RESUMO
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.
Assuntos
Estimulação Encefálica Profunda , Doença de Huntington , Doença de Huntington/cirurgia , Doença de Huntington/terapia , Humanos , Procedimentos Neurocirúrgicos/métodosRESUMO
The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions of hundreds of CAGs have been detected in Huntington's disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington's disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington's disease brains is required for pathogenesis. Therefore, the pathogenic repeat threshold in brain is longer than (CAG)40, as measured in blood, and is currently unknown. The mismatch repair gene MSH3 has become a major focus for therapeutic development, as unlike other mismatch repair genes, nullizygosity for MSH3 does not cause malignancies associated with mismatch repair deficiency. Potential treatments targeting MSH3 currently under development include gene therapy, biologics and small molecules, which will be assessed for efficacy in mouse models of Huntington's disease. The zQ175 knock-in model carries a mutation of approximately (CAG)185 and develops early molecular and pathological phenotypes that have been extensively characterized. Therefore, we crossed the mutant huntingtin allele onto heterozygous and homozygous Msh3 knockout backgrounds to determine the maximum benefit of targeting Msh3 in this model. Ablation of Msh3 prevented somatic expansion throughout the brain and periphery, and reduction of Msh3 by 50% decreased the rate of expansion. This had no effect on the deposition of huntingtin aggregation in the nuclei of striatal neurons, nor on the dysregulated striatal transcriptional profile. This contrasts with ablating Msh3 in knock-in models with shorter CAG repeat expansions. Therefore, further expansion of a (CAG)185 repeat in striatal neurons does not accelerate the onset of molecular and neuropathological phenotypes. It is striking that highly expanded CAG repeats of a similar size in humans cause disease onset before 2 years of age, indicating that somatic CAG repeat expansion in the brain is not required for pathogenesis. Given that the trajectory for somatic CAG expansion in the brains of Huntington's disease mutation carriers is unknown, our study underlines the importance of administering treatments targeting somatic instability as early as possible.
Assuntos
Proteína Huntingtina , Doença de Huntington , Expansão das Repetições de Trinucleotídeos , Doença de Huntington/genética , Doença de Huntington/terapia , Animais , Humanos , Expansão das Repetições de Trinucleotídeos/genética , Camundongos , Proteína Huntingtina/genética , Proteína 3 Homóloga a MutS/genética , Modelos Animais de Doenças , Proteínas do Tecido Nervoso/genética , Encéfalo/patologia , Encéfalo/metabolismoRESUMO
Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.
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Doença de Alzheimer , Doença de Huntington , Doenças Neurodegenerativas , Doença de Parkinson , Feminino , Gravidez , Humanos , Doenças Neurodegenerativas/terapia , Doença de Huntington/terapia , Doença de Parkinson/terapia , Células-TroncoRESUMO
INTRODUCTION: Palliative care focuses on improving patient and family quality of life by managing symptoms, psychosocial issues and spiritual concerns. Huntington's disease is a progressive neurodegenerative disorder with no current disease modifying therapy. Although the palliative care model has been postulated to be an integral part of HD care, there are gaps in knowledge about how this care should be implemented. This study aims to identify perceptions of palliative care in Huntington's Disease (HD), palliative care needs of people living with HD, and at what point they feel they would benefit from these resources. METHODS: Participants volunteered from a large academic institution patient base to be involved in semi structured interviews that explored patient and caregiver experience surrounding their diagnosis, disease management, quality of life, and areas for improvement. Inclusion criteria for participants was a diagnosis of Huntington's disease and/or a self-identified caregiver of a person living with the disease. RESULTS: A total of 12 independent patients, three independent caregivers, and five dyads completed the interviews. Themes identified included needs that would provide patient and caregiver centered treatment, current gaps in care, an openness and desire for palliative care, and knowledge about the desired timing of palliative care in treatment plans. CONCLUSION: People living with HD and caregivers of people with HD most desire access to treatment that would focus on symptom management, availability of social resources, advanced care planning and spiritual wellbeing. The preferred timing of this intervention for most individuals would be at the onset of symptoms.
Assuntos
Doença de Huntington , Cuidados Paliativos , Humanos , Doença de Huntington/terapia , Doença de Huntington/psicologia , Qualidade de Vida , Pesquisa Qualitativa , Cuidadores/psicologiaRESUMO
Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.
