Progress in gene therapy for neurological disorders

Simonato, Michele; Bennett, Jean; Boulis, Nicholas M.; Castro, María G.; Fink, David J.; Goins, William F.; Gray, Steven J.; Löwenstein, Pedro R.; Vandenberghe, Luk; Wilson, Thomas J.; Wolfe, John H.; Glorioso, Joseph C.

doi:10.1038/nrneurol.2013.56

Cited by 214 publications

(175 citation statements)

References 149 publications

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“…This cooperative function may have clinical relevance for adenovirus-mediated gene therapy exploiting the HSV-TK/GCV system. 70,71) …”

Section: Enbt1/slc43a3mentioning

confidence: 99%

Molecular Basis of Nucleobase Transport Systems in Mammals

Inoue

2017

Biological & Pharmaceutical Bulletin

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Nucleobases are water-soluble compounds that need specific transporters to cross biological membranes. Cumulative evidence based on studies using animal tissues and cells indicates that the carrier-mediated transport systems for purine and pyrimidine nucleobases can be classified into the following two types: concentrative transport systems that mediate nucleobase transport depending on the sodium ion concentration gradient; and other systems that mediate facilitated diffusion depending on the concentration gradient of the substrate. Recently, several molecular transporters that are involved in both transport systems have been identified. The function and activity of these transporters could be of pharmacological significance considering the roles that they play not only in nucleotide synthesis and metabolism but also in the pharmacokinetics and delivery of a variety of nucleobase analogues used in anticancer and antiviral drug therapy. The present review provides an overview of the recent advances in our understanding of the molecular basis of nucleobase transport systems, focusing on the transporters that mediate purine nucleobases, and discusses the involvement of intracellular metabolism in purine nucleobase transport and chemotherapy using ganciclovir.Key words purine nucleobase; transporter; salvage enzyme; equilibrative nucleoside transporter 1 (ENT1)/ solute carrier (SLC)29A1; ENT2/SLC29A2; equilibrative nucleobase transporter 1 (ENBT1)/ SLC43A3

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“…This cooperative function may have clinical relevance for adenovirus-mediated gene therapy exploiting the HSV-TK/GCV system. 70,71) …”

Section: Enbt1/slc43a3mentioning

confidence: 99%

Molecular Basis of Nucleobase Transport Systems in Mammals

Inoue

2017

Biological & Pharmaceutical Bulletin

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“…Recombinant viral-and nonviral-based gene transfer vectors have been employed that were delivered either directly into the CNS or into the systemic circulation (43)(44)(45)(46). Transplantation of stem cells that were genetically modifi ed ex vivo has also shown promise.…”

mentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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“…These concerns have been alleviated largely through the safety profile of vectors used and the skill of neurosurgical procedures [1,201]. In fact, there have been essentially no severe, adverse events associated with the most commonly used AAV vectors, or even oncolytic viruses for brain tumors, in clinical trials.…”

Section: Challengesmentioning

confidence: 99%

“…They comprise a variety of tools including delivery modalities, cells, biologic and synthetic vesicles/ NPs, and oligonucleotides. This section provides only a few examples of each; for a more comprehensive review see Simonato et al [1] and Nagabhushan Kalburgi et al [2].…”

Section: Promising New Strategiesmentioning

confidence: 99%

“…We will not attempt to review the entirety of clinical, preclinical, and basic research into nucleic acid-based neurotherapeutics. There are excellent reviews on each of these topics [1,2]. Instead, in this review our goal is to provide the reader with (1) an overview of the barriers to efficient gene delivery to the central nervous system (CNS) and (2) the state of the art in virus and nonviral-based neurotherapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Gene Therapy for the Nervous System: Challenges and New Strategies

et al. 2014

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Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

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Progress in gene therapy for neurological disorders

Cited by 214 publications

References 149 publications

Molecular Basis of Nucleobase Transport Systems in Mammals

Molecular Basis of Nucleobase Transport Systems in Mammals

Gene therapy for the neurological manifestations in lysosomal storage disorders

Gene Therapy for the Nervous System: Challenges and New Strategies

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