Scientific Publications

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262 Results

2022

Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals

Saida K, Maroofian R, Sengoku T, Mitani T, Pagnamenta AT, Marafi D, Zaki MS, O’Brien TJ, Karimiani EG, Kaiyrzhanov R, Takizawa M, Ohori S, Leong HY, Akay G, Galehdari H, Zamani M, Romy R, Carroll CJ, Toosi MB, Ashrafzadeh F, Imannezhad S, Malek H, Ahangari N, Tomoum H, Gowda VK, Srinivasan VM, Murphy D, Dominik N, Elbendary HM, Rafat K, Yilmaz S, Kanmaz S, Serin M, Krishnakumar D, Gardham A, Maw A, Rao TS, Alsubhi S, Srour M, Buhas D, Jewett T, Goldberg RE, Shamseldin H, Frengen E, Misceo D, Strømme P, Magliocco Ceroni JR, Kim CA, Yesil G, Sengenc E, Guler S, Hull M, Parnes M, Aktas D, Anlar B, Bayram Y, Pehlivan D, Posey JE, Alavi S, Madani Manshadi SA, Alzaidan H, Al-Owain M, Alabdi L, Abdulwahab F, Sekiguchi F, Hamanaka K, Fujita A, Uchiyama Y, Mizuguchi T, Miyatake S, Miyake N, Elshafie RM, Salayev K, Guliyeva U, Alkuraya FS, Gleeson JG, Monaghan KG, Langley KG, Yang H, Motavaf M, Safari S, Alipour M, Ogata K, Brown AEX, Lupski JR, Houlden H, Matsumoto N.

Genet Med. 2022 Oct 31:S1098-3600(22)00948-0. doi: 10.1016/j.gim.2022.09.010. Online ahead of print. ABSTRACT PURPOSE: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants. METHODS: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. RESULTS: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. CONCLUSION: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders. PMID:36318270 DOI:10.1016/j.gim.2022.09.010

October 31, 2022
Neurogenomics

Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding

Mark PR, Murray SA, Yang T, Eby A, Lai A, Lu D, Zieba J, Rajasekaran S, VanSickle EA, Rossetti LZ, Guidugli L, Watkins K, Wright MS, Bupp CP, Prokop JW.

Cold Spring Harb Mol Case Stud. 2022 Oct 28;8(6):a006169. doi: 10.1101/mcs.a006169. Print 2022 Oct. ABSTRACT We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in LRP1, in which segregation analysis helped dismiss additional variants of interest. LRP1 analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells. PMID:36307211 DOI:10.1101/mcs.a006169

October 28, 2022
rWGS

N-myc mediated translation control is a therapeutic vulnerability in medulloblastoma

Kuzuoglu-Ozturk D, Aksoy O, Schmidt C, Lea R, Larson JD, Phelps RRL, Nasholm N, Holt M, Contreras A, Huang M, Wong-Michalak S, Shao H, Wechsler-Reya R, Phillips JJ, Gestwicki JE, Ruggero D, Weiss WA.

Cancer Res. 2022 Oct 20:CAN-22-0945. doi: 10.1158/0008-5472.CAN-22-0945. Online ahead of print. ABSTRACT Deregulation of N-myc is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data unexpectedly revealed that N-myc regulates the expression of specific components (~5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic. PMID:36264168 DOI:10.1158/0008-5472.CAN-22-0945

October 20, 2022
Neuro-Oncology

Phenotypic continuum of NFU1-related disorders

Kaiyrzhanov R, Zaki MS, Lau T, Sen S, Azizimalamiri R, Zamani M, Sayin GY, Hilander T, Efthymiou S, Chelban V, Brown R, Thompson K, Scarano MI, Ganesh J, Koneev K, Gülaçar IM, Person R, Sadykova D, Maidyrov Y, Seifi T, Zadagali A, Bernard G, Allis K, Elloumi HZ, Lindy A, Taghiabadi E, Verma S, Logan R, Kirmse B, Bai R, Khalaf SM, Abdel-Hamid MS, Sedaghat A, Shariati G, Issa M, Zeighami J, Elbendary HM, Brown G, Taylor RW, Galehdari H, Gleeson JJ, Carroll CJ, Cowan JA, Moreno-De-Luca A, Houlden H, Maroofian R.

Ann Clin Transl Neurol. 2022 Oct 18. doi: 10.1002/acn3.51679. Online ahead of print. ABSTRACT Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum. PMID:36256512 DOI:10.1002/acn3.51679

October 18, 2022
Neurogenomics

Safety and efficacy of intraventricular immunovirotherapy with oncolytic HSV-1 for CNS cancers

Kang KD, Bernstock JD, Totsch SK, Gary SE, Rocco A, Nan L, Li R, Etminan T, Han X, Beierle EA, Eisemann T, Wechsler-Reya RJ, Bae S, Whitley R, Gillespie GY, Markert JM, Friedman GK.

Clin Cancer Res. 2022 Oct 14:CCR-22-1382. doi: 10.1158/1078-0432.CCR-22-1382. Online ahead of print. ABSTRACT PURPOSE: Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. EXPERIMENTAL DESIGN: HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and immunohistochemistry. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. RESULTS: A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. CONCLUSIONS: Toxicity from intraventricular oHSV can be mitigated resulting in therapeutic benefit. These data support clinical translation of intraventricular G207. PMID:36239623 DOI:10.1158/1078-0432.CCR-22-1382

October 14, 2022
Neuro-Oncology

Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma

Richard MA, Yang W, Sok P, Li M, Carmichael SL, von Behren J, Reynolds P, Fisher PG, Collins RT, Hobbs CA, Luke B, Shaw GM, Lupo PJ.