Assuntos
Doença de Huntington , Células-Tronco Neurais , Humanos , Camundongos , Animais , Doença de Huntington/genética , Doença de Huntington/terapia , Corpo Estriado , Neurônios , Fenótipo , Modelos Animais de Doenças , Camundongos Transgênicos , Proteína Huntingtina/genéticaRESUMO
BACKGROUND: Huntington's disease (HD) is a motor and cognitive neurodegenerative disorder due to prominent loss of striatal medium spiny neurons (MSNs). Cell replacement using human embryonic stem cells (hESCs) derivatives may offer new therapeutic opportunities to replace degenerated neurons and repair damaged circuits. METHODS: With the aim to develop effective cell replacement for HD, we assessed the long-term therapeutic value of hESC-derived striatal progenitors by grafting the cells into the striatum of a preclinical model of HD [i.e., adult immunodeficient rats in which the striatum was lesioned by monolateral injection of quinolinic acid (QA)]. We examined the survival, maturation, self-organization and integration of the graft as well as its impact on lesion-dependent motor alterations up to 6 months post-graft. Moreover, we tested whether exposing a cohort of QA-lesioned animals to environmental enrichment (EE) could improve graft integration and function. RESULTS: Human striatal progenitors survived up to 6 months after transplantation and showed morphological and neurochemical features typical of human MSNs. Donor-derived interneurons were also detected. Grafts wired in both local and long-range striatal circuits, formed domains suggestive of distinct ganglionic eminence territories and displayed emerging striosome features. Moreover, over time grafts improved complex motor performances affected by QA. EE selectively increased cell differentiation into MSN phenotype and promoted host-to-graft connectivity. However, when combined to the graft, the EE paradigm used in this study was insufficient to produce an additive effect on task execution. CONCLUSIONS: The data support the long-term therapeutic potential of ESC-derived human striatal progenitor grafts for the replacement of degenerated striatal neurons in HD and suggest that EE can effectively accelerate the maturation and promote the integration of human striatal cells.
Assuntos
Transplante de Tecido Encefálico , Células-Tronco Embrionárias Humanas , Doença de Huntington , Ratos , Animais , Humanos , Doença de Huntington/terapia , Corpo Estriado/fisiologia , Neurônios , Modelos Animais de DoençasRESUMO
Huntington's disease (HD) is a neurodegenerative disorder caused by an autosomal dominant mutation leading to an abnormal CAG repeat expansion. The result is the synthesis of a toxic misfolded protein, called the mutant huntingtin protein (mHTT). Most current treatments are palliative, but the latest research has expanded into multiple modalities, including stem cells, gene therapy, and even the use of 3D cell structures, called organoids. Stem cell research as a treatment for HD has included the use of various types of stem cells, such as mesenchymal stem cells, neural stem cells, embryonic stem cells, and even reprogrammed stem cells called induced pluripotent stem cells. The goal has been to develop stem cell transplant grafts that will replace the existing mutated neurons, as well as release existing trophic factors for neuronal support. Additionally, research in gene modification using CRISPR-Cas9, PRIME editing, and other forms of genetic modifications are continuing to evolve. Most recently, advancements in stem cell modeling have yielded 3D stem cell tissue models, called organoids. These organoids offer the unique opportunity to transplant a structured stem cell graft which, ideally, models normal human brain tissue more accurately. This manuscript summarizes the recent research in stem cells, genetic modifications, and organoids as a potential for treatment of HD.
Assuntos
Doença de Huntington , Células-Tronco Neurais , Doenças Neurodegenerativas , Humanos , Doença de Huntington/genética , Doença de Huntington/terapia , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Células-Tronco Embrionárias/metabolismo , Doenças Neurodegenerativas/metabolismoRESUMO
Huntington's disease (HD) is a severe neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify a fully chemically modified short interfering RNA (siRNA) that robustly silences Msh3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of Msh3 effectively blocked CAG-repeat expansion in the striatum of two HD mouse models without affecting tumor-associated microsatellite instability or mRNA expression of other MMR genes. Our findings establish a promising treatment approach for patients with HD and other repeat expansion diseases.
