Advancing Parkinson’s disease treatment: cell replacement therapy with neurons derived from pluripotent stem cells

Stem Cells, Journal Year: 2024, Volume and Issue: 42(9), P. 781 - 790

Published: June 21, 2024

Abstract The motor symptoms of Parkinson’s disease (PD) are caused by the progressive loss dopamine neurons from substantia nigra. There currently no treatments that can slow or reverse neurodegeneration. To restore lost neurons, international groups have initiated clinical trials using human embryonic induced pluripotent stem cells (PSCs) to derive neuron precursors used as transplants replace neurons. Proof-of-principle experiments in 1980s and 1990s showed grafts fetal ventral mesencephalon, which contains substantial nigra, could, under rare circumstances, disease. Improvements PSC technology genomics inspired researchers design PSC-derived cell replacement therapy for PD. We focus here on 4 such first-in-human begun US, Europe, Japan. provide an overview sources PSCs methods generate transplantation. discuss pros cons strategies allogeneic, immune-matched, autologous approaches novel overcoming rejection immune system. consider challenges safety efficacy durable engraftment, focusing genomics-based quality control assure will not become cancerous. Finally, since like these never been undertaken before, we comment value cooperation among rivals contribute advancements finally relief millions suffering

Language: Английский

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Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma

Cancers, Journal Year: 2023, Volume and Issue: 15(19), P. 4687 - 4687

Published: Sept. 22, 2023

Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities multiple myeloma. However, FISH a targeted analysis that can be challenging due to complexity The aim this study was evaluate potential optical genome mapping (OGM) detect significant cytogenetic myeloma and provide larger pangenomic information. OGM analyses were performed CD138-purified 20 patients. successfully detected structural variants (SVs) (IGH MYC rearrangements), copy number (CNVs) (17p/TP53 deletion, 1p deletion 1q gain/amplification) aneuploidy (gains odd-numbered chromosomes, monosomy 13) classically expected with led 30% increase prognosis yield at our institution when compared FISH. Despite challenges interpretation calls CNV losses non-diploid genomes, has replace as care clinical settings efficiently change how we identify prognostic predictive markers therapies future. To knowledge, first highlighting feasibility utility

Language: Английский

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Clinical Utility of Optical Genome Mapping as an Additional Tool in a Standard Cytogenetic Workup in Hematological Malignancies

Cancers, Journal Year: 2025, Volume and Issue: 17(9), P. 1436 - 1436

Published: April 25, 2025

Background and Objective: The primary objective of this study is to evaluate the added value optical genome mapping (OGM) when integrated into standard cytogenetic workup (SCGW) for hematological malignancies. Methods: cohort comprised 519 cases with different types OGM SCGW (including G-banded karyotyping fluorescence in situ hybridization) were performed on blood and/or bone marrow. analytical sensitivity OGM, defined as detection all additional cytogenomic aberrations, its clinical utility, referring aberrations diagnostic, prognostic, or therapeutic significance, assessed. Results: led increased utility 58% 15% cases, respectively. varied across malignancies, highest T-lymphoblast leukemia (52%), followed by mixed phenotype acute (43%), B-lymphoblastic (37%), other B-cell lymphomas (22%), mature T-cell leukemia/lymphoma (20%), chronic lymphocytic (14%), myeloid (13%), multiple myeloma mantle cell lymphoma (8%), myelodysplastic/myeloproliferative neoplasms (6%), myelodysplastic syndrome (5%), myeloproliferative (0%). Conclusion: Compared SCGW, detects approximately cases. provides at varying rates Given these differences, strategic triaging can help maximize focusing diseases where it offers most significant benefit.

Language: Английский

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Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia

Journal of Clinical Investigation, Journal Year: 2025, Volume and Issue: 135(9)

Published: May 1, 2025

BACKGROUNDT cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents unique model for the study persistent CTL expansions. Albeit autoimmunity implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL.METHODSThis comprehensive immunogenomic 92 consecutive patients from cohort full laboratory-clinical characterization (n = 271). Whole-exome profiling variants associated inborn errors immunity (IEI) and somatic mutations in lymphoid drivers was analyzed. Single-cell RNA-Seq TCR-Seq samples cancer lines were utilized establish biological correlations.RESULTSLymphocytopenia and/or hypogammaglobulinemia identified 186 241 (77%) patients. Genetic screening IEI revealed 43 rare heterozygous 38 different immune genes 34 (36%) (vs. 167/63,026 [0.26%] controls). High-confidence deleterious dominant, adult-onset IEIs detected 15 (16%) Carriers showed atypical features otherwise tied cryptic IEI, such as earlier onset, lower counts, mutational rate, higher proportions cytopenia/bone marrow failure than noncarriers. Somatic landscape, RNA-Seq, analyses supported imbalance caused by interactions drivers.CONCLUSIONSOur findings reveal that maladaptive expansions may stem open horizon clonal hematopoiesis bone failure.FUNDINGNIH; Aplastic Anemia MDS International Foundation; VeloSano; Edward P. Evans Instituto de Salud Carlos III; European Research Council; Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.

