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The past year has offered significant advancements in the field of non-small cell lung cancer (NSCLC), both in the early and advanced disease settings. The identification of guideline-recommended actionable targets has provided the foundation for developing multiple new therapeutic agents. There has been a focus on developing drugs designed to overcome acquired resistance, a limitation of tyrosine kinase inhibitor-based therapy in lung cancer. In addition, there is an emerging trend toward combination therapies for patients in the first-line setting with the goal of preventing or delaying resistance. Another promising area of development has been the use of antibody-drug conjugates, where there are the initial reports of central nervous system efficacy and activity in patients with genomic alterations. Over the past year, numerous publications and presentations have highlighted multiple therapeutic advances, offering new treatment options for patients with NSCLC. The focus of this review is to summarize the most impactful findings, emphasizing their significance in the evolving treatment landscape for NSCLC. Several landmark trials in lung cancer with practice-changing clinical implications have been presented and published in 2023. This article reviews a selection of these trials as they relate to early and advanced-stage oncogene-driven lung cancer. The ADAURA and ALINA trials, in which targeted therapy given in the adjuvant setting has demonstrated improved clinical outcomes, are reviewed. In the advanced-stage setting, recent trials in the context of specific oncogene drivers are reviewed, including EGFR, ALK, ROS1, RET, ERBB2 (HER2), BRAF, MET exon 14 skipping (METex14), and KRAS alterations. Also discussed are the results of several trials that have evaluated the use of combination therapies and resistance-mechanism agnostic treatment strategies. PLAIN LANGUAGE SUMMARY: Targeted therapy plays an important role for patients with early and advanced-stage non-small cell lung cancer carrying specific genetic alterations. New strategies that combine multiple therapies are now being studied in randomized clinical trials, with the goal of enhancing the effectiveness of targeted therapy for patients with advanced lung cancer.
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In the current era of precision medicine, the identification of genomic alterations has revolutionised the management of patients with solid tumours. Recent advances in the detection and characterisation of circulating tumour DNA (ctDNA) have enabled the integration of liquid biopsy into clinical practice for molecular profiling. ctDNA has also emerged as a promising biomarker for prognostication, monitoring disease response, detection of minimal residual disease and early diagnosis. In this Review, we discuss current and future clinical applications of ctDNA primarily in non-small cell lung cancer in addition to other solid tumours.
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Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Pulmonares , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Ácidos Nucleicos Livres/genética , DNA Tumoral Circulante/análise , DNA Tumoral Circulante/genética , Humanos , Biópsia Líquida , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genéticaRESUMO
Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.
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Neoplasias da Mama/fisiopatologia , Carcinoma Ductal de Mama/fisiopatologia , Transformação Celular Neoplásica , Glândulas Mamárias Humanas/fisiopatologia , Animais , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Linhagem da Célula/genética , Células Cultivadas , Código de Barras de DNA Taxonômico , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Lentivirus/genética , Glândulas Mamárias Humanas/citologia , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Fatores de Tempo , Transdução Genética , Proteínas ras/genéticaRESUMO
The timing of human puberty is highly variable, sexually dimorphic, and associated with adverse health outcomes. Over 20 genes carrying rare mutations have been identified in known pubertal disorders, many of which encode critical components of the hypothalamic-pituitary-gonadal (HPG) axis. Recent genome-wide association studies (GWAS) have identified more than 100 candidate genes at loci associated with age at menarche or voice breaking in males. We know little about the spatial, temporal or postnatal expression patterns of the majority of these puberty-associated genes. Using a high-throughput and sensitive microfluidic quantitative PCR strategy, we profiled the gene expression patterns of the mouse orthologs of 178 puberty-associated genes in male and female mouse HPG axis tissues, the pineal gland, and the liver at five postnatal ages spanning the pubertal transition. The most dynamic gene expression changes were observed prior to puberty in all tissues. We detected known and novel tissue-enhanced gene expression patterns, with the hypothalamus expressing the largest number of the puberty-associated genes. Notably, over 40 puberty-associated genes in the pituitary gland showed sex-biased gene expression, most of which occurred peri-puberty. These sex-biased genes included the orthologs of candidate genes at GWAS loci that show sex-discordant effects on pubertal timing. Our findings provide new insight into the expression of puberty-associated genes and support the possibility that the pituitary plays a role in determining sex differences in the timing of puberty.
