Preliminary Phase 2 Results Demonstrate Engraftment with Minimal Neutropenia with MGTA-456, a CD34+ Expanded Cord Blood (CB) Product in Patients Transplanted for Inherited Metabolic Disorders (IMD)

Background: IMDs including mucopolysaccharidosis type IH (MPS1/Hurler Syndrome), metachromatic leukodystrophy (MLD), globoid cell leukodystrophy (GLD) and cerebral adrenoleukodystrophy (cALD) are progressive, fatal diseases affecting the central nervous system which are treatable through allogeneic hematopoietic stem cell transplantation (HSCT). CB, in the absence of a matched donor, is the preferred source of stem cells as it is rapidly available and allows greater flexibility in allele matching. As a result of low cell doses, CB transplants in IMD are associated with prolonged periods of neutropenia and reported graft failure rates in up to ~20% (Lum et al 2017 Bone Marrow Transplant 52:846-53; Mallhi et al 2017 BBMT 23:119-25). MGTA-456 is a first-in-class cell therapy produced from a single CB unit using an aryl hydrocarbon receptor antagonist in a 15-day expansion culture of CD34+ cells. In previous phase 1/2 studies, 24 adult and 3 pediatric patients with hematologic malignancies treated with myeloablative conditioning (MAC) and MGTA-456 demonstrated a median 324-fold expansion of CD34+ cells, all patients engrafted, and the time to neutrophil recovery was significantly reduced by a median of 9 days compared to historical controls (Wagner et al 2016 Cell Stem Cell 18:144-55; Wagner et al 2017 Blood 130 supp:662 abstr). Furthermore, higher CD34+ dose has been correlated with improved engraftment and outcomes in IMD transplant patients (Prasad et al 2008 Blood 112:2979-89...
Source: Blood - Category: Hematology Authors: Tags: 732. Clinical Allogeneic Transplantation: Results: Poster II Source Type: research

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Increases in the number of cell therapies in the preclinical and clinical phases have prompted the need for reliable and noninvasive assays to validate transplant function in clinical biomanufacturing. We developed a robust characterization methodology composed of quantitative bright-field absorbance microscopy (QBAM) and deep neural networks (DNNs) to noninvasively predict tissue function and cellular donor identity. The methodology was validated using clinical-grade induced pluripotent stem cell–derived retinal pigment epithelial cells (iPSC-RPE). QBAM images of iPSC-RPE were used to train DNNs that predicted iPSC-...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
The advent of human induced pluripotent stem cells (iPSCs) provided a means for avoiding ethical concerns associated with the use of cells isolated from human embryos. The number of labs now using iPSCs to generate photoreceptor, retinal pigmented epithelial (RPE), and more recently choroidal endothelial cells has grown exponentially. However, for autologous cell replacement to be effective, manufacturing strategies will need to change. Many tasks carried out by hand will need simplifying and automating. In this issue of the JCI, Schaub and colleagues combined quantitative brightfield microscopy and artificial intelligence...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
The recent article by Hicks et  al1 is very helpful in clarifying the long-standing debate concerning arteriovenous (AV) access ligation following successful kidney transplantation. The authors found that AV access ligation is uncommon in the United States, is not associated with post-transplantation allograft failure, and offer ed no reduction in all-cause mortality. They concluded that AV access ligation should be reserved for access-related complications, such as dialysis access-associated hand ischemia.
Source: Journal of Vascular Surgery - Category: Surgery Authors: Tags: Letter to the Editor Source Type: research
Reena Goswami1, Gayatri Subramanian2, Liliya Silayeva1, Isabelle Newkirk1, Deborah Doctor1, Karan Chawla2, Saurabh Chattopadhyay2, Dhyan Chandra3, Nageswararao Chilukuri1 and Venkaiah Betapudi1,4* 1Neuroscience Branch, Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD, United States 2Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States 4Department of Physiology and Biophysics, Case Western Reserve University, Clev...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Publication date: Available online 3 December 2018Source: Multiple Sclerosis and Related DisordersAuthor(s): Ji Zhou, Xiaopeng Lu, Yao Zhang, Taoyun Ji, Yiwen Jin, Min Xu, Xinhua Bao, Yuehua Zhang, Hui Xiong, Xingzhi Chang, Yuwu Jiang, Ye WuABSTRACTBackgroundSome studies have reported clinical features of relapsing MOG-IgG-associated CNS demyelination principally in Caucasians children. It is not clear whether Chinese children share the same phenotype.ObjectiveTo delineate the clinical characteristics in Chinese children with relapsing MOG-IgG-associated demyelination.MethodsA follow-up study on 23 Children with relapsing ...
Source: Multiple Sclerosis and Related Disorders - Category: Neurology Source Type: research
We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
AbstractDementia represents one of the most diffuse disorders of our Era. Alzheimer ’s disease is the principle cause of dementia worldwide. Metabolic, infectious, autoimmune, inflammatory, and genetic dementias represent a not negligible number of disorders, with increasing numbers in younger subjects. Due to the heterogeneity of patients and disorders, the diagnosis of dementia is challenging. In the present article, we propose a practical diagnostic approach following the two-step investigation procedure. The first step includes basic blood tests and brain neuroimaging, performed on all patients. After this first-...
Source: Neurological Sciences - Category: Neurology Source Type: research
Conclusions:Alexander’s disease is a rare leukodystrophy with both AD and sporadic pattern of inheritance. It is caused by a loss of function mutation in the alpha isoform of glial fibrillary acidic protein (GFAP.) This patient’s neuropathic pain likely represented a central pain syndrome due to the spinal and medullary degeneration. Our case illustrates that neuropathic pain may be a presenting symptoms of Alexander’s disease, and the importance of a broad differential in the workup of a common referral complaint.Disclosure: Dr. Massa has nothing to disclose. Dr. Beaber has nothing to disclose. Dr. Brons...
Source: Neurology - Category: Neurology Authors: Tags: General Neurology: The Eyes Have It and White Matter Matters Source Type: research
Sulfatides (3-O-sulfogalactosylceramides, sulfated galactocerebrosides, SM4) are esters of sulfuric acid with galactosylceramides. These acidic glycosphingolipids, present at the external leaflet of the plasma membrane, are synthesized by a variety of mammalian cells. They are especially abundant in the myelin sheath of oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Studies using cerebroside galactosyltransferase-deficient mice revealed that sulfatides are responsible for proper structure and functioning of myelin. Large amounts of sulfatides are also found in the kidney,...
Source: Postepy higieny i medycyny doswiadczalnej - Category: Research Tags: Review article Source Type: research
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