Gene Therapy in Parkinsonʼs Disease

Feng, Linyin; Maguire‐Zeiss, Kathleen A.

doi:10.2165/11533740-000000000-00000

Cited by 70 publications

(21 citation statements)

References 159 publications

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“…It affects about 4 million people worldwide and this number is expected to grow as the average age of the population increases. PD characterized by degenerative processes in the CNS resulted in progressive loss of dopamine-producing cells in the substantia nigra (Feng & Maguire-Zeiss, 2010). Early symptoms of the disease include shaking, slowness, and difficulty with walking.…”

Section: Cns Clinical Trials Utilizing Retroviral Vectorsmentioning

confidence: 99%

Clinical Applications Involving CNS Gene Transfer

Kantor

McCown

Leone

et al. 2014

Advances in Genetics

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Diseases of the central nervous system (CNS) have traditionally been the most difficult to treat by traditional pharmacological methods, due mostly to the blood–brain barrier and the difficulties associated with repeated drug administration targeting the CNS. Viral vector gene transfer represents a way to permanently provide a therapeutic protein within the nervous system after a single administration, whether this be a gene replacement strategy for an inherited disorder or a disease-modifying protein for a disease such as Parkinson's. Gene therapy approaches for CNS disorders has evolved considerably over the last two decades. Although a breakthrough treatment has remained elusive, current strategies are now considerably safer and potentially much more effective. This chapter will explore the past, current, and future status of CNS gene therapy, focusing on clinical trials utilizing adeno-associated virus and lentiviral vectors.

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Section: Cns Clinical Trials Utilizing Retroviral Vectorsmentioning

confidence: 99%

Clinical Applications Involving CNS Gene Transfer

Kantor

McCown

Leone

et al. 2014

Advances in Genetics

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“…Current pharmacological treatment of Parkinson's disease is insufficient, contains serious side effects and even loses its efficiency by time [3,4]. As one alternative strategy the use of gene therapy has been intensively studied to improve the treatment of Parkinson's disease [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…A number of gene delivery vectors and therapeutic genes have been used to study the potential of gene delivery in experimental models of Parkinson's disease [7,8]. Viral vectors have been more effective and useful than nonviral vectors for in vivo gene transfections despite that they have in general higher toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…adenovirus, adeno-associated virus and lentivirus vectors. Therapeutic genes which have been used especially to enhance dopamine synthesis are amino acid decarboxylase (AADC), tyrosine hydroxylase (TH) and GTP cyclohydrolase I, and those to improve especially the condition of dopaminergic cells are neurotrophic factor genes as glial cell derived growth factor (GDNF) and neurturin [7,8]. In the animal models the use of gene therapy has been efficient, the synthesis of dopamine has increased and the experimental measures and symptoms of Parkinson's disease improved.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

Raasmaja¹,

Lehtonen²,

Kääriäinen³

et al. 2013

OJGen

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The use of gene therapy has been intensively studied as a potential method to treat Parkinson's disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the outcome of gene delivery or on the physiological state of target tissues have not been analyzed as much and systematically. Therefore, we have infused adenovirus vectors expressing either a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into striatum in a rat model of PD. The experimental procedures were tested using the Ad lacZ vector in order to optimize concentrations, volumes, infusion speeds and transfection times. The expression of Ad lacZ vector was lower and declined earlier in the lesioned than unlesioned striatum suggesting that the lesion affects on the transfection efficiency and outcome of gene transfection. The effect of three different approaches of Ad TH vector transfection was compared: 1) the delivery of Ad TH gene vector alone into one single site of striatum, 2) the delivery of Ad TH gene vector alone into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into one site of striatum followed by a continuous infusion of tetrahydrobiopterin (BH4) cofactor with a mini pump. There was a small and transient unsignificant decrease in the turning behavior when the Ad TH vector was delivered into one site of the striatum. Simultaneous infusion into several sites or together with BH4 cofactor did not improve more the effect of gene delivery. Thus, although the effects were unsignificant, the Ad TH transfection seemed to decrease the turning behavior in the rat model of PD and the optimal effect was seen at some specific doses and time points. Furthermore, the outcome of gene therapy could depend in addition to the amount and efficacy of gene vectors also on the physiological state and experimental strategies.

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“…TPH-1 is generally found in the pineal body and gut, and TPH-2 is selectively expressed in brain. DDC is known as a key molecule for neuronal disease (13). Findings of a recent study indicated that DDC is a novel co-activator of the androgen receptor (AR) in prostate tissues (14).…”

Section: Introductionmentioning

confidence: 99%

Serotonin synthesis and metabolism-related molecules in a human prostate cancer cell line

et al. 2011

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Abstract. Prostate cancer is one of the most common tumors in males and its incidence is steadily increasing worldwide. Serotonin or 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter that mediates a wide variety of physiological effects. An increase in the number of 5-HT-releasing neuroendocrine (NE) cells has been correlated with tumor progression. However, it is particularly unclear whether released 5-HT or the release of 5-HT has a role in tumor cell growth. We hypothesized that 5-HT synthesis and metabolism in NE cells regulate the growth of prostate cancer cells. In the present study, 5-HT was found to play a role as a cell growth factor in prostate cancer cells. Moreover, the pharmacological inhibition of 5-HT synthesis and metabolism interrupted the growth of prostate cancer cells. To confirm the existence of 5-HT in prostate cancer cells, we performed ELISA, HPLC, RT-PCR and immunohistochemical analyses. A high expression of tryptophan hydroxylase (TPH-1), dopa decarboxylase (DDC) and monoamine oxidase A (MAO-A) was noted in the prostate cancer cells when compared with normal prostate cells. Previous studies showed that 5-HT stimulated the proliferation of prostate cancer cells mediated by 5-HT receptors 5-HTR1A and R1B. However, cell proliferation was significantly inhibited when siRNA for both DDC and TPH-1 was transfected to the cells. Consequently, we propose that the secretion system of prostate NE cells capable of 5-HT synthesis and metabolism plays a significant role in prostate tumor generation and progression. These findings provide crucial clues for the development of potential pharmacotherapeutics to slow prostate tumor progression.

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Gene Therapy in Parkinsonʼs Disease

Cited by 70 publications

References 159 publications

Clinical Applications Involving CNS Gene Transfer

Clinical Applications Involving CNS Gene Transfer

Tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

Serotonin synthesis and metabolism-related molecules in a human prostate cancer cell line

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