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Maturidade Sexual/genética , Transcriptoma/genética , Animais , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Sistema Hipotálamo-Hipofisário , Hipotálamo/metabolismo , Masculino , Camundongos , Análise em Microsséries , Hipófise/metabolismo , Sistema Hipófise-Suprarrenal , Caracteres Sexuais , Fatores SexuaisRESUMO
Mechanisms that control the levels and activities of reactive oxygen species (ROS) in normal human mammary cells are poorly understood. We show that purified normal human basal mammary epithelial cells maintain low levels of ROS primarily by a glutathione-dependent but inefficient antioxidant mechanism that uses mitochondrial glutathione peroxidase 2. In contrast, the matching purified luminal progenitor cells contain higher levels of ROS, multiple glutathione-independent antioxidants and oxidative nucleotide damage-controlling proteins and consume O2 at a higher rate. The luminal progenitor cells are more resistant to glutathione depletion than the basal cells, including those with in vivo and in vitro proliferation and differentiation activity. The luminal progenitors also are more resistant to H2O2 or ionizing radiation. Importantly, even freshly isolated "steady-state" normal luminal progenitors show elevated levels of unrepaired oxidative DNA damage. Distinct ROS control mechanisms operating in different subsets of normal human mammary cells could have differentiation state-specific functions and long-term consequences.
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Células Epiteliais/classificação , Células Epiteliais/metabolismo , Glutationa/metabolismo , Glândulas Mamárias Humanas/citologia , Estresse Oxidativo/fisiologia , Western Blotting , Dano ao DNA/fisiologia , Citometria de Fluxo , Humanos , Consumo de Oxigênio/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Células-Tronco/metabolismoRESUMO
Many normal adult tissues contain rare stem cells with extensive self-maintaining regenerative potential. During development, the stem cells of the hematopoietic and neural systems undergo intrinsically specified changes in their self-renewal potential. In the mouse, mammary stem cells with transplantable regenerative activity are first detectable a few days before birth. They share some phenotypic properties with their adult counterparts but are enriched in a subpopulation that displays a distinct gene expression profile. Here we show that fetal mammary epithelial cells have a greater direct and inducible growth potential than their adult counterparts. The latter feature is revealed in a novel culture system that enables large numbers of in vitro clonogenic progenitors as well as mammary stem cells with serially transplantable activity to be produced within 7 days from single fetal or adult input cells. We further show that these responses are highly dependent on novel factors produced by fibroblasts. These findings provide new avenues for elucidating mechanisms that regulate normal mammary epithelial stem cell properties at the single-cell level, how these change during development, and how their perturbation may contribute to transformation.
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Células Epiteliais/citologia , Glândulas Mamárias Animais/citologia , Células 3T3 , Animais , Células Epiteliais/fisiologia , Feminino , Imuno-Histoquímica , Glândulas Mamárias Animais/fisiologia , CamundongosAssuntos
Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/diagnóstico , Ácidos Nucleicos Livres/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/sangue , Resistencia a Medicamentos Antineoplásicos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/genética , Técnicas de Diagnóstico Molecular/métodos , Mutação , Medicina de Precisão/métodosRESUMO
The mammary gland undergoes dynamic changes throughout life. In the mouse, these begin with initial morphogenesis of the gland in the mid-gestation embryo followed by hormonally regulated changes during puberty and later in adulthood. The adult mammary gland contains a hierarchy of cell types with varying potentials for self-maintenance and differentiation. These include cells able to produce complete, functional mammary glands in vivo and that contain daughter cells with the same remarkable regenerative potential, as well as cells with more limited clonogenic activity in vitro. Here we review how applying in vitro and in vivo methods for quantifying these cells in adult mammary tissue to fetal mammary cells has enabled the first cells fulfilling the functional criteria of transplantable, isolated mammary stem cells to be identified a few days before birth. Thereafter, the number of these cells increases rapidly. Populations containing these fetal stem cells display growth and gene expression programs that differ from their adult counterparts but share signatures characteristic of certain types of breast cancer. Such observations reinforce growing evidence of important differences between tissue-specific fetal and adult cells with stem cell properties and emphasize the merits of investigating their molecular basis.
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Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Células-Tronco/citologia , Animais , Feminino , HumanosRESUMO
INTRODUCTION: ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here, we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 antibody-drug conjugate (ADC) therapeutic strategy. METHODS: Our institutional next-generation DNA sequencing data (OncoPanel) from 5769 NSCLC samples (5075 patients) were queried for cases having high-level ERBB2 amplification (≥6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib or HER2 ADCs (trastuzumab deruxtecan and trastuzumab emtansine) was evaluated in NSCLC preclinical models and patients with ERBB2 amplification. RESULTS: High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathologic and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further reveal that trastuzumab deruxtecan is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy. CONCLUSIONS: High-level ERBB2 amplification reliably predicts HER2 overexpression in patients with NSCLC, and HER2 ADC is effective therapy in this population.