Language: Английский

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Analytic Validation of Optical Genome Mapping in Hematological Malignancies

Biomedicines, Journal Year: 2023, Volume and Issue: 11(12), P. 3263 - 3263

Published: Dec. 9, 2023

Structural variations (SVs) play a key role in the pathogenicity of hematological malignancies. Standard-of-care (SOC) methods such as karyotyping and fluorescence situ hybridization (FISH), which have been employed globally for past three decades, significant limitations terms resolution number recurrent aberrations that can be simultaneously assessed, respectively. Next-generation sequencing (NGS)-based technologies are now widely used to detect clinically sequence variants but limited their ability accurately SVs. Optical genome mapping (OGM) is an emerging technology enabling genome-wide detection all classes SVs at significantly higher than FISH. OGM requires neither cultured cells nor amplification DNA, addressing culture biases. This study reports clinical validation laboratory-developed test (LDT) according stringent regulatory (CAP/CLIA) guidelines SV different In total, 60 cases with malignancies (of various subtypes), 18 controls, 2 cancer cell lines were this study. Ultra-high-molecular-weight DNA was extracted from samples, fluorescently labeled, run on Bionano Saphyr system. A total 215 datasets, Inc.luding replicates, generated, analyzed successfully. Sample data then using either disease-specific or pan-cancer-specific BED files prioritize calls known diagnostically prognostically relevant. Sensitivity, specificity, reproducibility 100%, 96%, Following validation, 14 10 controls outside laboratories showing 96.4%. found more relevant compared SOC testing due its resolution. The results demonstrate superiority over traditional accurate diagnosis

Language: Английский

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Genomic technologies for detecting structural variations in hematologic malignancies

Blood Research, Journal Year: 2024, Volume and Issue: 59(1)

Published: Feb. 13, 2024

Genomic structural variations in myeloid, lymphoid, and plasma cell neoplasms can provide key diagnostic, prognostic, therapeutic information while elucidating the underlying disease biology. Several molecular diagnostic approaches play a central role evaluating hematological malignancies. Traditional cytogenetic assays, such as chromosome banding fluorescence situ hybridization, are essential components of current workup that guide clinical care for most hematologic However, each assay has inherent limitations, including limited resolution detecting small low coverage, only detect alterations target regions. Recently, rapid expansion increasing availability novel comprehensive genomic technologies have led to their use laboratories management translational research. This review aims describe relevance malignancies introduce may facilitate personalized tumor characterization treatment.

Language: Английский

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Genomic structural variants analysis in leukemia by a novel cytogenetic technique: Optical genome mapping

Cancer Science, Journal Year: 2024, Volume and Issue: 115(11), P. 3543 - 3551

Published: Aug. 24, 2024

Abstract Genomic structural variants (SVs) play a pivotal role in driving the evolution of hematologic malignancies, particularly leukemia, which genetic abnormalities are crucial features. Detecting SVs is essential for achieving precise diagnosis and prognosis these cases. Karyotyping, often complemented by fluorescence situ hybridization and/or chromosomal microarray analysis, provides standard diagnostic outcomes various types front‐line testing leukemia. Recently, optical genome mapping (OGM) has emerged as promising technique due to its ability detect all identified other cytogenetic methods within one single assay. Furthermore, OGM revealed additional clinically significant clinical laboratories, underscoring considerable potential enhancing cases This review aims elucidate principles conventional techniques OGM, with focus on technical performance applications diagnosing prognosticating myelodysplastic syndromes, acute myeloid lymphoblastic chronic lymphocytic

Language: Английский

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Optical Genome Mapping as a Tool to Unveil New Molecular Findings in Hematological Patients with Complex Chromosomal Rearrangements

Genes, Journal Year: 2023, Volume and Issue: 14(12), P. 2180 - 2180

Published: Dec. 5, 2023

Standard cytogenetic techniques (chromosomal banding analysis—CBA, and fluorescence in situ hybridization—FISH) show limits characterizing complex chromosomal rearrangements structural variants arising from two or more breaks. In this study, we applied optical genome mapping (OGM) to fully characterize cases of at high resolution. case 1, an acute myeloid leukemia (AML) patient showing chromothripsis, OGM analysis was concordant with classic helped better refine breakpoints. The results 2, a non-Hodgkin lymphoma, were only partially agreement previous analyses define clonal heterogeneity, overcoming the bias related selection due cell culture techniques. both cases, led identification molecular markers, helping pathogenesis, classification, prognosis analyzed patients. Despite extensive efforts study hematologic diseases, standard methods display unsurmountable limits, while is tool that has power overcome these limitations provide higher As also shows defining regions repetitive nature, combining CBA obtain complete characterization would be desirable.

