RESUMEN
INTRODUCTION: Huntington's disease (HD) is a hereditary condition caused by the expansion of the CAG trinucleotide in the huntingtin gene on chromosome 4, resulting in motor, cognitive, and psychiatric disorders that significantly impact patients' quality of life. Despite the lack of effective treatments for the disease, various surgical strategies have been explored to alleviate symptoms and slow its progression. METHODOLOGY: A comprehensive systematic literature review was conducted, including MeSH terms, yielding only 38 articles that were categorized based on the surgical procedure. The study aimed to describe the types of surgeries performed and their efficacy in HD patients. RESULTS: Deep brain stimulation (DBS) involved 41 predominantly male patients with bilateral implantation in the globus pallidus, showing a preoperative Unified Huntington's Disease Rating Scale (UHDRS) score of 60.25 ± 16.13 and a marked postoperative value of 48.54 ± 13.93 with a p < 0.018 at one year and p < 0.040 at three years. Patients experienced improvement in hyperkinesia but worsening of bradykinesia. Additionally, cell transplantation in 119 patients resulted in a lower preoperative UHDRS score of 34.61 ± 14.61 and a significant postoperative difference of 32.93 ± 15.87 (p < 0.016), respectively, in the first to third years of following. Some now, less used procedures were crucial for understanding brain function, such as pallidotomies in 3 patients, showing only a 25 % difference from their baseline. CONCLUSION: Despite advancements in technology, there is still no curative treatment, only palliative options. Promising treatments like trophic factor implantation offer new prospects for the future.
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Estimulación Encefálica Profunda , Enfermedad de Huntington , Enfermedad de Huntington/cirugía , Enfermedad de Huntington/terapia , Humanos , Procedimientos Neuroquirúrgicos/métodosRESUMEN
BACKGROUND: Clinically assisted nutrition and hydration via percutaneous endoscopic gastrostomy (PEG) is a therapeutic option to ameliorate the difficulties associated with enhanced catabolism, weight loss, and dysphagia in Huntington's disease (HD). OBJECTIVES: The objective is to provide insights into demographics, staging (Shoulson-Fahn), complications, weight trajectories, and survival rates in people with HD (pwHD) who underwent PEG. METHODS: This retrospective study included 705 consecutive pwHD who attended our HD clinic between July 2006 and March 2024, of whom 52 underwent PEG. A control group (n = 52), comprising pwHD without PEG, were closely matched for sex, stage, age, CAG length, and disease burden score at PEG. The study was registered as a service evaluation at the National Hospital for Neurology and Neurosurgery. RESULTS: PEG prevalence was 15.0% (n = 52/347) among manifest pwHD: 4.8% (n = 3/62) for Stage 3; 33.3% (n = 16/48) for stage 4; and 44.1% (n = 30/68) for stage 5. Commonest indications were dysphagia, weight loss, and inadequate oral intake. Complications included chest infection, tube dislodgement, and peristomal and skin infections. Modeling of weight trajectories after PEG found no difference between PEG and non-PEG groups. Mortality rate was 34.6% (n = 18/52) in the PEG and 36.5% (n = 19/52) in the non-PEG groups (P = 0.84). Treatment duration (until study endpoint or death) was 3.48 years (interquartile range = 1.71-6.02; range = 0.23-18.8), with 65.4% (n = 34/52) alive at the study endpoint. CONCLUSION: PEG in pwHD at-risk for weight loss may help slow weight loss. Prospective studies are required to strengthen PEG decision-making in pwHD. PEG survival was much longer than other dementias, highlighting the need to consider PEG independently in pwHD.