Assuntos
Doença de Huntington , Proteína 3 Homóloga a MutS , Expansão das Repetições de Trinucleotídeos , Animais , Camundongos , Corpo Estriado/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/terapia , Doença de Huntington/metabolismo , Neostriado/metabolismo , RNA de Cadeia Dupla , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Expansão das Repetições de Trinucleotídeos/genética , Proteína 3 Homóloga a MutS/genéticaRESUMO
BACKGROUND: As Huntington's disease (HD) is a progressive disease for which there is no cure yet, patients in the advanced stage of HD may benefit from palliative care. OBJECTIVE: To review the literature focusing on palliative care in advanced stage HD, and the level of evidence. METHODS: Publications between 1993 and October 29th, 2021 from 8 databases (Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier, PMC PubMed Central and Pubmed) were included. The literature was deductively classified based on topics that are part of the definition of palliative care, or as care-related topics that emerged from the literature. Levels of evidence I (high) - V (low) were determined as defined by the Joanna Briggs Institute. RESULTS: Our search resulted in 333 articles, 38 of which were included. The literature covered four domains of palliative care: physical care, psychological care, spiritual care, and social care. Four other topics in the literature were: advance care planning, end-of-life needs assessments, pediatric HD care, and need for health care services. Most literature was underpinned by a low level of evidence, except for the topics on social care (Level III-V), advance care planning (Level II-V) and end-of-life needs assessments (Level II-III). CONCLUSIONS: To deliver adequate palliative care in advanced HD, both general and HD-specific symptoms and problems need to be addressed. As the level of evidence in existing literature is low, further research is essential to improve palliative care and to meet patient's wishes and needs.
Assuntos
Planejamento Antecipado de Cuidados , Enfermagem de Cuidados Paliativos na Terminalidade da Vida , Doença de Huntington , Criança , Humanos , Cuidados Paliativos/métodos , Doença de Huntington/terapia , MorteRESUMO
Stem cells have been the subject of research for years due to their enormous therapeutic potential. Most neurological diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are incurable or very difficult to treat. Therefore new therapies are sought in which autologous stem cells are used. They are often the patient's only hope for recovery or slowing down the progress of the disease symptoms. The most important conclusions arise after analyzing the literature on the use of stem cells in neurodegenerative diseases. The effectiveness of MSC cell therapy has been confirmed in ALS and HD therapy. MSC cells slow down ALS progression and show early promising signs of efficacy. In HD, they reduced huntingtin (Htt) aggregation and stimulation of endogenous neurogenesis. MS therapy with hematopoietic stem cells (HSCs) inducted significant recalibration of pro-inflammatory and immunoregulatory components of the immune system. iPSC cells allow for accurate PD modeling. They are patient-specific and therefore minimize the risk of immune rejection and, in long-term observation, did not form any tumors in the brain. Extracellular vesicles derived from bone marrow mesenchymal stromal cells (BM-MSC-EVs) and Human adipose-derived stromal/stem cells (hASCs) cells are widely used to treat AD. Due to the reduction of Aß42 deposits and increasing the survival of neurons, they improve memory and learning abilities. Despite many animal models and clinical trial studies, cell therapy still needs to be refined to increase its effectiveness in the human body.
Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Doença de Huntington , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Humanos , Doenças Neurodegenerativas/terapia , Esclerose Lateral Amiotrófica/terapia , Células-Tronco , Doença de Huntington/patologia , Doença de Huntington/terapia , Doença de Parkinson/terapiaRESUMO
The monogenic nature of Huntington's disease (HD) and other neurodegenerative diseases caused by the expansion of glutamine-encoding CAG repeats makes them particularly amenable to gene therapy. Here we show the feasibility of replacing expanded CAG repeats in the mutant HTT allele with a normal CAG repeat in genetically engineered pigs mimicking the selective neurodegeneration seen in patients with HD. A single intracranial or intravenous injection of adeno-associated virus encoding for Cas9, a single-guide RNA targeting the HTT gene, and donor DNA containing the normal CAG repeat led to the depletion of mutant HTT in the animals and to substantial reductions in the dysregulated expression and neurotoxicity of mutant HTT and in neurological symptoms. Our findings support the further translational development of virally delivered Cas9-based gene therapies for the treatment of genetic neurodegenerative diseases.
