytotoxicity, drug leakage, reticuloendothelial system uptake, and hemolysis . Therefore, the design of nano-osmolyte drugs that are nontoxic, biocompatible, and target-specific is an urgent need for better therapeutics of protein aggregation disorders. , …”

Section: Introductionmentioning

confidence: 99%

“… 13 , 14 , 16 Moreover, nanocarrier systems can be exploited as an emerging delivery method to enhance the permeability of the BBB through various strategies such as PEGlylated liposomes, functionalized nanoparticles, and microcapsules and thereby releasing the therapeutic amount of nano-osmolytes with prolonged shelf life to the targeted site of the brain. 17 Recently, researchers have shown that polylactide- co -glycolide (PLGA) NP conjugated glycopeptide can pass the BBB at the optimum level as a reference to the injected dose. 18 In this direction, PEGylated conjugated biomolecules or polymeric nanoparticles have been extensively used as nanocarriers against the disadvantages of using nanoparticles in terms of immunogenicity, cytotoxicity, drug leakage, reticuloendothelial system uptake, and hemolysis.…”

Section: Introductionmentioning

confidence: 99%

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Nano-Osmolyte Conjugation: Tailoring the Osmolyte-Protein Interactions at the Nanoscale

Sharma,

Dar,

Wijayasinghe

et al. 2023

ACS Omega

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Osmolytes are small organic compounds accumulated at higher concentrations in the cell under various stress conditions like high temperature, high salt, high pressure, etc. Osmolytes mainly include four major classes of compounds including sugars, polyols, methylamines, and amino acids and their derivatives. In addition to their ability to maintain protein stability and folding, these osmolytes, also termed as chemical chaperones, can prevent protein misfolding and aggregation. Although being efficient protein folders and stabilizers, these osmolytes exhibit certain unavoidable limitations such as nearly molar concentrations of osmolytes being required for their effect, which is quite difficult to achieve inside a cell or in the extracellular matrix due to nonspecificity and limited permeability of the blood–brain barrier system and reduced bioavailability. These limitations can be overcome to a certain extent by using smart delivery platforms for the targeted delivery of osmolytes to the site of action. In this context, osmolyte-functionalized nanoparticles, termed nano-osmolytes, enhance the protein stabilization and chaperone efficiency of osmolytes up to 105 times in certain cases. For example, sugars, polyols, and amino acid functionalized based nano-osmolytes have shown tremendous potential in preventing protein aggregation. The enhanced potential of nano-osmolytes can be attributed to their high specificity at low concentrations, high tunability, amphiphilicity, multivalent complex formation, and efficient drug delivery system. Keeping in view the promising potential of nano-osmolytes conjugation in tailoring the osmolyte–protein interactions, as compared to their molecular forms, the present review summarizes the recent advancements of the nano-osmolytes that enhance the protein stability/folding efficiency and ability to act as artificial chaperones with increased potential to prevent protein misfolding disorders. Some of the potential nano-osmolyte aggregation inhibitors have been highlighted for large-scale screening with future applications in aggregation disorders. The synthesis of nano-osmolytes by numerous approaches and future perspectives are also highlighted.

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The state of treatment approach and diagnostics in Canavan disease with focus on the determination of N-acetylasparic acid

et al. 2016

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Enhanced brain distribution of modified aspartoacylase

Cited by 5 publications

References 40 publications

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Nano-Osmolyte Conjugation: Tailoring the Osmolyte-Protein Interactions at the Nanoscale

The state of treatment approach and diagnostics in Canavan disease with focus on the determination of N-acetylasparic acid

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