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Gastrostomía , Enfermedad de Huntington , Humanos , Masculino , Femenino , Gastrostomía/métodos , Gastrostomía/efectos adversos , Enfermedad de Huntington/mortalidad , Enfermedad de Huntington/cirugía , Enfermedad de Huntington/terapia , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Trastornos de Deglución/etiología , Centros de Atención Terciaria , Resultado del Tratamiento , Pérdida de Peso , Anciano , Nutrición Enteral/métodosRESUMEN
Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by a triad of symptoms: motor, cognitive and psychiatric. HD is caused by a genetic mutation, expansion of the CAG repeat in the huntingtin gene, which results in loss of medium spiny neurons (MSNs) of the striatum. Cell replacement therapy (CRT) has emerged as a possible therapy for HD, aiming to replace those cells lost to the disease process and alleviate its symptoms. Initial pre-clinical studies used primary fetal striatal cells to provide proof-of-principal that CRT can bring about functional recovery on some behavioral tasks following transplantation into HD models. Alternative donor cell sources are required if CRT is to become a viable therapeutic option and human pluripotent stem cell (hPSC) sources, which have undergone differentiation toward the MSNs lost to the disease process, have proved to be strong candidates. The focus of this chapter is to review work conducted on the functional assessment of animals following transplantation of hPSC-derived MSNs. We discuss different ways that graft function has been assessed, and the results that have been achieved to date. In addition, this chapter presents and discusses challenges that remain in this field.
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Enfermedad de Huntington , Células Madre Pluripotentes , Animales , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/cirugía , Neuronas , Tratamiento Basado en Trasplante de Células y Tejidos , Cuerpo EstriadoRESUMEN
Huntington's disease is a rare, severe, and inherited neurodegenerative disorder that affects young adults. To date, there is no treatment to stop its progression. The primary atrophy of the striatum in HD, is limited in space and centrally focalised in the brain and thus constitutes a good candidate for graft. Therefore, transplantation of foetal cells from the ganglionic eminence, the germinal zone of the striatum, has the potential to restore disrupted fronto-cortical circuits and corresponding clinical functions. The international Multicentric intracerebral Grafting in Huntington's disease trial was not as successful as two pilot trials (Créteil and London) which showed promising results in the 2000s, displaying stabilisation/recovery of symptoms in some patients. A point-by-point comparison of the differences between MIG-HD and the pilot trial from Créteil in which similar data are available provides lessons on the grafting procedure and allows for strategic thinking before embarking on future trials. MIG-HD demonstrated the existence of intracerebral alloimmunisation leading to acute or chronic graft rejection into the brain and showed the limitations of surgical standardisation and immunosuppression. It has also improved the safety of the procedure and provided guidance for the follow-up of future patients. Indeed, even if disease modifiers treatments are currently the focus of intense research, they may not stop or slow the progression of the disease sufficiently, or even be administered in all patients, to prevent brain atrophy in all cases. Although disease-modifying therapies are currently the subject of intense research, they may not stop or slow disease progression sufficiently, or may not be given to all patients to prevent brain atrophy. A combination with intracerebral transplantation to repair the damaged structures may thus prove beneficial. Altogether, pursuing research in intracerebral transplantation remains necessary.
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Enfermedad de Huntington , Enfermedades Neurodegenerativas , Atrofia , Encéfalo/patología , Encéfalo/cirugía , Cuerpo Estriado/trasplante , Humanos , Enfermedad de Huntington/cirugíaRESUMEN
No disponible
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Humanos , Femenino , Persona de Mediana Edad , Dilatación Gástrica/diagnóstico por imagen , Dilatación Gástrica/cirugía , Enfermedad de Huntington/diagnóstico por imagen , Obstrucción Intestinal/etiología , Radiografía Abdominal/métodos , Dilatación Patológica/diagnóstico por imagen , Enfermedad de Huntington/cirugía , Colectomía/métodos , Tomografía Computarizada por Rayos X , Obstrucción Intestinal/diagnóstico por imagenRESUMEN
For patients with incurable neurodegenerative disorders such as Huntington's (HD) and Parkinson's disease, cell transplantation has been explored as a potential treatment option. Here, we present the first clinicopathological study of a patient with HD in receipt of cell-suspension striatal allografts who took part in the NEST-UK multicenter clinical transplantation trial. Using various immunohistochemical techniques, we found a discrepancy in the survival of grafted projection neurons with respect to grafted interneurons as well as major ongoing inflammatory and immune responses to the grafted tissue with evidence of mutant huntingtin aggregates within the transplant area. Our results indicate that grafts can survive more than a decade post-transplantation, but show compromised survival with inflammation and mutant protein being observed within the transplant site. Ann Neurol 2018;84:950-956.