Assuntos
Doença de Huntington , Animais , Suínos , Doença de Huntington/genética , Doença de Huntington/terapia , Doença de Huntington/metabolismo , Expansão das Repetições de Trinucleotídeos , Sistemas CRISPR-Cas/genética , Engenharia GenéticaRESUMO
Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR-Cas13d system (Cas13d-CAGEX) that eliminates toxic CAGEX RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d-CAGEX via an adeno-associated viral vector selectively reduces mutant HTT mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of mutant HTT protein aggregates. These phenotypic improvements lasted for at least eight months without adverse effects and with minimal off-target transcriptomic effects. Taken together, we demonstrate proof of principle of an RNA-targeting CRISPR-Cas13d system as a therapeutic approach for HD, a strategy with implications for the treatment of other dominantly inherited disorders.
Assuntos
Doença de Huntington , Camundongos , Animais , Doença de Huntington/genética , Doença de Huntington/terapia , Doença de Huntington/metabolismo , RNA , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Corpo Estriado/metabolismo , RNA Mensageiro/metabolismo , Fenótipo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Modelos Animais de DoençasRESUMO
Cell therapeutics have entered into an exciting era, with first-in-person clinical trials underway for Parkinson's disease and novel cell therapies in development for other neurodegenerative diseases. In the hope of ensuring successful translation of these novel cell products to the clinic, a significant amount of preclinical work continues to be undertaken. Rodent models of neural transplantation are required to thoroughly assess the survival, safety and efficacy of novel therapeutics. It is critical to produce robust and reliable preclinical data, in order to increase the likelihood of clinical success. As a result, significant effort has been driven into generating ever more relevant model systems, from genetically modified disease models to mice with humanized immune systems. Despite this, several challenges remain in the quest to assess human cells in the rodent brain long-term. Here, with a focus on models of Parkinson's and Huntington's disease, we discuss key considerations for choosing an appropriate rodent model for neural transplantation. We also consider the challenges associated with long-term survival and assessment of functional efficacy in these models, as well as the need to consider the clinical relevance of the model. While the choice of model will be dependent on the scientific question, by considering the caveats associated with each model, we identify opportunities to optimize the preclinical assessment and generate reliable data on our novel cell therapeutics.
Assuntos
Doença de Huntington , Doença de Parkinson , Humanos , Camundongos , Animais , Doença de Huntington/terapia , Doença de Parkinson/terapia , Modelos Animais , Terapia Baseada em Transplante de Células e Tecidos , Modelos BiológicosRESUMO
Huntington's disease (HD) is a neurodegenerative inherited genetic disorder, which leads to the onset of motor, neuropsychiatric and cognitive disturbances. HD is characterized by the loss of gamma-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs). To date, there is no treatment for HD. Mesenchymal stem cells (MSCs) provide a substantial therapeutic opportunity for the HD treatment. Herein, we investigated the therapeutic potential of human immature dental pulp stem cells (hIDPSC), a special type of MSC originated from the neural crest, for HD treatment. Two different doses of hIDPSC were intravenously administrated in a subacute 3-nitropropionic acid (3NP)-induced rat model. We demonstrated hIDPSC homing in the striatum, cortex and subventricular zone using specific markers for human cells. Thirty days after hIDPSC administration, the cells found in the brain are still express hallmarks of undifferentiated MSC. Immunohistochemistry quantities analysis revealed a significant increase in the number of BDNF, DARPP32 and D2R positive stained cells in the striatum and cortex in the groups that received hIDPSC. The differences were more expressive in animals that received only one administration of hIDPSC. Altogether, these data suggest that the intravenous administration of hIDPSCs can restore the BDNF, DARPP32 and D2R expression, promoting neuroprotection and neurogenesis.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Fosfoproteína 32 Regulada por cAMP e Dopamina , Doença de Huntington , Transplante de Células-Tronco , Células-Tronco , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Polpa Dentária/citologia , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Humanos , Doença de Huntington/genética , Doença de Huntington/terapia , Infusões Intravenosas , Ratos , Células-Tronco/citologiaRESUMO
Context: Huntington's disease (HD) is a neurodegenerative disorder characterized by mid-life onset, cognitive decline, and behavioral disturbance. Objective: We conducted a review of the end-of-life (EOL) experience of HD patients and their families. Methods: We searched 5 electronic databases. Eligible studies were published in English and contained outcomes related to PC, end-of-life (EOL), advance directives (ADs), symptom management, or hospice use for HD adults. Results: We screened 1566 studies, assessed 244 studies, and included 27 studies. Symptom Prevalence: Decedent data showed greater likelihood of pneumonia, choking, nutritional deficiencies, and skin ulcers. HD patients in hospice experienced pain, anxiety, nausea, and dyspnea. Psychiatric symptoms included dysphoria, agitation, irritability, apathy, and anxiety. Psychosis is associated with worse cognition, function, and behavioral disturbance. Symptom Management: Electroconvulsive therapy (ECT) and venlafaxine improved depression. Suicidal ideation improved with talking, self-management, medication, and discussing EOL wishes. Tetrabenazine improved chorea. Experience as Illness Progressed: HD patients require home care within two years of diagnosis. Only one study reported use of palliative care services (4%). HD patients are admitted to the hospital late in disease course and are often discharged to long-term care facilities (LTCF). Advance Care Planning: Two studies created tools to navigate EOL decisions. Most HD patients had EOL wishes; only familiarity with HD predicted having EOL wishes. Few had ADs or discussed EOL wishes with their families. Clinicians drive EOL discussions. Views on physician-assisted death (PAD) and euthanasia varied widely. Conclusions: Research is needed to further assess the PC needs of HD patients and to provide care recommendations.