Birth Defects Res. 2022 Oct 13. doi: 10.1002/bdr2.2105. Online ahead of print. ABSTRACT BACKGROUND: There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on “CHD-lymphoma” associations. METHODS: From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma. RESULTS: After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta = 0.04) relative to both unaffected individuals (mean beta = 0.93, p = 1.5 × 10-12 ) and individuals with complex CHD (mean beta = 0.95, p = 3.8 × 10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies. CONCLUSIONS: We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma. PMID:36226634 DOI:10.1002/bdr2.2105

October 13, 2022

Dormant SOX9-positive cells facilitate MYC-driven recurrence of medulloblastoma

Borgenvik A, Holmberg KO, Bolin S, Zhao M, Savov V, Rosén G, Hutter S, Garancher A, Suryo Rahmanto A, Bergström T, Olsen TK, Mainwaring OJ, Sattanino D, Verbaan AD, Rusert JM, Sundstrom A, Ballester Bravo M, Dang Y, Wenz AS, Richardson S, Fotaki G, Hill RM, Dubuc AM, Kalushkova A, Remke M, Cancer M, Jernberg-Wiklund H, Giraud G, Chen X, Taylor MD, Sangfelt O, Clifford SC, Schuller U, Wechsler-Reya RJ, Weishaupt H, Swartling FJ.

Cancer Res. 2022 Oct 11:CAN-22-2108. doi: 10.1158/0008-5472.CAN-22-2108. Online ahead of print. ABSTRACT Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, while MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. PMID:36219398 DOI:10.1158/0008-5472.CAN-22-2108

October 11, 2022
Neuro-Oncology

Dispatches from Biotech beginning BeginNGS: Rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey

Kingsmore SF, The BeginNGS Consortium. 

Am J Med Genet C Semin Med Genet. 2022 Oct 11. doi: 10.1002/ajmg.c.32005. Online ahead of print. ABSTRACT In this Dispatch from Biotech, we briefly review the urgent need for extensive expansion of newborn screening (NBS) by genomic sequencing, and the reasons why early attempts had limited success. During the next decade transformative developments will continue in society and in the pharmaceutical, biotechnology, informatics, and medical sectors that enable prompt addition of genetic disorders to NBS by rapid whole genome sequencing (rWGS) upon introduction of new therapies that qualify them according to the Wilson and Jungner criteria (Wilson, J. M. G., & Jungner, G., World Health Organization. (1968). Principles and Practice of Screening for Disease. World Health Organization. Retrieved from https://apps.who.int/iris/handle/10665/37650). Herein we describe plans, progress, and clinical trial designs for BeginNGS (Newborn Genome Sequencing to end the diagnostic and therapeutic odyssey), a new international, pre-competitive, public-private consortium that proposes to implement a self-learning healthcare delivery system for screening all newborns for over 400 hundred genetic diseases, diagnostic confirmation, implementation of effective treatment, and acceleration of orphan drug development. We invite investigators and stakeholders worldwide to join the consortium in a prospective, multi-center, international trial of the clinical utility and cost effectiveness of BeginNGS. PMID:36218021 DOI:10.1002/ajmg.c.32005

October 11, 2022
Newborn Screening

Approaches to long-read sequencing in a clinical setting to improve diagnostic rate

Sanford Kobayashi E, Batalov S, Wenger AM, Lambert C, Dhillon H, Hall RJ, Baybayan P, Ding Y, Rego S, Wigby K, Friedman J, Hobbs C, Bainbridge MN. 

Sci Rep. 2022 Oct 9;12(1):16945. doi: 10.1038/s41598-022-20113-x. ABSTRACT Over the past decade, advances in genetic testing, particularly the advent of next-generation sequencing, have led to a paradigm shift in the diagnosis of molecular diseases and disorders. Despite our present collective ability to interrogate more than 90% of the human genome, portions of the genome have eluded us, resulting in stagnation of diagnostic yield with existing methodologies. Here we show how application of a new technology, long-read sequencing, has the potential to improve molecular diagnostic rates. Whole genome sequencing by long reads was able to cover 98% of next-generation sequencing dead zones, which are areas of the genome that are not interpretable by conventional industry-standard short-read sequencing. Through the ability of long-read sequencing to unambiguously call variants in these regions, we discovered an immunodeficiency due to a variant in IKBKG in a subject who had previously received a negative genome sequencing result. Additionally, we demonstrate the ability of long-read sequencing to detect small variants on par with short-read sequencing, its superior performance in identifying structural variants, and thirdly, its capacity to determine genomic methylation defects in native DNA. Though the latter technical abilities have been demonstrated, we demonstrate the clinical application of this technology to successfully identify multiple types of variants using a single test. PMID:36210382 DOI:10.1038/s41598-022-20113-x

October 9, 2022
rWGS

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors

Foster JB, Griffin C, Rokita JL, Stern A, Brimley C, Rathi K, Lane MV, Buongervino SN, Smith T, Madsen PJ, Martinez D, Delaidelli A, Sorensen PH, Wechsler-Reya RJ, Karikó K, Storm PB, Barrett DM, Resnick AC, Maris JM, Bosse KR.

J Immunother Cancer. 2022 Sep;10(9):e004450. doi: 10.1136/jitc-2021-004450. ABSTRACT BACKGROUND: Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target. METHODS: We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing. RESULTS: We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2-4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. CONCLUSION: Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors. PMID:36167467 | DOI:10.1136/jitc-2021-004450

September 27, 2022
Neuro-Oncology

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