ABSTRACT
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.
Subject(s)
Huntington Disease , Pluripotent Stem Cells , Animals , Humans , Huntington Disease/genetics , Huntington Disease/surgery , Neurons , Cell- and Tissue-Based Therapy , Corpus StriatumABSTRACT
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.
Subject(s)
Huntington Disease , Neurodegenerative Diseases , Atrophy , Brain/pathology , Brain/surgery , Corpus Striatum/transplantation , Humans , Huntington Disease/surgerySubject(s)
Huntington Disease , Child , Developmental Disabilities , Humans , Huntington Disease/surgery , Stereotaxic TechniquesABSTRACT
No disponible
Subject(s)
Humans , Female , Middle Aged , Gastric Dilatation/diagnostic imaging , Gastric Dilatation/surgery , Huntington Disease/diagnostic imaging , Intestinal Obstruction/etiology , Radiography, Abdominal/methods , Dilatation, Pathologic/diagnostic imaging , Huntington Disease/surgery , Colectomy/methods , Tomography, X-Ray Computed , Intestinal Obstruction/diagnostic imagingABSTRACT
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.
Subject(s)
Allografts/pathology , Huntington Disease/surgery , Acetylcholinesterase/metabolism , Adult , Antigens, CD/metabolism , Brain/pathology , Brain Tissue Transplantation/methods , Calbindin 2/metabolism , Humans , Huntingtin Protein/genetics , Huntington Disease/genetics , Interneurons/metabolism , Interneurons/pathology , Male , Microglia/metabolism , Microglia/pathology , Nerve Tissue Proteins/metabolism , Parvalbumins/metabolismABSTRACT
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.
Subject(s)
Cord Blood Stem Cell Transplantation/methods , Corpus Striatum/physiology , Huntington Disease , Motor Activity/physiology , Oxidative Stress/physiology , Stem Cells/physiology , Animals , Antigens, CD/metabolism , Cell Death , Cell Differentiation/physiology , Cell Line , Convulsants/toxicity , Corpus Striatum/drug effects , Dendrites/pathology , Disease Models, Animal , Electromyography , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Glial Fibrillary Acidic Protein/metabolism , Gliosis/complications , Humans , Huntington Disease/chemically induced , Huntington Disease/pathology , Huntington Disease/physiopathology , Huntington Disease/surgery , Hydrogen Peroxide/pharmacology , Male , Nitro Compounds/toxicity , Oxidants/pharmacology , Propionates/toxicity , Rats , Rotarod Performance Test , Stem Cells/drug effects , Time Factors , Umbilical Cord/cytology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
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.
Subject(s)
Cell Transplantation , GABAergic Neurons/pathology , Huntington Disease/pathology , Laser Capture Microdissection , Animals , Brain/pathology , Cell Survival , Disease Models, Animal , Huntington Disease/metabolism , Huntington Disease/surgery , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Longitudinal Studies , Treatment Outcome , Adult , Algorithms , Antipsychotic Agents/adverse effects , Body Mass Index , Cluster Analysis , Female , Humans , Huntington Disease/surgery , Male , Middle Aged , Models, Statistical , Obesity , Precision MedicineABSTRACT
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)
Subject(s)
Humans , Cuba , Neurology/history , Nervous System Diseases/rehabilitation , Neuronal Plasticity/physiology , Parkinson Disease/drug therapy , Parkinson Disease/surgery , Huntington Disease/surgery , Cell- and Tissue-Based Therapy/mortality , Cell- and Tissue-Based Therapy/trends , Levodopa/therapeutic use , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/surgery , Electroencephalography/methods , Models, Animal , Quality of Life , NeurosciencesABSTRACT
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.
Subject(s)
Anesthesia, General/methods , Huntington Disease/complications , Intubation, Intratracheal/methods , Rare Diseases , Androstanols/administration & dosage , Anesthetics, Intravenous/administration & dosage , Female , Fentanyl/administration & dosage , Gastrostomy/methods , Humans , Huntington Disease/physiopathology , Huntington Disease/surgery , Middle Aged , Neuromuscular Nondepolarizing Agents/administration & dosage , Propofol/administration & dosage , Respiratory Aspiration/prevention & control , RocuroniumABSTRACT
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.
