Treatment Of Huntington's Disease Research Articles

Adenovirus-Mediated Silencing of Huntingtin Expression by shRNA

Huntington's disease (HD) is an inherited autosomal dominant, neurodegenerative disease that is caused by a gain of function mutation characterized by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (htt) gene. Since hairpin small interference RNA (shRNA) technology allows inhibition of specific gene expression in vitro and in vivo, vector-mediated expression of an shRNA directed to htt mRNA could form the basis of a new treatment modality for HD. By initial plasmid transfection of 293 cells, we identified one exon 1-targeted shRNA, which efficiently inhibited expression of an htt exon 1-GFP fusion protein and the endogenous htt gene. A replication-deficient adenovirus (Ad) vector Adie-1-1 was constructed to express this shRNA from the U6 promoter. In A549 cells expressing exon 1 of htt with an expanded CAG allele, Adie- 1-1 efficiently prevented htt exon 1 expression and htt aggregate formation. In addition, in different neuronal and nonneuronal cell lines, Adie-1-1 efficiently inhibited the expression of endogenous htt. Together, this data indicates the delineation of an shRNA strategy that may become the basis for treatment of HD.

Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a toxic gain of function in the huntingtin (htt) protein. The contribution of wild-type htt function to the pathogenesis of HD is currently uncertain. To assess the role of wild-type htt in HD, we generated YAC128 mice that do not express wild-type htt (YAC128-/-) but express the same amount of mutant htt as normal YAC128 mice (YAC128+/+). YAC128-/- mice perform worse than YAC128+/+ mice in the rotarod test of motor coordination (P = 0.001) and are hypoactive compared with YAC128+/+ mice at 2 months (P = 0.003). Striatal neuropathology was not clearly worse in YAC128-/- mice compared with YAC128+/+ mice. There was no significant effect of decreased wild-type htt on striatal volume, neuronal counts or DARPP-32 expression but a modest worsening of striatal neuronal atrophy was evident (6%, P = 0.03). The testis of YAC128+/+ mice showed atrophy and degeneration, which was markedly worsened in the absence of wild-type htt (P = 0.001). YAC128+/+ mice also showed a male specific deficit in survival compared with WT mice which was exacerbated by the loss of wild-type htt (12-month-male survival, P < 0.001). Overall, we demonstrate that the loss of wild-type htt influences motor dysfunction, hyperkinesia, testicular degeneration and impaired lifespan in YAC128 mice. The mild effect of wild-type htt on striatal phenotypes in YAC128 mice suggests that the characteristic striatal neuropathology in HD is caused primarily by the toxicity of mutant htt and that replacement of wild-type htt will not be an adequate treatment for HD.

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A(2A) adenosine receptor (A(2A)-R)-selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D-microMRI analysis revealed that CGS reversed the enlarged ventricle-to-brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. (1)H-MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin-positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5'AMP-activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD.

Disturbed Ca2+signaling and apoptosis of medium spiny neurons in Huntington's disease

Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca2+) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD.

Development of novel therapies for Huntington's disease: hope and challenge1

Huntington's disease (HD) is an autosomal dominant neurological disease. It is a fatal neurological disorder affecting 5-10 out of 10,000 people. While there are intensive research efforts focusing on uncovering molecular mechanisms of the pathogenesis of HD, a number of studies have begun to look for effective therapies for HD. There is a large body of encouraging news on novel therapeutic developments. The present paper reviews drugs used for symptomatic treatment of HD and experimental therapies targeting HD molecular pathology.

Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the number of polyglutamine-encoding CAG repeats in the gene that encodes the huntingtin (htt) protein. A property of the mutant protein that is intimately involved in the development of the disease is the propensity of the glutamine-expanded protein to misfold and generate an N-terminal proteolytic htt fragment that is toxic and prone to aggregation. Intracellular antibodies (intrabodies) against htt have been shown to reduce htt aggregation by binding to the toxic fragment and inactivating it or preventing its misfolding. Intrabodies may therefore be a useful gene-therapy approach to treatment of the disease. However, high levels of intrabody expression have been required to obtain even limited reductions in aggregation. We have engineered a single-domain intracellular antibody against htt for robust aggregation inhibition at low expression levels by increasing its affinity in the absence of a disulfide bond. Furthermore, the engineered intrabody variable light-chain (V(L))12.3, rescued toxicity in a neuronal model of HD. We also found that V(L)12.3 inhibited aggregation and toxicity in a Saccharomyces cerevisiae model of HD. V(L)12.3 is significantly more potent than earlier anti-htt intrabodies and is a potential candidate for gene therapy treatment for HD. To our knowledge, this is the first attempt to improve affinity in the absence of a disulfide bond to improve intrabody function. The demonstrated importance of disulfide bond-independent binding for intrabody potency suggests a generally applicable approach to the development of effective intrabodies against other intracellular targets.

Chemotherapy for the Brain: The Antitumor Antibiotic Mithramycin Prolongs Survival in a Mouse Model of Huntington's Disease

Huntington's disease (HD) is a fully penetrant autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in the Huntingtin gene. Transcriptional dysfunction, excitotoxicity, and oxidative stress have all been proposed to play important roles in the pathogenesis of HD. This study was designed to explore the therapeutic potential of mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic. Pharmacological treatment of a transgenic mouse model of HD (R6/2) with mithramycin extended survival by 29.1%, greater than any single agent reported to date. Increased survival was accompanied by improved motor performance and markedly delayed neuropathological sequelae. To identify the functional mechanism for the salubrious effects of mithramycin, we examined transcriptional dysfunction in R6/2 mice. Consistent with transcriptional repression playing a role in the pathogenesis of HD, we found increased methylation of lysine 9 in histone H3, a well established mechanism of gene silencing. Mithramycin treatment prevented the increase in H3 methylation observed in R6/2 mice, suggesting that the enhanced survival and neuroprotection might be attributable to the alleviation of repressed gene expression vital to neuronal function and survival. Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD.

Deranged neuronal calcium signaling and Huntington disease

Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Htt exp and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Htt exp and deranged Ca 2+ signaling in MSN neurons. Experimental evidence indicates that (1) Ca 2+ homeostasis is abnormal in mitochondria isolated from lymphoblasts of HD patients and from brains of the YAC72 HD mouse model; (2) Htt exp leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in MSN from YAC72 HD mouse model; and (3) Htt exp binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP 3R1) carboxy-terminus and causes sensitization of InsP 3R1 to activation by InsP 3 in planar lipid bilayers and in MSN. Based on these results we propose that Htt exp-induced cytosolic and mitochondrial Ca 2+ overload of MSN plays an important role in the pathogenesis of HD and that Ca 2+ signaling blockers may play a beneficial role in treatment of HD.

The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease progression in a transgenic mouse model of Huntington's disease

Chronic glutamate mediated excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Both, inhibition of glutamate release through stimulation of presynaptic metabotropic glutamate receptor (mGluR) 2 and blockade of postsynaptic mGluR5 have been demonstrated to be neuroprotective against excitotoxicity. R6/2 HD transgenic mice which express an expanded CAG triplet repeat serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with either the mGluR2 agonist LY379268 (1.2 mg/kg) or with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (100 mg/kg) orally from a presymptomatic stage until death to investigate their potential disease modifying effects. We found that survival time in both the MPEP treated mice and the LY379268 treated mice was significantly increased in comparison to placebo treated transgenic controls (14.87±0.14 and 14.22±0.11 weeks versus 12.87±0.11 weeks, respectively). Additionally, the progressive decline in motor coordination of HD transgenic mice as tested with the rotarod test was significantly attenuated in MPEP- but not in LY379268-treated mice. Early pathological hyperactivity, which can be found in placebo treated HD transgenic mice, was significantly attenuated by both MPEP and LY379268 treatment. Immunohistologial examination of HD characteristic neuronal intranuclear inclusion (NII), however, demonstrated no effect on NII formation by either of the treatments applied. These data suggest that inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment in HD.