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Aloinjertos/patología , Enfermedad de Huntington/cirugía , Acetilcolinesterasa/metabolismo , Adulto , Antígenos CD/metabolismo , Encéfalo/patología , Trasplante de Tejido Encefálico/métodos , Calbindina 2/metabolismo , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Interneuronas/metabolismo , Interneuronas/patología , Masculino , Microglía/metabolismo , Microglía/patología , Proteínas del Tejido Nervioso/metabolismo , Parvalbúminas/metabolismoRESUMEN
Huntington disease (HD) is an inherited disorder hallmarked by progressive deterioration of specific neurons, followed by movement and cognitive anomalies. Cell therapy approaches in neurodegenerative conditions have concentrated on the replenishment of lost/dying neurons with functional ones. Multipotent mesenchymal stem cells (MSCs) have been represented as a potential remedy for HD. In this study, we evaluated the in vitro and in vivo efficacy of umbilical cord matrix stem cells (UCMSCs) and their paracrine effect against oxidative stress with a specific focus on HD. To this end, UCMSCs were isolated, immunophenotypically characterized by the positive expression of MSC markers, and exhibited multilineage potentiality. Besides, synthesis of neurotrophic factors of GDNF and VEGF by UCMSC was confirmed. Initially, PC12 cells were exposed to superoxide in the presence of conditioned media (CM) collected from UCMSC (UCMSC-CM) and cell viability plus neuritogenesis were measured. Next, bilateral striatal transplantation of UCMSC in 3-nitropropionic acid (3-NP) lesioned rat models was conducted, and 1 month later, post-graft analysis was performed. According to our in vitro results, CM of UCMSC protected PC12 cells against oxidative stress and considerably enhanced cell viability and neurite outgrowth. On the other hand, transplanted UCMSC survived, decreased gliosis, and ameliorated motor coordination and muscle activity, along with an increase in striatal volume as well as in dendritic length of the striatum in HD rats. Collectively, our findings imply that UCMSCs provide an enriched platform by largely their paracrine factors, which downgrades the unfavorable effects of oxidative stress.
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Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Cuerpo Estriado/fisiología , Enfermedad de Huntington , Actividad Motora/fisiología , Estrés Oxidativo/fisiología , Células Madre/fisiología , Animales , Antígenos CD/metabolismo , Muerte Celular , Diferenciación Celular/fisiología , Línea Celular , Convulsivantes/toxicidad , Cuerpo Estriado/efectos de los fármacos , Dendritas/patología , Modelos Animales de Enfermedad , Electromiografía , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/complicaciones , Humanos , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/patología , Enfermedad de Huntington/fisiopatología , Enfermedad de Huntington/cirugía , Peróxido de Hidrógeno/farmacología , Masculino , Nitrocompuestos/toxicidad , Oxidantes/farmacología , Propionatos/toxicidad , Ratas , Prueba de Desempeño de Rotación con Aceleración Constante , Células Madre/efectos de los fármacos , Factores de Tiempo , Cordón Umbilical/citología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Organotypic brain slice cultures have been recently used to study neurodegenerative disorders such as Parkinson's disease and Huntington's disease (HD). They preserve brain three-dimensional architecture, synaptic connectivity and brain cells microenvironment. Here, we developed an innovative model of Huntington's disease from coronal rat brain slices, that include all the areas involved in the pathology. HD-like neurodegeneration was obtained in only one week, in a single step, during organotypic slice preparation, without the use of neurotoxins. HD-like histopathology was analysed and after one week, a reduction of 40% of medium spiny neurons was observed. To analyse new therapeutic approaches in this innovative HD model, we developed a novel protocol of laser microdissection to isolate and analyse by RT-qPCR, grafted cells as well as surrounding tissue of fresh organotypic slices. We determined that laser microdissection could be performed on a 400µm organotypic slice after alcohol dehydration protocol, allowing the analysis of mRNA expression in the rat tissue as well as in grafted cells. In conclusion, we developed a new approach for modeling Huntington's disease ex vivo, and provided a useful innovative method for screening new potential therapies for neurodegenerative diseases especially when associated with laser microdissection.
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Trasplante de Células , Neuronas GABAérgicas/patología , Enfermedad de Huntington/patología , Captura por Microdisección con Láser , Animales , Encéfalo/patología , Supervivencia Celular , Modelos Animales de Enfermedad , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/cirugía , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Heterogeneity in treatment efficacy is a major concern in clinical trials. Clustering may help to identify the treatment responders and the non-responders. In the context of longitudinal cluster analyses, sample size and variability of the times of measurements are the main issues with the current methods. Here, we propose a new two-step method for the Clustering of Longitudinal data by using an Extended Baseline. The first step relies on a piecewise linear mixed model for repeated measurements with a treatment-time interaction. The second step clusters the random predictions and considers several parametric (model-based) and non-parametric (partitioning, ascendant hierarchical clustering) algorithms. A simulation study compares all options of the clustering of longitudinal data by using an extended baseline method with the latent-class mixed model. The clustering of longitudinal data by using an extended baseline method with the two model-based algorithms was the more robust model. The clustering of longitudinal data by using an extended baseline method with all the non-parametric algorithms failed when there were unequal variances of treatment effect between clusters or when the subgroups had unbalanced sample sizes. The latent-class mixed model failed when the between-patients slope variability is high. Two real data sets on neurodegenerative disease and on obesity illustrate the clustering of longitudinal data by using an extended baseline method and show how clustering may help to identify the marker(s) of the treatment response. The application of the clustering of longitudinal data by using an extended baseline method in exploratory analysis as the first stage before setting up stratified designs can provide a better estimation of treatment effect in future clinical trials.
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Estudios Longitudinales , Resultado del Tratamiento , Adulto , Algoritmos , Antipsicóticos/efectos adversos , Índice de Masa Corporal , Análisis por Conglomerados , Femenino , Humanos , Enfermedad de Huntington/cirugía , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Obesidad , Medicina de PrecisiónRESUMEN
Introducción: Con la creación en 1989 del CIREN, Cuba entró en la nueva era de la neurología. Durante la segunda mitad del siglo XX los conceptos de la neurociencia evolucionaron del estatismo a un sistema adaptable y cambiante, moldeado por la experiencia, a través de la propiedad de plasticidad neuronal. El objetivo del trabajo es presentar los logros más relevantes de este esfuerzo de investigación enesta institución.Desarrollo: Además de la atención de pacientes cubanos y extranjeros, se ha desarrollado una intensa investigación sobre todas las herramientas potenciales que podrían servir para recuperar o restaurar la función nerviosa afectada por traumatismos o enfermedad. El paso inicial fue el trasplante neural de células dopaminérgicas a pacientes parkinsonianos. Otras intervenciones de la neurocirugía funcional o resectiva también se intentaron para trastornos del movimiento o epilepsia. La investigación básica ha contribuido a confirmar los beneficios esperados para tratar con éxito los trastornos degenerativos, y los programas de neurorrehabilitación diseñados tratan deinducir un entorno promotor de la plasticidad para maximizar la recuperación.Conclusiones: La investigación en el CIREN ocupa un lugar privilegiado. Algunos resultados han traído nuevos tratamientos clínicos y quirúrgicos. Otros, principalmente los de investigación básica, aún no han encontrado una traducción terapéutica. Pero todos han contribuido en gran medida a dar forma al perfil único de esta institución cubana. La manera de avanzar en los pasos firmes hacia eseobjetivo, es el camino de una ciencia sólida y de alto nivel(AU)
Introduction: With the creation in 1989 of CIREN, Cuba entered the new era of neurology. During the second half of the twentieth century the concepts of neuroscience evolved from statist to an adaptable and changing system, shaped by experience, through the property ofneuronal plasticity. The objective of the work is to present the most relevant achievements of this research effort in this institution.Development: In addition to the care of Cuban and foreign patients, an intense research has been developed on all the potential tools that could be used to recover or restore nerve function affected by trauma or disease. The initial step was the neural transplantation of dopaminergic cells to parkinsonian patients. Other interventions of functional or resective neurosurgery were also tried for movement disorders or epilepsy. Basic research has helped to confirm benefits expected to successfully treat degenerative disorders, andneurorehabilitation programs designed to induce a plasticity promoting environment to maximize recovery.Conclusions: Research at CIREN occupies a privileged place in the interests of the institution. Some results have brought new clinical andsurgical treatments. Others, mainly those of basic research, have not yet found a therapeutic translation. But all have contributed greatly to shaping the unique profile of this Cuban institution. The way to advance in the firm steps towards that goal is the trend of a solid and high level science(AU)
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Humanos , Cuba , Neurología/historia , Enfermedades del Sistema Nervioso/rehabilitación , Plasticidad Neuronal/fisiología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/cirugía , Enfermedad de Huntington/cirugía , Tratamiento Basado en Trasplante de Células y Tejidos/mortalidad , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Levodopa/uso terapéutico , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/cirugía , Electroencefalografía/métodos , Modelos Animales , Calidad de Vida , NeurocienciasRESUMEN
We present a case that highlights the issues surrounding the delivery of a safe general anaesthetic to a patient with Huntington's disease (HD) and bulbar dysfunction. In the case of a 46-year-old patient undergoing laparoscopic percutaneous endoscopic gastrostomy tube insertion, we discuss the rationale behind our chosen method and anaesthetic agents as well as airway issues specific to HD. In a patient whose condition would not allow for an awake fibreoptic intubation, we opted for a modified rapid sequence induction. Special considerations were made with regard to muscle relaxation given the complications associated with inadequate paralysis and reversal in patients with HD. The technique we describe may also apply to other patient categories, such as patients with movement disorders, bulbar dysfunction and dementia.
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Anestesia General/métodos , Enfermedad de Huntington/complicaciones , Intubación Intratraqueal/métodos , Enfermedades Raras , Androstanoles/administración & dosificación , Anestésicos Intravenosos/administración & dosificación , Femenino , Fentanilo/administración & dosificación , Gastrostomía/métodos , Humanos , Enfermedad de Huntington/fisiopatología , Enfermedad de Huntington/cirugía , Persona de Mediana Edad , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Propofol/administración & dosificación , Aspiración Respiratoria/prevención & control , RocuronioRESUMEN
INTRODUCTION: Immune dysfunction, promoted by pro-inflammatory cytokines, plays a pivotal role in neurodegeneration associated with Huntington's disease. AIMS: The aim of this study was to investigate the emerging immunoregulatory and antiinflammatory properties of Sertoli cells in Huntington's disease. METHODS: The experimental R6/2 mouse model of Huntington's disease was treated by a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells and lifespan, motor performance and striatal inflammatory pattern have been evaluated. RESULTS: The results of this study demonstrated that a single intraperitoneal injection of microencapsulated prepubertal porcine Sertoli cells uniquely improved performances and extended the life expectancy of R6/2 Huntington's disease mice, by immune dysfunction modulation in brain. CONCLUSIONS: This study highlights the immunomodulatory and trophic role of Sertoli cells that could be of help in the treatment of neurodegenerative disorders.
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Composición de Medicamentos/métodos , Enfermedad de Huntington/cirugía , Células de Sertoli/fisiología , Células de Sertoli/trasplante , Animales , Animales Recién Nacidos , Apoptosis/genética , Apoptosis/fisiología , Cuerpo Estriado/citología , Ciclooxigenasa 2/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/fisiología , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/mortalidad , Enfermedad de Huntington/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Actividad Motora/fisiología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Análisis de Supervivencia , Porcinos , Repeticiones de Trinucleótidos/genéticaRESUMEN
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells. Our results suggest that preconditioning stem cells with the mood stabilizers lithium and VPA before transplantation may serve as an effective strategy for enhancing the therapeutic efficacy of stem cell-based therapies.
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Antimaníacos/administración & dosificación , Enfermedad de Huntington/cirugía , Cloruro de Litio/farmacología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Esquema de Medicación , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Masculino , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Fosfopiruvato Hidratasa/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.
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Conducta Animal , Trasplante de Tejido Fetal , Feto , Enfermedad de Huntington , Eminencia Media/trasplante , Actividad Motora , Animales , Xenoinjertos , Humanos , Enfermedad de Huntington/fisiopatología , Enfermedad de Huntington/cirugía , RatasRESUMEN
Huntington disease (HD) is a devastating neurological disorder caused by an extended CAG repeat in exon 1 of the gene that encodes the huntingtin (HTT) protein. HD pathology involves a loss of striatal medium spiny neurons (MSNs) and progressive neurodegeneration affects the striatum and other brain regions. Because HTT is involved in multiple cellular processes, the molecular mechanisms of HD pathogenesis should be investigated on multiple levels. On the cellular level, in vitro stem cell models, such as induced pluripotent stem cells (iPSCs) derived from HD patients and HD embryonic stem cells (ESCs), have yielded progress. Approaches to differentiate functional MSNs from ESCs, iPSCs, and neural stem/progenitor cells (NSCs/NPCs) have been established, enabling MSN differentiation to be studied and disease phenotypes to be recapitulated. Isolation of target stem cells and precursor cells may also provide a resource for grafting. In animal models, transplantation of striatal precursors differentiated in vitro to the striatum has been reported to improve disease phenotype. Initial clinical trials examining intrastriatal transplantation of fetal neural tissue suggest a more favorable clinical course in a subset of HD patients, though shortcomings persist. Here, we review recent advances in the development of cellular HD models and approaches aimed at cell regeneration with human stem cells. We also describe how genome editing tools could be used to correct the HTT mutation in patient-specific stem cells. Finally, we discuss the potential and the remaining challenges of stem cell-based approaches in HD research and therapy development.
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Enfermedad de Huntington/cirugía , Células-Madre Neurales/fisiología , Trasplante de Células Madre/métodos , Investigación Biomédica Traslacional , Animales , Modelos Animales de Enfermedad , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genéticaRESUMEN
Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0-49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.
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Cuerpo Estriado/trasplante , Antígenos HLA , Enfermedad de Huntington/sangre , Enfermedad de Huntington/cirugía , Isoanticuerpos/sangre , Aloinjertos , Femenino , Feto , Humanos , Masculino , Factores de TiempoRESUMEN
Human mesenchymal stem cells (hMSCs) have been presented as alternative sources of cells to be transplanted into the brain in neurodegenerative disorders. In this regard, the efficacy of hMSCs transplants in reducing motor and non-motor deficits in a quinolinic acid (QA) rat model of Huntington's disease (HD) was tested in the present study. After unilateral lesions in striatum by QA, the isolated and purified hMSCs from liposuction of healthy male donors were transplanted into the damaged striatum of the rats. The cells were stably transfected with a vector containing TurboGFP and JRed to make it possible to trace them after transplantation. Animals were tested by motor and non-motor function tests at different times after the cell transplantation. The hMSCs survived 7 weeks in the brains. An improvement was observed in behavioral tests such as apomophine-induced rotation, hanging wire, and rotarod for the hMSC-treated rats. Anxiety like behaviors were decreased in hMSCs-treated animals when they were examined using open field, elevated plus maze, light and dark box, and novelty suppressed feeding tests. Compared to QA, the hMSCs treatment decreased motor activities. These results confirmed the potential efficacy of hMSCs in treatment of behavioral defects in HD. Generally, the data demonstrated that xenologous transplantation of hMSCs could be considered as an ideal candidate for treatment of neurodegenerative diseases, especially HD.
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Tejido Adiposo/citología , Cuerpo Estriado/metabolismo , Enfermedad de Huntington/cirugía , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Trasplante Heterólogo/métodos , Animales , Ansiedad , Cuerpo Estriado/patología , Cuerpo Estriado/cirugía , Modelos Animales de Enfermedad , Humanos , Enfermedad de Huntington/patología , Enfermedad de Huntington/psicología , Masculino , Células Madre Mesenquimatosas/citología , Actividad Motora , Ratas , Ratas Wistar , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
BACKGROUND: Restoration of functions in Huntington's disease (HD) by neurotransplantation stems from the formation of a striatum-like structure capable of establishing host connections as a result of grafted striatal neuroblast maturation. For the first time, we demonstrated some developmental steps accomplished by progenitor cells in the brain of an HD patient and analysed the molecular asset of the human primordium. CASE REPORT: Surgery involved bilateral (two sessions) stereotactic, caudate-putaminal transplantation of whole ganglionic eminence fragments from single legally aborted fetuses. MRI showed that the tissue deposits of the left hemisphere grew and joined to constitute a single tissue mass that remodelled basal ganglia anatomy and remained stable in size over time. No evidence of graft growth was observed contralaterally. PET demonstrated increased striatal and stable cortical metabolism. Unified Huntington's Disease Rating Scale assessments demonstrated improvement of motor performances, which faded over the 36-month follow-up. Cognitive performance tended to decrease at a lower rate than before transplantation. CONCLUSION: The striatal primordium grew into the host brain and this process was associated with metabolic change and some clinical benefit. The study suggests the plasticity and reparative potential of un-manipulated primordium in an era where promising cell-based therapies are still in their infancy.