Language: Английский

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A Next Generation Cytogenetic Approach to Elucidate the Complex Genetic Structure of Hematologic Neoplasms: Optical Genome Mapping

OSMANGAZİ JOURNAL OF MEDICINE, Journal Year: 2024, Volume and Issue: 46(2)

Published: Jan. 18, 2024

Hematolojik neoplazilerin tanısında ve tedavi yaklaşımlarının belirlenmesinde genetik anomalilerin rolü, konvansiyonel sitogenetik yöntemlerin gelişmesiyle birlikte paralel giden bir araştırma alanı olmuştur. Bu süreç moleküler yöntemler ile farklı boyuta taşınmıştır. teknikler çoğu zaman sitogenetiğin eksik kalan yanlarını tamamlamış ancak yerini alamamıştır. Günümüze geldiğimizde ise Optik Genom Haritalama (OGH), alabilecek en muhtemel aday olarak görünmektedir. OGH, teorik karyotip, FISH kromozomal mikroarray yöntemlerini aynı platformda buluşturan yeni nesil yaklaşım sergiler. Hücre kültürü gereksinimi amplifikasyon gerektirmemesi, hedefe spesifik yöntem olmaması önemli artılarıdır. Klasik saptanan tüm sayısal yapısal anomalileri saptayabilirken zamanda kompleks karyotiplerin yapısını doğru şekilde aydınlatabilir. Ayrıca daha önce tanımlanmamış anomaliler de tespit edebilir ki bu durum hematolojik neoplazilerde minimal rezidual hastalık takibinde belirteçlerin bulunmasına olanak tanır. Tüm bunlar neoplazili hastaların klinik yönetimine rehberlik edecek unsurlardır. Ancak kırık noktaları tekrarlayan bölgeleri veya sentromer telomer bölgelerini psödootozomal içeren edemez. yöntemin dezavantajıdır. Yine heterojen etmede genoma sunar. Sonuç açıdan baktığımızda tek başına yıllarca bilgi aracı olan kromozom analizi, gerekli teknik analitik iyileştirmelerin ardından belki gelecekte OGH’ye bırakacaktır.

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Optical Genome Mapping for Cryptic Chromosomal Rearrangements Identification in Clinical Practice

Maternal-Fetal Medicine, Journal Year: 2024, Volume and Issue: 6(2), P. 124 - 127