216. Gene Therapy of Huntington Disease Using RNA Interference and Sleeping Beauty Transposon

Huntington Disease (HD) is a devastating neurologic disorder that is characterized by the abnormal expansion of a CAG repeat in the first exon of the huntingtin gene. This expansion results in the expression of a mutant huntingtin protein with an elongated polyglutamine stretch. The presence and aggregation of this mutant protein is responsible for the characteristic loss of the striatal neurons in HD leading to the clinically observed motor, psychiatric and cognitive deficits. Currently there is no effective treatment to prevent the neuronal loss associated with HD. The aim of this study was to evaluate an innovative gene therapy strategy combining RNA interference (RNAi) and gene transfer via the nonviral Sleeping Beauty (SB) transposon (Tn) system to mitigate the detrimental effects of the mutant huntingtin protein. While RNAi has been successfully used to suppress mammalian gene expression, a major shortcoming is the transient nature of the effect due to the intracellular degradation of the synthetic small interfering RNA (siRNA) molecules and/or the vector encoding the siRNA. By integration of the siRNA construct into the host genome via SB-mediated transposition, long-term suppression of gene expression can be achieved. SB is a functional vertebrate class II Tn element that mediates successful chromosomal insertion and long-term expression of its cargo transgenes in both cell culture and in vivo. We have constructed SB-Tns carrying siRNA transgenes targeting Exons 1, 7 and 62 of the human huntingtin gene. Real-time RT-PCR was used to quantify the huntingtin mRNA transcript levels in human neuroblastoma cells following transfection of the siRNA SB-Tns. In addition, DNA was isolated and subjected to bisulfite-mediated genomic sequencing to determine changes in methylation patterns. The results indicated that significant decreases up to 80% in huntingtin mRNA transcript levels relative to control were observed with several of the siRNA constructs. Interestingly, there was no evidence of increased methylation of CpGs in the regions of the hungtingtin sequence targeted by the siRNAs, suggesting that these specific siRNAs do not invoke epigenetic genomic modification. In addition, stereotaxic injection of an SB-Tn DsRed2 vector into the brains of HD transgenic mice resulted in significant expression of the reporter construct. In conclusion, huntingtin-specific siRNA constructs can down regulate huntingtin gene expression in cell culture. When delivered by the nonviral SB transposon, such constructs can potentially lead to long-term suppression of the mutant huntingtin gene expression, thus obliterating the harmful effects of the mutant protein. The combination of siRNAs, the SB transposon and an accurate transgenic mouse model now allows us to pursue a gene therapy approach for the treatment of HD.

Diagnosis of Huntington disease.

Huntington disease (HD) is a rare, progressive, and fatal autosomal dominant neurodegenerative disorder, typically of adult onset. We reviewed the literature concerning the molecular diagnosis of HD. The discovery of the genetic etiology of HD, a trinucleotide expansion mutation on chromosome 4p, has led to the development of increasingly reliable and valid diagnostic tests that can be applied to symptomatic patients, individuals at risk for HD but currently asymptomatic, fetuses, and embryos. However, the unstable nature of the HD mutation, the lack of effective treatments for HD, the mid-adulthood age of disease onset, and the existence of disorders with the same clinical presentation but different etiology all complicates diagnostic testing. Conscientious laboratory work, knowledgeable interpretation of genetic test results, and the availability of pre- and posttest counseling are essential components of HD diagnosis.

The endocannabinoid system and Huntington's disease.

