Versatile Somatic Gene Transfer for Modeling Neurodegenerative Diseases

Klein, Ronald L.; Wang, David B.; King, Michael A.

doi:10.1007/s12640-009-9080-7

Cited by 7 publications

(14 citation statements)

References 157 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[79, 80]). Here, we will focus on recombinant adeno-associated viruses (rAAVs), which are popular among the available viral vectors (comparisons of other viral vectors can be found in Chapter 1).…”

Section: Potential Caveats Associated With Transgenic Modelsmentioning

confidence: 99%

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

Combs

Kneynsberg

Kanaan

2016

Methods in Molecular Biology

View full text Add to dashboard Cite

Dementias are among the most common neurological disorders, and Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD remains a looming health crisis despite great efforts to learn the mechanisms surrounding the neuron dysfunction and neurodegeneration that accompanies AD primarily in the medial temporal lobe. In addition to AD, a group of diseases known as frontotemporal dementias (FTDs) are degenerative diseases involving atrophy and degeneration in the frontal and temporal lobe regions. Importantly, AD and a number of FTDs are collectively known as tauopathies due to the abundant accumulation of pathological tau inclusions in the brain. The precise role tau plays in disease pathogenesis remains an area of strong research focus. A critical component to effectively study any human disease is the availability of models that recapitulate key features of the disease. Accordingly, a number of animal models are currently being pursued to fill the current gaps in our knowledge of the causes of dementias and to develop effective therapeutics. Recent developments in gene therapy-based approaches, particularly in recombinant adeno-associated viruses (rAAVs), have provided new tools to study AD and other related neurodegenerative disorders. Additionally, gene therapy approaches have emerged as an intriguing possibility for treating these diseases in humans. This chapter explores the current state of rAAV models of AD and other dementias, discuss recent efforts to improve these models, and describe current and future possibilities in the use of rAAVs and other viruses in treatments of disease.

show abstract

Section: Potential Caveats Associated With Transgenic Modelsmentioning

confidence: 99%

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

Combs

Kneynsberg

Kanaan

2016

Methods in Molecular Biology

View full text Add to dashboard Cite

show abstract

“…Adeno-associated virus (AAV) vectors are efficient for gene delivery to neurons and have, therefore, been used extensively in both basic and clinical studies, due to the efficient expression, and the relatively minor immune response [1–3]. Natural AAV is a single-stranded parvovirus with a genome of approximately 4.7 kb [4].…”

Section: Introductionmentioning

confidence: 99%

“…Most people have been exposed to wild-type AAV and are seropositive for AAV antibodies [4]. Recombinant AAV vectors only retain 4% of the viral genome, the inverted terminal repeats, express no viral genes and are thought to persist as nonintegrated episomes [1–3]. All of these properties contribute to why gene transfer using the recombinant vector is relatively well-tolerated in various target tissues in various species.…”

Section: Introductionmentioning

confidence: 99%

“…The first characterizations of AAV gene transfer in the brain of rodents were by Kaplitt et al [5] and McCown et al [6], which demonstrated the potential for widespread, long-term and well-tolerated transgene expression. The efficiency improved due to a number of refinements in production/purification, promoter, AAV capsid serotype (subtype) and delivery methods [1]. Gene transfer in the CNS with AAV vectors has been extensively reviewed [1–3], while here we focus on recent results with the AAV9 serotype, which has become the vector of choice for many investigators.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The advent of AAV9 expands applications for brain and spinal cord gene delivery

Dayton

Wang

Klein

2012

Expert Opinion on Biological Therapy

124

View full text Add to dashboard Cite

Introduction-Straightforward studies compared adeno-associated virus (AAV) serotypes to determine the most appropriate one for robust expression in the CNS. AAV9 was efficient when directly injected into the brain, but more surprisingly, AAV9 produced global expression in the brain and spinal cord after a peripheral, systemic route of administration to neonatal mice.Areas covered-Topics include AAV9 gene delivery from intraparenchymal, intravenous, intrathecal and intrauterine routes of administration, and related preclinical studies and disease models. Systemic AAV9 gene transfer yields remarkably consistent neuronal expression, though only in early development. AAV9 is versatile to study neuropathological proteins: microtubuleassociated protein tau and transactive response DNA-binding protein 43 kDa (TDP-43).Expert opinion-AAV9 will be more widely used based on current data, although other natural serotypes and recombineered vectors may also support or improve upon wide-scale expression. A peripheral-to-central gene delivery that can affect the entire CNS without having to inject the CNS is promising for basic functional experiments, and potentially for gene therapy. Systemic or intracerebrospinal fluid routes of AAV9 administration should be considered for spinal muscular atrophy, lysosomal storage diseases and amyotrophic lateral sclerosis, if more neuronal expression can be achieved in adults, or if glial expression can be exploited.

show abstract

“…The progress in studying the etiology and patho genesis of NDDs and the role of aggregation prone proteins in these processes is tightly associated with the use of in vitro and in vivo models [10][11][12][13][14][15][16][17], which have already made it possible to experimentally repro duce the main steps of the pathogenesis of individual diseases.…”

Section: Proteinopathies Neurodegenerative Disorders With Protein Agmentioning

confidence: 99%

Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology

et al. 2012

View full text Add to dashboard Cite

A number of neurodegenerative disorders were recently coalesced into a group of proteinopathies based on the similarity of molecular mechanisms underlying their pathogenesis. A key step in the develop ment of proteinopathies is a structural change that triggers aggregation of the proteins that are intrinsically prone to form aggregates owing to their physical and chemical properties. The review considers the recent progress in the field of proteinopathies with a special focus on the properties of aggregation prone proteins, the main stages of the development of molecular pathology, and the role of cell clearance systems in the pro gression of neurodegeneration. Recent modifications made to the nomenclature of neurodegenerative dis eases on the basis of the molecular mechanism of neurodegeneration are also addressed.

show abstract

Versatile Somatic Gene Transfer for Modeling Neurodegenerative Diseases

Cited by 7 publications

References 157 publications

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

Gene Therapy Models of Alzheimer’s Disease and Other Dementias

The advent of AAV9 expands applications for brain and spinal cord gene delivery

Proteinopathies, neurodegenerative disorders with protein aggregation-based pathology

Contact Info

Product

Resources

About