A phase1 study of stereotactic gene delivery of AAV2‐NGF for Alzheimer's disease

Rafii, Michael S.; Baumann, Tiffany L.; Bakay, Roy A.E.; Ostrove, Jeffrey M.; Siffert, João; Fleisher, Adam; Herzog, Christopher R.; Barba, David; Pay, Mary; Salmon, David P.; Chu, Yaping; Kordower, Jeffrey H.; Bishop, Kathie M.; Keator, David B.; Potkin, Steven G.; Bartus, Raymond T.

doi:10.1016/j.jalz.2013.09.004

Cited by 193 publications

(139 citation statements)

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“…In a small phase I clinical study (8 patients) reported in 2005, transfected fibroblasts with permanent expression of NGF were implanted in the forebrain of the patients, and significant increase in neuronal activity was reported (179). Also, a more recent Phase I clinical study with ex vivo gene delivery to AD patients demonstrated enhanced cerebral metabolism and cognitive function without significant adverse effects (180). Positron emission tomographic (PET) scans confirmed the inhibition of the metabolic decline expected in AD patients.…”

Section: Nerve Growth Factormentioning

confidence: 99%

Alzheimer’s Disease: Dawn of a New Era?

et al. 2017

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Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Section: Nerve Growth Factormentioning

confidence: 99%

Alzheimer’s Disease: Dawn of a New Era?

et al. 2017

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“…While much progress is clearly being made in the field of non-viral gene delivery, clinical trials involving viral delivery of genes such as NGF [225], glutamic acid decarboxylase [226], neurturin [227] (a structural relative of GDNF), and ProSavin (tyrosine hydroxylase, AADC, and cyclohydrolase 1) [228] to the brain are providing mounting evidence for the safety of such therapeutic strategies. By 2012, 28 clinical trials involving gene therapies for neurodegenerative disorders had taken place [229].…”

Section: Cynomolgus Monkeymentioning

confidence: 99%

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

Newland

Werner

et al. 2015

Progress in Polymer Science

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a b s t r a c tParkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons and represents a growing health burden to western societies. Like many neurodegenerative disorders the cause is unknown, however, as the pathogenesis becomes ever more elucidated, it is becoming clear that effective delivery is a key issue for new therapeutics. The versatility of today's polymerization techniques allows the synthesis of a wide range of polymer materials which hold great potential to aid in the delivery of small molecules, proteins, genetic material or cells. In this review, we capture the recent advances in polymer based therapeutics of the central nervous system (CNS). We place the advances in historical context and, furthermore, provide future prospects in line with newly discovered advancements in the understanding of PD and other neurodegenerative disorders. This review provides researchers in the field of polymer chemistry and materials science an up-to-date understanding of the requirements placed upon materials designed for use in the CNS aiding the focus of polymer therapeutic design.

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“…The majority of AAV clinical trials for neurological diseases have used vectors carrying the CMV immediate early promoter followed by a chimeric intron composed of a CMV splice donor and a human globin splice acceptor [113][114][115][116], or a version of the CAG/CBA promoter, described above [117][118][119]. Two other clinical trials have tested AAV vectors carrying mammalian promoters such as the mouse phosphoglycerate kinase (PGK) promoter [120], or the rat neuron-specific enolase (NSE) promoter [121].…”

Section: Challengesmentioning

confidence: 99%

“…Positron emission tomography (PET) of AADC activity has shown newly expressed enzyme in the injected structures and stability of expression over a long period [116]. Also a recent report shows evidence of nerve growth factor (NGF) expression in the post-mortem brain of Alzheimer's patients enrolled in a trial using an AAV2-NGF vector [117].…”

Section: Challengesmentioning

confidence: 99%

“…Thus, for example, AAV vectors injected into brains to deliver NGF in Alzheimer's disease [248], neurturin or glia cell-derived neurotrophic factor (GDNF) in Parkinson's disease [249,250], and insulin-like growth factor I in ALS [251] have proven safe, but with no demonstrable benefit. This apparent lack of benefit may relate to the late stage of the diseases at the time of treatment, the progressive nature of the diseases and/or the inability to quantitate minor benefit with lack of a robust biomarker [201].…”

Section: Changing the Brain Environmentmentioning

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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A phase1 study of stereotactic gene delivery of AAV2‐NGF for Alzheimer's disease

Cited by 193 publications

References 50 publications

Alzheimer’s Disease: Dawn of a New Era?

Alzheimer’s Disease: Dawn of a New Era?

Prospects for polymer therapeutics in Parkinson's disease and other neurodegenerative disorders

Gene Therapy for the Nervous System: Challenges and New Strategies

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