Kunihiko Ikeguchi's research while affiliated with Jichi Medical University and other places
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Publications (53)
Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated virus (AAV) vector-mediated gene d...
A 21-year-old woman developed left hemiparesis during work and was hospitalized. Her National Institutes of Health Stroke Scale score was 4. Hyperintense areas in the left basal ganglia, corona radiata, and cortex of the temporal lobe were found by brain diffusion-weighted magnetic resonance imaging, indicating acute cerebral infarction. Echocardio...
Background
Previously, we identified a creatine kinase brain-type antibody (anti-CKB) to be associated with paraneoplastic cerebellar degeneration (PCD) using a proteomic approach. Immunohistochemistry indicated that anti-CKB reacted with both mouse cerebellar neurons and bladder cancer tissues. Moreover, we detected anti-CKB in sera from 2 PCD pat...
Creatinine (Cr) as a marker of renal function has limited value in amyotrophic lateral sclerosis (ALS) because patients with ALS have reduced muscle mass. Thus, there is a need for alternative methods of assessing renal function. Cystatin C (CysC), which is unaffected by muscle mass, is potentially an ideal biomarker of nephrotoxicity in ALS; howev...
AimIdentification of sensitive surrogate markers that indicate disease progression in amyotrophic lateral sclerosis might be useful in clinical trials and clinical care. Determination of the creatinine/cystatin C (Cr/CysC) ratio eliminates the effect of renal function on serum creatinine levels; therefore, we considered that the ratio might serve a...
Previous studies addressing preoperative steroid treatment have revealed that control of myasthenia gravis (MG) with steroids prior to surgery appeared to stabilize postoperative status. The purpose of our study was to clarify the clinical benefits of the preoperative programmed high-dose steroid treatment on the long-term outcomes of MG patients....
Botulism is a neuroparalytic disease caused by neurotoxins produced by Clostridium botulinum. Food-borne botulism is a kind of exotoxin-caused food intoxication. Although this disease is rarely reported in Japan now, it is a cause of great concern because of its high mortality rate, and botulism cases should be treated as a public health emergency....
Botulism is a rare but potentially life-threatening motor and autonomic paralytic syndrome caused by the action of neurotoxins released by Clostridium botulinum. The modern syndromes of botulism have 6 forms: 4 naturally occurring syndromes and 2 human-induced syndromes. Food-borne botulism is caused by ingestion of foods contaminated with botulinu...
Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patient...
Regulation of gene expression is necessary to avoid possible adverse effects of gene therapy due to excess synthesis of transgene products. To reduce transgene expression, we developed a viral vector-mediated somatic regulation system using inducible Cre recombinase. A recombinant adeno-associated virus (AAV) vector expressing Cre recombinase fused...
Molecular Therapy (2004) 9, S403–S403; doi: 10.1016/j.ymthe.2004.06.996
1051. A Fail-Safe System for Gene Therapy of Parkinson's Disease; Application of Removable Expression Cassette To Prevent Overproduction of Dopamine in a Rat Model
Shin-ichi Muramatsu1, Xiaog-gang Li1,2, Takashi Okada2, Mika Kodera1, Yuko Nara1, Naomi Takino1, Kunihiko Ikeguch...
Parkinson's disease (PD) is a progressive movement disorder marked by selective degeneration of dopaminergic neurons of the substantia nigra and severe decrease in the dopamine (DA) content of the striatum. Replacement of DA is important to alleviate the motor symptoms of the disease. The DA precursor, L-3,4-dihydroxyphenylalanine (L-dopa), which i...
Adeno-associated virus (AAV) vector has been developed as an attractive gene delivery system with proven safety. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The purpose of this report was to investigate transgenic GDNF exp...
This chapter presents recombinant adeno-associated viral (rAAV) vector that represents one of the most powerful vehicles for delivering therapeutic genes into mammalian brains. In rodents and nonhuman primates, a substantial number of striatal neurons can be transduced with high titer rAAV vectors through simple stereotaxic injection. Although chro...
We report the results of clinical and genetic studies on a Japanese SPG4 family.
Family N included eight patients in four generations with autosomal dominant transmission. We performed neurological and molecular analyses on the SPG4 gene in the family members comprising three patients, 12 at-risk individuals, and three normal spouses.
The three pat...
The recombinant adeno-associated viral (rAAV) vector is a powerful tool for delivering therapeutic genes into mammalian brains. In rodents and non-human primates, a substantial number of striatal neurons can be transduced with high titer rAAV vectors by simple stereotaxic injection. Efficient and long-term expression of genes for dopamine (DA)-synt...
Early-onset ataxia with hypoalbuminemia is regarded as a variant form of Friedreich ataxia in Japan. Early-onset ataxia with hypoalbuminemia and ataxia with ocular motor apraxia have been considered as the same clinical entity because of the recent identification of a common mutation in the aprataxin gene. A new clinical entity named early-onset at...
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive lethal disease that involves selective annihilation of motoneurons. Glial cell line-derived neurotrophic factor (GDNF) is proposed to be a promising therapeutic agent for ALS and other motor neuron diseases. Because adeno-associated virus (AAV) has been developed as an attractive gen...
Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a function...
Objectives:
To obtain a simple and reliable clinical parameter for the diagnosis of multiple sclerosis among patients with neurological diseases.
Patients and methods:
Heparinized peripheral blood was obtained from patients with multiple sclerosis and those with non-inflammatory neurological diseases and healthy volunteers. A new enzyme immunoas...
One potential strategy for gene therapy of Parkinson's disease (PD) is the local production of dopamine (DA) in the striatum induced by restoring DA-synthesizing enzymes. In addition to tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), GTP cyclohydrolase I (GCH) is necessary for efficient DA production. Using adeno-associate...
Parkinson’s disease (PD) is a common disorder characterized by progressive disturbance in the control of movement, and the symptoms result from a progressive loss of dopaminergic neurons in the substantia nigra. These neurons send dopamine down to their nerve endings that are located in the striatum. The severity of PD is proportional to the declin...
A 49-year-old woman with diabetes mellitus developed progressive weakness and atrophy of both thighs rendering her wheelchair-bound within two months. The neurological findings and electrophysiological test results were compatible with diabetic amyotrophy (DA). Immediately after intravenous immunoglobulin (IVIg) therapy (20 g x 3 days), she became...
A 74-year-old man developed abnormal forgetfulness, soon followed by unstable speech content and marked disorientation. At 77 years of age, the patient started to occasionally fall, an aspect of progressive supranuclear palsy. He then became bedridden. The patient eventually died of pneumonia at 79 years of age. Neuropathological examination reveal...
Parkinson's disease (PD), a neurological disease suited to gene therapy, is biochemically characterized by a severe decrease in the dopamine content of the striatum. One current strategy for gene therapy of PD involves local production of dopamine in the striatum achieved by inducing the expression of enzymes involved in the biosynthetic pathway fo...
Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of dopamine-synthesizing enzymes [tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)...
Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of enzymes in the biosynthetic pathway for dopamine. Tyrosine hydroxylase (TH) catalyzes the synthesis of...
Interleukin (IL)-1beta and nerve growth factor (NGF) were measured for the first time in the brain (caudate nucleus and putamen, and frontal cortex) from control mice and mice treated with a parkinsonism-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), by highly-sensitive sandwich enzyme-linked immunosorbent assays (ELISAs)...
Glial cell line-derived neurotrophic factor (GDNF) is known as a potent neurotrophic factor for dopaminergic neurons. Since adeno-associated virus (AAV) vector is a suitable vehicle for gene transfer into neurons, rat E14 mesencephalic cells were transduced with an AAV vector expressing GDNF. When compared with mock transduction, a larger number of...
Somatic gene therapy is a logical approach to the treatment and correction of inherited disorders, and the concept that genetic manipulation might be used to treat diseases is also applied to the treatment of acquired disorders, such as cancer and AIDS. Accordingly, the types of diseases under consideration for gene therapy are diverse, and many di...
Adrenoleukodystrophy (ALD) is a hitherto untreatable, X-linked recessive disorder of the central nervous system characterized by the systemic accumulation of very-long-chain fatty acids. Although various treatments have been proposed, objective evidence of their efficacy is insufficient. This is partly due to the absence of an appropriate method fo...
Bilateral lesions of the pedunculopontine nucleus area produced by injection of ibotenic acid in rats resulted in severe impairment of acquisition of both one-trial passive avoidance and two-way shuttle-box active avoidance, while retention and retrieval of acquired avoidance behaviors were perfectly preserved and neither short-term nor long-term b...
Choline acetyltransferase activities were measured in various forebrain regions 3, 7, 14, 21 and 28 days after bilateral lesions of the pedunculopontine nucleus area with ibotenic acid. The decrease was predominant in the ventral tegmental area and medial thalamus (especially at the caudal level). The decrease recovered as rapidly as 21 days after...
Areas of pedunculopontine nuclei (PPN) of rats were Iesioned bilaterally by local injection of ibotenic acid. The medial thalamus (MT) where the cholinergic efferent fibers of the PPN terminate was also Iesioned bilaterally by local injection of ethylcholine mustard aziridinium ion. Testing of these Iesioned rats for passive as well as active avoid...
Pedunculopontine nucleus areas were lesioned bilaterally in the rat by local injection of kainic acid. When rats so treated were tested for active avoidance behavior in shuttle boxes we found that their avoidance acquisition was completely abolished, whereas their intertrial locomotor activity and escape behavior were not affected. In the lesioned...
Citations
... No robust increase in FMT uptake for two years was observedin the cortical regions. In addition to the putamen, there were significant increases in the median FMT uptake in the globus pallidus and substantia nigra (Fig. 2B; Supplementary Fig. 4A), indicating possible anterograde transportation given that AAV2 has not been reported to retrogradely transport24,25 . Moreover, deep brain regions, including the VTA and DCN that modulate dopaminergic signaling, exhibited no increased FMT uptake(Supplementary Fig. 4B). ...
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... Для повышения тропности AAВ к различным тканям и клеткам ЦНС, включая олигодендроциты, астроциты и нейроны, в целях изучения в доклинических исследованиях (ДКИ) на различных видах животных препаратов ГТ, разрабатываются различные AAВ-капсиды. Оптимизированные AAВ демонстрируют повышение экспрессии трансгена и терапевтической безопасности при изучении на экспериментальных моделях таких НДЗ, как БА, БХ, БП [13][14][15][16][17][18][19][20]. ...
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... The frequency of family history of first or second relatives was similar between groups (symptomatic carriers 88.9% vs. CARASIL 74.1%, p = 0.112). Five parents of CARASIL patients with R274Q, P285L, V297M, and R302X mutations had a history of stroke (1,2,11,(40)(41)(42). Furthermore, two parents of CARASIL patients who were carriers of E42fs (4) and G295R mutations (20) had leukoencephalopathy. ...
... Most frequently, the symptoms that suggest the possibility of a myxoma diagnosis are secondary to those of intracardiac obstruction (vertigo, palpitations, dyspnea, and cardiac insufficiency), which appear in up to 70% of patients. In less than 10% of cases, atrial myxomas are diagnosed incidentally and are asymptomatic [1,4,[50][51][52]. In our case, the constitutional and intracardiac obstruction symptoms were absent, with our patient having only central and peripheral embolic manifestations (cerebral ischemic stroke and splenic infarction). ...
... In addition, this antibody was also detected in the serum of the patient with sensorymotor neuropathy that manifested as PNS. This antibody was identified in five PNS patients, and this autoantigen expression was recognized in the human cerebellum and cancer[2]. These results demonstrated that anti-CKB antibody might be a novel antibody with regard to PNS. ...
... The CVD morbidity in participants with higher Cr/CysC ratios was lower than that in participants with lower Cr/CysC ratios [3.3% in quartile 4 (Q4, ≥1. 26) vs. 14% in quartile 1 (Q1, ≤0.89)]. Significant differences in uric acid, cholesterol, BMI, HbA1c, ethnicity, diabetes, hypertension, hyperlipidemia, BMI, and smoking were found among participants with different quartiles of Cr/CysC ratios (all p < 0.05). ...
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... A similar conclusion was noted with preoperative high-dose steroid therapy in a retrospective Japanese cohort where the patients who received preoperative steroids had significantly higher probability of achieving pharmacological remission. [40] The effects of thymectomy are experimentally shown to be synergistic rather than independent of pharmacological immune modulation. [41] The impact of the timing of the immune modulation on these effects needs to specifically be addressed in future studies. ...
... Importantly, CysC is unaffected by several factors such as age, sex, and muscle mass 19 and CysC concentrations were found to be a reliable marker for kidney function overall 20 . CysC based equations outperformed creatinine equations in evaluating kidney function in primary neuromuscular diseases 21 and in ALS patients 22 . ...
... A wide range of factors have been shown to have neuroprotective effect against MPP^/MPTP toxicity in vitro and in vivo. A partial list includes the growth factors brain derived neurotrophic factor (BDNF) (Beck et al., 1992), epidermal 25 growth factor (Hadjiconstantinou et al., 1991, Yoshinaga et al., 1998, fibroblast growth factors 1 and 2 (Otto and Unsicker, 1990), and glial cell line derived neurotrophic factor (GDNF) family members (Hou et al., 1996, Horger et al., 1998, Fan et al., 1998; of these, GDNF is the most widely characterised in animal models, and has been tested in clinical trials for Parkinson's disease. ...
... In fact, several studies discuss a role for PPT in cognition, despite contradictory findings [49][50][51]. Excitotoxic lesions of this structure apparently affect only encoding of acquired avoidance behaviors, not affecting consolidation and retrieval [52]. [51] demonstrated a deficit in sustained attention after selective lesions of cholinergic neurons within the PPT. ...