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Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas , Amplificação de Genes , Neoplasias Pulmonares , Receptor ErbB-2 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Animais , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Idoso , Camundongos , Trastuzumab/uso terapêutico , Trastuzumab/farmacologia , Prevalência , Afatinib/uso terapêutico , Afatinib/farmacologia , Ado-Trastuzumab Emtansina/uso terapêutico , Ado-Trastuzumab Emtansina/farmacologiaRESUMO
Molecular genotyping for advanced solid malignancies has transformed the clinical management of patients with metastatic disease. Treatment decisions in a growing number of tumors require knowledge of molecularly driven alterations in order to select optimal targeted therapy. Although genomic testing of tumor tissue is the gold standard for identifying targetable genomic alterations, biopsy samples are often limited or difficult to access. This has paved the way for the development of plasma-based approaches for genomic profiling. Recent advances in the detection of plasma-circulating tumor DNA (ctDNA) have enabled the integration of plasma-based molecular profiling into clinical practice as an alternative or complementary tool for genomic testing in the setting of advanced cancer, to facilitate the identification of driver mutations to guide initial treatment and diagnose resistance. Several guidelines now recommend the use of plasma where tumor tissue is limited to identify a targetable genomic alteration. Current plasma-based assays can evaluate multiple genes in comprehensive panels, and their application in advanced disease will be increasingly incorporated into standard practice. This review focuses on current and future applications of plasma ctDNA-based assays in advanced solid malignancies, while highlighting some limitations in implementing this technology into clinical practice.
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ROS1 rearrangements are identified in 1-2% of lung adenocarcinoma cases, and reflex testing is guideline-recommended. We developed a decision model for population-based ROS1 testing from a Canadian public healthcare perspective to determine the strategy that optimized detection of true-positive (TP) cases while minimizing costs and turnaround time (TAT). Eight diagnostic strategies were compared, including reflex single gene testing via immunohistochemistry (IHC) screening, fluorescence in-situ hybridization (FISH), next-generation sequencing (NGS), and biomarker-informed (EGFR/ALK/KRAS wildtype) testing initiated by pathologists and clinician-initiated strategies. Reflex IHC screening with FISH confirmation of positive cases yielded the best results for TAT, TP detection rate, and cost. IHC screening saved CAD 1,000,000 versus reflex FISH testing. NGS was the costliest reflex strategy. Biomarker-informed testing was cost-efficient but delayed TAT. Clinician-initiated testing was the least costly but resulted in long TAT and missed TP cases, highlighting the importance of reflex testing. Thus, reflex IHC screening for ROS1 with FISH confirmation provides a cost-efficient strategy with short TAT and maximizes the number of TP cases detected.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Canadá , Atenção à Saúde , Detecção Precoce de Câncer , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , ReflexoAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de DoençaAssuntos
Neoplasias Pulmonares , Humanos , Biomarcadores , Fenótipo , Genótipo , Imunoterapia , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Contact with bereaved caregivers is not standard practice among cancer physicians, and little is known about its impact on caregivers. OBJECTIVE: Our aim was to describe the experiences and opinions of caregivers regarding bereavement contact from healthcare providers (HCP). DESIGN: Semistructured qualitative interviews were conducted with 61 bereaved caregivers. SUBJECTS: Bereaved caregivers of advanced cancer patients who had completed a randomized controlled trial of an early palliative care intervention were approached one to five years after the patient's death. Caregivers completed qualitative interviews from April 2012 to March 2015 after completion of quantitative measures. APPROACH: In semistructured interviews, bereaved caregivers were asked to describe the contact they received from HCP after the patient's death and their opinions about bereavement contact. We used thematic analysis informed by grounded theory to code and analyze the data. RESULTS: Of 60 caregivers included in the study, 30 (50%) received bereavement contact. There were no thematic differences between trial arms. The themes "contact reflects caring," "contact offers support," and "contact facilitates closure" were prominent among those who were contacted. "Contact is a courtesy," "contact is not always necessary," and "caregiver-initiated contact" were most evident among those who were not contacted. Overall, contact was appreciated by those who received it; for those who did not, reactions included rationalization, ambivalence, and regret. No negative consequences of contact were reported. CONCLUSIONS: Bereavement contact is well received and may be missed if not provided. These data support integration of bereavement contact into routine supportive care for caregivers.
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Atitude do Pessoal de Saúde , Luto , Cuidadores/psicologia , Família/psicologia , Neoplasias/mortalidade , Oncologistas/psicologia , Relações Profissional-Família , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
Cellular barcoding offers a powerful approach to characterize the growth and differentiation activity of large numbers of cotransplanted stem cells. Here, we describe a lentiviral genomic-barcoding and analysis strategy and its use to compare the clonal outputs of transplants of purified mouse and human basal mammary epithelial cells. We found that both sources of transplanted cells produced many bilineage mammary epithelial clones in primary recipients, although primary clones containing only one detectable mammary lineage were also common. Interestingly, regardless of the species of origin, many clones evident in secondary recipients were not detected in the primary hosts, and others that were changed from appearing luminal-restricted to appearing bilineage. This barcoding methodology has thus revealed conservation between mice and humans of a previously unknown diversity in the growth and differentiation activities of their basal mammary epithelial cells stimulated to grow in transplanted hosts.