Published: April 1, 2024

To editor: Balanced chromosomal rearrangements (BCRs), predominantly reciprocal translocations and inversions represent disease-related structural variations (SVs) that directly disrupt gene structure function. Moreover, BCRs predispose offspring to unbalanced rearrangements, resulting in adverse pregnancy outcomes.1 The timely accurate identification of carriers is crucial for minimizing the risk associated outcomes, assessing recurrent risk, planning appropriate management. Conventional cytogenetic karyotyping serves as standard first-tier approach BCR detection, yielding a rate 2%–4% miscarriage population.2 However, its limited resolution (typically around 5–10 Mb) poses challenges detecting cryptic with smaller or similarly banded segments, well complex SVs involving multiple chromosomes. Optical genome mapping (OGM), an emerging technology from Bionano Genomics, has high nearly all types genomic been recognized revolution next-generation cytogenomic analysis.3,4 A growing number studies have recently demonstrated efficiency superiority OGM various clinical settings, including both prenatal postnatal congenital conditions, hematological other malignancies.5–7 Here, we explore value identifying using case series our practice. This study was approved by ethics committee Nanjing Drum Tower Hospital affiliated University Medical School (no. 2021-464-02). Case presentation Three couples Chinese origin, nonconsanguineous healthy, were enrolled this due history outcomes. female first couple gravida 1, para 1 (G1P1). She previously gave birth seemingly healthy boy after uneventful pregnancy, but he noted delayed motor development milestones early infancy. did not exhibit language until age five; at point, diagnosed developmental delay intellectual disability. second G5P1. Her prior pregnancies included abortion medically indicated (first pregnancy), live girl moderate disability 6 years (second two spontaneous miscarriages 7–8 weeks' gestation, intrauterine fetal demise 18 weeks (fifth pregnancy). underwent fourth findings negative: undergo genetic testing nor products conception analyzed. third experienced during her pregnancies, which prompted evaluation karyotyping. findings, however, negative. ended 34 gestation. terminal deletion duplication on separated chromosomes, potentially deriving parental found whole exome sequencing peripheral blood proband family, chromosome microarray analysis most recent families (Table 1). These individuals attended Obstetrics Gynecology Center School, seeking guidance concerning future pregnancies. Genetic counseling offered before any written, informed consent provided initiation. Table - Offspring copy variation, optical mapping, fluorescence situ hybridization results. CNVs Couple Gender carrier Location CN Length (Mb) Structural Variation Breakpoints (GRCh38/hg38) FISH Female 2q37.3-qter 3 5.1 46,XX,t(2;10)(q37.3;p15.3) chr2::237,006,752-237,025,670 t(2;10)(2p+,10p+;2q+,10q+) 10p15.3-pter 2.6 chr10:2,612,834-2,622,310 2 9q34.3-qter 2.9 46,XX,t(9;22)(q34.3;q13.2) chr9:135,192,382-135,199,824 t(9;22)(9p+,22q+;9q+) 22q13.2-qter 8.0 chr22:42,686,810-42,715,235 4q34.3-qter 10.7 46,XX,t(4;12)(q34.3;p12.3)* chr4:179,355,987-179,361,221 t(4;12)(4p+,12p+;4q+,12q+) chr4:180,005,910-180,009,061 12p12.3-pter 16.1 chr12:16,068,858-16,074,606 *The derivative 12 consists 4q34.3-4qter (10.1 inverted direction, 4q34.3 (0.6 forward 12p12.3-12qter segment.CNV: Copy variation; CN: number; FISH: Fluorescence hybridization; Mb: Megabyte; OGM: mapping. For identification, (Bionano Inc., USA), (FISH) G-banded performed simultaneously samples obtained couples. In brief, (450–550 bands) lymphocytes according protocol. Fluorescent-labeled bacterial artificial probes designed prepared, conducted Be Creative Lab (Beijing) Co. Ltd. OGM, ultra-high molecular weight DNA extracted, labeled, processed Genomics Saphyr® platform manufacturer protocols Inc. Juno (Hangzhou) Ltd.). Genome map assembly Solve™ (v3.7) software; OGM-specific pipelines managed Access™ (v1.7) software, direct alignment consensus maps reference human (GRCh38/hg38).3,4 As shown Figures 2, identified imbalances three couples; breakpoints closely aligned rearrangements. All remained undetectable G-banding. Sizes translocated segments ranged Mb 2. Translocated over 10 size, could also remain thus be defined "large rearrangements."8 couple, chromosomes 4 large Mb, respectively, detected technique involves labeling fluorophores via action methyltransferase DLE-1 recognition motif CTTAAG, producing 14–15 labels per 100 kb; balanced small 30 kb.3,4 makes it promising method BCRs; agreement those studies.9,10Figure 1: Results forcryptic (A–E) (F–H). Mapping recombinant (chr2, upper panel) (chr10, lower panel). B Model rearrangement. C Circos plot fromOGM. D image, arrows indicating occurrence (der(10)) (der(2)) (left right panels, colored signals ends). E Karyotyping chr2 chr10 (red representing OGM-predicted breakpoints). F chr9 chr22 (left), circos indicates translocation (right). G image showing der (22) der(9) panels ends).H BCRs: rearrangements; mapping.Figure 2: FISH, results 3. showed chr4 (upper chr12 (middle breakpoints. Lower panel segment der(12) segments. OGM. Schematic representation (lower (arrows) der(4) (right occurrences. chr12, predicted marked red arrows. BCR: rearrangement; mapping.Detailed information about another superior characteristic when compared FISH.3,4 Although validated methods, consistency nevertheless underscored reliability SV 22q11.23 likely disrupted A4GALT (OMIM 607922), autosomal recessive phenotype.11 No OMIM genes based breakpoint location. Furthermore, revealed consisted Mb), direction unexpectedly, (Fig. 2A, C), suggesting insertional involved BCR.12 Insertional are rare events require least breaks, donor one insertion site acceptor chromosome.12 Studies proportion even apparent BCRs, encompass complexity clearly visualized routine karyotyping.13 Because capacity provide comprehensive, high-resolution overview structures, can help resolve such complexity. highlighted context, only considering described cases high-risk without knowledge potential imbalances. histories outcomes known issues heredity, great significance guide establishing diagnosis often challenging. example, although their attempt either probands. considered these circumstances, next attempted under misleading influence negative findings. reliable alternative detection certainly efficacy relevant BCRs. Nevertheless, imbalances, less than ideal highly comprehensive analyses genome-wide level. Unlike requires specific probes, utilizes evenly distributed throughout genome, eliminating need specificity significantly enhancing detection.3,4 Taken together, should first-line comprehensively evaluating helping establish allowing optimal decision-making certain abnormality considered. Conclusion Our highlight especially suspected. further SVs, additional (i.e., experiencing miscarriages) general population required.

Language: Английский

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