The research in Huntington's disease (HD) has been growing exponentially during the last decade, since the discovery of the genetic basis that leads to neurodegeneration. HD is one of several progressive neurodegenerative disorders, in which the underlying mutation is a CAG expansion encoding a polyglutamine tract in a specific protein, which in the case of HD, is called huntingtin. The first clinical symptoms of HD are generally psychiatric abnormalities, most commonly depression and mood disturbances. Involuntary choreiform movements and dementia develop over the next 15-20 years, and death generally results from complications derived from immobility. There is currently no cure, or even an effective therapy to offset the decline in mental and motor capabilities suffered by those affected by HD, but recent studies have started to examine the usefulness of different classes of new compounds. Among these, plant-derived, synthetic or endogenous cannabinoids have been proposed to have therapeutic value for the treatment of HD, since they act on cannabinoid CB(1) receptors located in the basal ganglia circuitry, that is affected by the striatal atrophy typical of HD. Recent studies have characterized the changes in these receptors, as well as their endogenous ligands, in the basal ganglia in a variety of animal models of HD. The results are indicative that the endocannabinoid system becomes hypofunctional in this disease, which could be related to the hyperkinesia typical of the earliest phases of this disease. In addition, it has been proposed that the loss of these receptors might be involved in the process of pathogenesis itself. This, together with the well-known protective properties of cannabinoid-related compounds, suggest that, in addition to a symptomatic usefulness, cannabinoids might also serve to delay or to arrest the development of this disease. The present article will review all recent data dealing with the biochemical, pharmacological and therapeutic bases that support a potential role of cannabinoids in the pathogenesis and/or therapeutic treatment of this motor disorder.

Antisense downregulation of mutant huntingtin in a cell model.

Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by an expansion of a CAG repeat sequence in the HD gene. The repeat encodes an expanded polyglutamine tract in the protein huntingtin. The still unknown pathological mechanisms leading to death of specific neurons in the brains of HD patients correlate with the expression of mutant huntingtin. Therefore, we have studied whether mutant huntingtin expression can be downregulated by antisense technique. NT2 precursor cells and differentiated postmitotic NT2-N neurons, respectively, were transfected with plasmid constructs containing exon 1 of the HD gene with expanded CAG repeats in frame with the reporter protein EGFP. The transfected cell cultures were treated with a phosphorothioated antisense oligonucleotide (PS-ASHD/20+) or a control oligonucleotide either by cotransfection or by addition to the culture medium. Expression of the fusion protein containing the mutant huntingtin fragment resulted in diffuse green fluorescence in the cytoplasm and formation of aggregates in some of the NT2 cells and NT2-N neurons. We obtained antisense sequence-specific inhibition of expression of the fusion protein and/or suppression of the aggregate formation in both cell types. In the NT2 cells the antisense effect was dependent on the way of administration of the oligo. The PS-antisense oligo is effective in downregulation of mutant huntingtin, and the reduction of aggregate formation is a sensitive biological marker. The findings suggest that antisense knockdown of huntingtin could be a useful strategy for treatment of HD, and could also be suitable for studies of the normal and pathological function of huntingtin in different cellular model systems.

Cystamine Inhibits Caspase Activity: IMPLICATIONS FOR THE TREATMENT OF POLYGLUTAMINE DISORDERS

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormally expended polyglutamine domain. There is no effective treatment for HD; however, inhibition of caspase activity or prevention of mitochondria dysfunction delays disease progression in HD mouse models. Similarly administration of cystamine, which can inhibit transglutaminase, prolonged survival of HD mice, suggesting that inhibition of transglutaminase might provide a new treatment strategy. However, it has been suggested that cystamine may inhibit other thiol-dependent enzymes in addition to transglutaminase. In this study we show that cystamine inhibits recombinant active caspase-3 in a concentration-dependent manner. At low concentrations cystamine is an uncompetitive inhibitor of caspase-3 activity, becoming a non-competitive inhibitor at higher concentrations. The IC(50) for cystamine-mediated inhibition of caspase-3 activity in vitro was 23.6 microm. In situ cystamine inhibited in a concentration-dependent manner the activation of caspase-3 by different pro-apoptotic agents. Additionally, cystamine inhibited caspase-3 activity to the same extent in cell lines stably overexpressing wild type tissue transglutaminase (tTG), a mutant inactive tTG, or an antisense for tTG, demonstrating that cystamine inhibits caspase activity independently of any effects it may have on the transamidating activity of tTG. Finally, treatment with cystamine resulted in a robust increase in the levels of glutathione. These findings demonstrate that cystamine may prolong neuronal survival and delay the onset of HD by inhibiting caspases and increasing the level of antioxidants such as glutathione.

NEW DATA IN ON DETECTION, PROGRESSION, AND TREATMENT OF HUNTINGTON DISEASE

NEW DATA IN ON DETECTION, PROGRESSION, AND TREATMENT OF HUNTINGTON DISEASE

Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease.

Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo-treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole-treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro-aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD.

Coenzyme Q 10 as a Possible Treatment for Neurodegenerative Diseases

Coenzyme Q 10 (CoQ 10 ) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q 10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ 10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ 10 significantly extended survival in a transgenic mouse model of ALS. CoQ 10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N -methyl- d -aspartate (NMDA) receptor antagonist, remacemide. CoQ 10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.

Clinical Improvisation within Neurological Disease

The purpose of this paper is to examine how clinical improvisation techniques influence the structure of a Huntington's Disease (HD) patient's expressive responses. The paper reviews the literature pertaining to music therapy in the treatment of HD, highlighting that there has been no anecdotal or empirical link made between the specific use of clinical improvisation and the degree of structure in the patient's expressive responses. A case study is then used to illustrate the influence that musical structures have in the organisation of a HD patient's musically expressive and interactive responses. Given the lack of intervention available to meet the expressive and interactive needs of a non-verbal HD patient, this paper argues that music therapy has an important role to play.

Open interconnected model of basal ganglia-thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease.

The early stages of Huntington's disease (HD) present with motor, cognitive, and emotional symptoms. Correspondingly, current models implicate dysfunction of the motor, associative, and limbic basal ganglia-thalamocortical circuits. Available data, however, indicate that in the early stages of the disease, striatal damage is mainly restricted to the associative striatum. Based on an open interconnected model of basal ganglia-thalamocortical organization, we provide a detailed account of the mechanisms by which associative striatal pathology may lead to the complex pattern of motor, cognitive, and emotional symptoms of early HD. According to this account, the degeneration of a direct and several indirect pathways arising from the associative striatum leads to impaired functioning of: (1) the motor circuit, resulting in chorea and bradykinesia, (2) the associative circuit, resulting in abnormal eye movements, "frontal-like" cognitive deficits and "cognitive disinhibition," and (3) the limbic circuit, resulting in affective and psychiatric symptoms. When relevant, this analysis is aided by comparing the symptomatology of HD patients to that of patients with mild to moderate Parkinson's disease, since in the latter there is similar dysfunction of direct pathways but opposite dysfunction of indirect pathways. Finally, we suggest a potential novel treatment of HD and provide supportive evidence from a rat model of the disease.

New Therapeutic Approaches for the Treatment of Huntington’s Disease

The use of transplantation (TR) of fetal neural tissue as a therapeutic method started much later in patients suffering from Huntington's disease (HD) than in those with Parkinson's disease. The clinical trial, following a wide range of animal experiments (neurotoxic models and newly also transgenic mice), includes about 30 HD patients until now. Because of limited use of the human fetal tissue by ethical and technical concerns, there is necessity to search for the alternative sources for neural grafting. The first attempt with xenotransplantation (in 12 HD patients) and with TR of encapsulated genetically modified cells (in 6 HD patients) was performed, but no appreciable improvement of status in any of those patients was noted. Since no effective pharmacological treatment of HD is available, the TR of fetal neural tissue is now the only therapeutic approach which provides a reduction of symptoms in most of grafted patients. The possibilities are enormous offered by neural stem cells, optionally by embryonic stem cells, which could be expanded in cultures, cloned or genetically modified and then grafted into the patient's brain. On the other hand, the neural progenitor and stem cells, normally present within the subependymal layer of the lateral brain ventricles also in adulthood, might be induced to become an endogenous source of glia and neurons participating in the brain's repair.