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Técnicas de Cultura de Células/métodos , Diferenciação Celular , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Humanas/citologia , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Linhagem da Célula , Proliferação de Células , Tamanho Celular , Células Clonais , Células Epiteliais/citologia , Células Epiteliais/transplante , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , RegeneraçãoRESUMO
The BRG1 catalytic subunit of SWI/SNF-related complexes is required for mammalian development as exemplified by the early embryonic lethality of Brg1 null homozygous mice. BRG1 is also a tumor suppressor and, in mice, 10% of heterozygous (Brg1(null/+)) females develop mammary tumors. We now demonstrate that BRG1 mRNA and protein are expressed in both the luminal and basal cells of the mammary gland, raising the question of which lineage requires BRG1 to promote mammary homeostasis and prevent oncogenic transformation. To investigate this question, we utilized Wap-Cre to mutate both Brg1 floxed alleles in the luminal cells of the mammary epithelium of pregnant mice where WAP is exclusively expressed within the mammary gland. Interestingly, we found that Brg1(Wap-Cre) conditional homozygotes lactated normally and did not develop mammary tumors even when they were maintained on a Brm-deficient background. However, Brg1(Wap-Cre) mutants did develop ovarian cysts and uterine tumors. Analysis of these latter tissues showed that both, like the mammary gland, contain cells that normally express Brg1 and Wap. Thus, tumor formation in Brg1 mutant mice appears to be confined to particular cell types that require BRG1 and also express Wap. Our results now show that such cells exist both in the ovary and the uterus but not in either the luminal or the basal compartments of the mammary gland. Taken together, these findings indicate that SWI/SNF-related complexes are dispensable in the luminal cells of the mammary gland and therefore argue against the notion that SWI/SNF-related complexes are essential for cell survival. These findings also suggest that the tumor-suppressor activity of BRG1 is restricted to the basal cells of the mammary gland and demonstrate that this function extends to other female reproductive organs, consistent with recent observations of recurrent ARID1A/BAF250a mutations in human ovarian and endometrial tumors.
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Linhagem da Célula , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Neoplasias Mamárias Animais/prevenção & controle , Proteínas Nucleares/metabolismo , Cistos Ovarianos/prevenção & controle , Fatores de Transcrição/metabolismo , Neoplasias Uterinas/patologia , Neoplasias Uterinas/prevenção & controle , Animais , Apoptose , Transformação Celular Neoplásica/patologia , Células Epiteliais/metabolismo , Feminino , Deleção de Genes , Humanos , Integrases/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas do Leite/metabolismo , Cistos Ovarianos/metabolismo , Cistos Ovarianos/patologia , Fenótipo , Gravidez , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Neoplasias Uterinas/metabolismoRESUMO
BACKGROUND: Rett Syndrome (RTT) is an Autism Spectrum Disorder and the leading cause of mental retardation in females. RTT is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment. Our objective is to develop viral vectors for MECP2 gene transfer into Neural Stem Cells (NSC) and neurons suitable for gene therapy of Rett Syndrome. METHODOLOGY/PRINCIPAL FINDINGS: We generated self-inactivating (SIN) retroviral vectors with the ubiquitous EF1alpha promoter avoiding known silencer elements to escape stem-cell-specific viral silencing. High efficiency NSC infection resulted in long-term EGFP expression in transduced NSC and after differentiation into neurons. Infection with Myc-tagged MECP2-isoform-specific (E1 and E2) vectors directed MeCP2 to heterochromatin of transduced NSC and neurons. In contrast, vectors with an internal mouse Mecp2 promoter (MeP) directed restricted expression only in neurons and glia and not NSC, recapitulating the endogenous expression pattern required to avoid detrimental consequences of MECP2 ectopic expression. In differentiated NSC from adult heterozygous Mecp2(tm1.1Bird)+/- female mice, 48% of neurons expressed endogenous MeCP2 due to random inactivation of the X-linked Mecp2 gene. Retroviral MECP2 transduction with EF1alpha and MeP vectors rescued expression in 95-100% of neurons resulting in increased dendrite branching function in vitro. Insulated MECP2 isoform-specific lentiviral vectors show long-term expression in NSC and their differentiated neuronal progeny, and directly infect dissociated murine cortical neurons with high efficiency. CONCLUSIONS/SIGNIFICANCE: MeP vectors recapitulate the endogenous expression pattern of MeCP2 in neurons and glia. They have utility to study MeCP2 isoform-specific functions in vitro, and are effective gene therapy vectors for rescuing dendritic maturation of neurons in an ex vivo model of RTT.