Assuntos
Planejamento Antecipado de Cuidados , Cuidados Paliativos na Terminalidade da Vida , Doença de Huntington , Assistência Terminal , Adulto , Humanos , Doença de Huntington/psicologia , Doença de Huntington/terapia , Cuidados PaliativosRESUMO
Huntington's disease is a fatal neurodegenerative disorder caused by an inherited mutation in the huntingtin (HTT) gene comprising an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat sequence that results in a pathogenic huntingtin protein. Adeno-associated viral (AAV) gene therapy containing a primary artificial microRNA (pri-amiRNA) specifically targeting HTT messenger RNA (mRNA) has the potential to provide long-lasting therapeutic benefit, through durable reduction of mutant HTT expression after a single administration. The efficiency and precision of processing of the pri-amiRNA precursor to the mature guide (G) strand by transduced cells are critical for specific and potent HTT mRNA lowering. The selection of the optimized pri-amiRNA comprised a series of in vitro studies followed by in vivo studies in small and then large mammals. Our studies demonstrate the predictivity of certain cell culture systems and rodent models for nonhuman primates with respect to some, but not all key features of pri-amiRNA processing. In addition, our results show that the processing of pri-amiRNAs to the mature guide strand can differ greatly across different scaffolds and sequences while providing the same levels of target lowering. Importantly, our data demonstrate that there is a combinatorial effect of guide and passenger (P) strand sequences, together with the scaffold, on pri-amiRNA processing, with different guide and passenger strand sequences within the same scaffold dramatically altering pri-amiRNA processing. Taken together, our results highlight the importance of optimizing not only target lowering but also the efficiency and precision of pri-amiRNA processing in vitro, in rodents and in large mammals to identify the most potent and selective AAV gene therapy that harnesses the endogenous microRNA (miRNA) biogenesis pathway for target lowering without perturbing the endogenous cellular miRNA profile. The optimized pri-amiRNA was selected with this focus on efficiency and precision of pri-amiRNA processing in addition to its pharmacological activity on HTT mRNA lowering and general tolerability in vivo.
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Doença de Huntington , MicroRNAs , Animais , Terapia Genética , Vetores Genéticos/genética , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/terapia , Camundongos , MicroRNAs/genética , Primatas/genéticaRESUMO
BACKGROUND: People with Huntington's disease (HD) often become institutionalized and more frequently die away from the home setting. The reasons behind differences in end-of-life care are poorly understood. Less than 5% of people with HD report utilization of palliative care (PC) or hospice services, regardless of the lack of curative therapies for this neurodegenerative disease. It is unknown what factors are associated with in-patient specialty PC consultation in this population and how PC might be related to discharge disposition. OBJECTIVES: To determine what HD-specific (e.g., psychosis) and serious illness-specific factors (e.g., resuscitation preferences) are associated with PC encounters in people with HD and explore how PC encounters are associated with discharge disposition. DESIGN: We analyzed factors associated with PC consultation for people with HD using discharge data from the National Inpatient Sample and the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality. An anonymized, cross-sectional, and stratified sample of 20% of United States hospitalizations from 2007 through 2014 were included using ICD-9 codes. RESULTS: 8521 patients with HD were admitted to the hospital. Of those, 321 (3.8%) received specialty PC. Payer type, (specifically private insurer or other insurer as compared to Medicare), income, (specifically the top quartile as compared to the bottom quartile), mortality risk, D.N.R., aspiration pneumonia, and depression were significantly associated with PC in a multivariate model. Among those who received PC, the odds ratio (OR) of discharge to a facility was 0.43 (95% CI, 0.32-0.58), whereas the OR of discharge to home with services was 2.25 (95% CI 1.57-3.23), even after adjusting for possible confounders. CONCLUSIONS: Among patients with HD, economic factors, depression, and serious illness-specific factors were associated with PC, and PC was associated with discharge disposition. These findings have implications for the adaptation of inpatient PC models to meet the needs of persons with HD.