Subject(s)
Drug Compounding/methods , Huntington Disease/surgery , Sertoli Cells/physiology , Sertoli Cells/transplantation , Animals , Animals, Newborn , Apoptosis/genetics , Apoptosis/physiology , Corpus Striatum/cytology , Cyclooxygenase 2/metabolism , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Female , Gene Expression Regulation/physiology , Humans , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntington Disease/genetics , Huntington Disease/mortality , Huntington Disease/physiopathology , Male , Mice , Mice, Transgenic , Motor Activity/physiology , Nitric Oxide Synthase Type II/metabolism , Survival Analysis , Swine , Trinucleotide Repeats/geneticsABSTRACT
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.
Subject(s)
Antimanic Agents/administration & dosage , Huntington Disease/surgery , Lithium Chloride/pharmacology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/drug effects , Valproic Acid/pharmacology , Animals , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Drug Administration Schedule , Female , Gene Expression/drug effects , Gene Expression/genetics , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Male , Mesenchymal Stem Cells/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Phosphopyruvate Hydratase/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism , Up-Regulation/drug effectsABSTRACT
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.
Subject(s)
Huntington Disease/surgery , Neural Stem Cells/physiology , Stem Cell Transplantation/methods , Translational Research, Biomedical , Animals , Disease Models, Animal , Humans , Huntingtin Protein , Huntington Disease/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/geneticsABSTRACT
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.
Subject(s)
Behavior, Animal , Fetal Tissue Transplantation , Fetus , Huntington Disease , Median Eminence/transplantation , Motor Activity , Animals , Heterografts , Humans , Huntington Disease/physiopathology , Huntington Disease/surgery , RatsABSTRACT
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.
Subject(s)
Adipose Tissue/cytology , Corpus Striatum/metabolism , Huntington Disease/surgery , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Transplantation, Heterologous/methods , Animals , Anxiety , Corpus Striatum/pathology , Corpus Striatum/surgery , Disease Models, Animal , Humans , Huntington Disease/pathology , Huntington Disease/psychology , Male , Mesenchymal Stem Cells/cytology , Motor Activity , Rats , Rats, Wistar , Rotarod Performance TestABSTRACT
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.
Subject(s)
Corpus Striatum/transplantation , HLA Antigens , Huntington Disease/blood , Huntington Disease/surgery , Isoantibodies/blood , Allografts , Female , Fetus , Humans , Male , Time FactorsABSTRACT
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.
Subject(s)
Brain Tissue Transplantation , Corpus Striatum/pathology , Fetal Tissue Transplantation , Huntington Disease/surgery , Neuronal Plasticity , Telencephalon/transplantation , Adult , Brain Tissue Transplantation/methods , Central Nervous System Agents/therapeutic use , Cognition Disorders/etiology , Combined Modality Therapy , Corpus Striatum/diagnostic imaging , Fetal Tissue Transplantation/methods , Follow-Up Studies , Gene Expression Profiling , Graft Survival , Humans , Huntington Disease/drug therapy , Huntington Disease/pathology , Huntington Disease/psychology , Italy , Magnetic Resonance Imaging , Male , Neuroimaging , Positron-Emission Tomography , Robotics , Severity of Illness Index , Stereotaxic Techniques , Telencephalon/embryology , Telencephalon/metabolismABSTRACT
PURPOSE: Intrastriatal neural transplantation using multiple grafts is an experimental approach to the treatment of Huntington's disease (HD). Brain atrophy makes stereotactic plans in these patients a tedious procedure with a risk of suboptimal spatial distribution of the grafts in transplantation procedures. Here we present a self-developed software to optimize the surgical stereotactic planning for bilateral neurotransplantation procedures. It allows close to symmetrical distribution of the stereotactic coordinates in relation to the mid-commissural point (MCP), proposing automatically the planning coordinates for the first transplanted hemisphere and mirrored coordinates to be used in the contra-lateral hemisphere. METHODS: Twenty-two consecutive HD patients underwent bilateral stereotactic striatal transplantation. Two caudate nucleus and four putaminal tracks were planned bilaterally. For the second, contra-lateral transplantation, the coordinates were mirrored in order to determine contralateral targets and trajectories. Intra-individual comparison between software given coordinates and finally used coordinates was performed. RESULTS: No statistical significance was found comparing a) the differences between coordinates proposed by the software and the final coordinates and b) the distribution of the transplantation sites in relation to the midline for the right vs. left hemisphere. No intra- or postoperative transplantation-related adverse events occurred. CONCLUSIONS: The use of model-based and mirrored coordinates allowed optimal spatial distribution of the grafts. Minor changes were required comparing right to left coordinates giving proof-of principle. The initial use of the software suggests that it may be useful in experimental transplantation trials where neural cell grafts are to be implanted into predefined target sites in the human brain, whether unilateral or bilateral.