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Doença de Huntington , Doenças Neurodegenerativas , Idoso , Estudos Transversais , Hospitalização , Humanos , Doença de Huntington/epidemiologia , Doença de Huntington/terapia , Medicare , Cuidados Paliativos , Estudos Retrospectivos , Estados UnidosRESUMO
BACKGROUND: Human embryonic stem cells (hESCs) transplantation had shown to provide a potential source of cells in neurodegenerative disease studies and lead to behavioral recovery in lentivirus transfected or, toxin-induced Huntington's disease (HD) rodent model. Here, we aimed to observe if transplantation of superparamagnetic iron oxide nanoparticle (SPION)-labeled hESCs could migrate in the neural degenerated area and improve motor dysfunction in an AAV2-Htt171-82Q transfected Huntington rat model. METHODS: All animals were randomly allocated into three groups at first: HD group, sham group, and control group. After six weeks, the animals of the HD group and sham group were again divided into two subgroups depending on animals receiving either ipsilateral or contralateral hESCs transplantation. We performed cylinder test and stepping test every two weeks after AAV2-Htt171-82Q injection and hESCs transplantation. Stem cell tracking was performed once per two weeks using T2 and T2*-weighted images at 4.7 Tesla MRI. We also performed immunohistochemistry and immunofluorescence staining to detect the presence of hESCs markers, huntingtin protein aggregations, and iron in the striatum. RESULTS: After hESCs transplantation, the Htt virus-injected rats exhibited significant behavioral improvement in behavioral tests. SPION labeled hESCs showed migration with hypointense signal in MRI. The cells were positive with ßIII-tubulin, GABA, and DARPP32. CONCLUSION: Collectively, our results suggested that hESCs transplantation can be a potential treatment for motor dysfunction of Huntington's disease.
Assuntos
Células-Tronco Embrionárias Humanas , Doença de Huntington , Doenças Neurodegenerativas , Animais , Humanos , Ratos , Modelos Animais de Doenças , Células-Tronco Embrionárias Humanas/metabolismo , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/terapia , LentivirusRESUMO
Aggregation of proteins is a prominent hallmark of virtually all neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Little progress has been made in their treatment to slow or prevent the formation of aggregates by post-translational modification and regulation of cellular responses to misfolded proteins. Here, we introduce a label-free, laser-based photothermal treatment of polyglutamine (polyQ) aggregates in a C. elegans nematode model of huntingtin-like polyQ aggregation. As a proof of principle, we demonstrated that nanosecond laser pulse-induced local photothermal heating can directly disrupt the aggregates so as to delay their accumulation, maintain motility, and extend the lifespan of treated nematodes. These beneficial effects were validated by confocal photothermal, fluorescence, and video imaging. The results obtained demonstrate that our theranostics platform, integrating photothermal therapy without drugs or other chemicals, combined with advanced imaging to monitor photothermal ablation of aggregates, initiates systemic recovery and thus validates the concept of aggregate-disruption treatments for neurodegenerative diseases in humans.
Assuntos
Doença de Huntington/etiologia , Doença de Huntington/metabolismo , Agregados Proteicos/efeitos da radiação , Agregação Patológica de Proteínas/metabolismo , Animais , Caenorhabditis elegans , Modelos Animais de Doenças , Humanos , Doença de Huntington/patologia , Doença de Huntington/terapia , Lasers , Terapia com Luz de Baixa Intensidade , Peptídeos/metabolismo , Terapia Fototérmica , Agregação Patológica de Proteínas/terapia , Proteínas Recombinantes de Fusão/metabolismoRESUMO
BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients. METHODS: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected. RESULTS: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%. CONCLUSIONS: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed.