Browsing by Author "Wenger, David A"
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Item Open Access Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.(Genetics in medicine : official journal of the American College of Medical Genetics, 2016-12) Wasserstein, Melissa P; Andriola, Mary; Arnold, Georgianne; Aron, Alan; Duffner, Patricia; Erbe, Richard W; Escolar, Maria L; Estrella, Lissette; Galvin-Parton, Patricia; Iglesias, Alejandro; Kay, Denise M; Kronn, David F; Kurtzberg, Joanne; Kwon, Jennifer M; Langan, Thomas J; Levy, Paul A; Naidich, Thomas P; Orsini, Joseph J; Pellegrino, Joan E; Provenzale, James M; Wenger, David A; Caggana, MicheleBackground
Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006.Methods
Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT.Results
Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease.Conclusions
These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.Item Open Access Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease.(Orphanet journal of rare diseases, 2018-02) Kwon, Jennifer M; Matern, Dietrich; Kurtzberg, Joanne; Wrabetz, Lawrence; Gelb, Michael H; Wenger, David A; Ficicioglu, Can; Waldman, Amy T; Burton, Barbara K; Hopkins, Patrick V; Orsini, Joseph JBACKGROUND:Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes. FINDINGS:Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion. CONCLUSION:This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.Item Open Access Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease.(Molecular genetics and metabolism, 2021-09) Thompson-Stone, Robert; Ream, Margie A; Gelb, Michael; Matern, Dietrich; Orsini, Joseph J; Levy, Paul A; Rubin, Jennifer P; Wenger, David A; Burton, Barbara K; Escolar, Maria L; Kurtzberg, JoanneObjective
To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD).Methods
KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD.Results
Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%.Conclusion
The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.Item Open Access Newborn screening for Krabbe disease in New York State: the first eight years' experience.(Genetics in medicine : official journal of the American College of Medical Genetics, 2016-03) Orsini, Joseph J; Kay, Denise M; Saavedra-Matiz, Carlos A; Wenger, David A; Duffner, Patricia K; Erbe, Richard W; Biski, Chad; Martin, Monica; Krein, Lea M; Nichols, Matthew; Kurtzberg, Joanne; Escolar, Maria L; Adams, Darius J; Arnold, Georgianne L; Iglesias, Alejandro; Galvin-Parton, Patricia; Kronn, David F; Kwon, Jennifer M; Levy, Paul A; Pellegrino, Joan E; Shur, Natasha; Wasserstein, Melissa P; Caggana, Michele; New York State Krabbe Disease ConsortiumPurpose
Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006.Methods
Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination.Results
Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease.Conclusions
The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.Item Open Access Preclinical characterization of DUOC-01, a cell therapy product derived from banked umbilical cord blood for use as an adjuvant to umbilical cord blood transplantation for treatment of inherited metabolic diseases.(Cytotherapy, 2015-06) Kurtzberg, Joanne; Buntz, Susan; Gentry, Tracy; Noeldner, Pamela; Ozamiz, April; Rusche, Benjamin; Storms, Robert W; Wollish, Amy; Wenger, David A; Balber, Andrew EBackground aims
Cord blood (CB) transplantation slows neurodegeneration during certain inherited metabolic diseases. However, the number of donor cells in the brain of patients does not appear to be sufficient to provide benefit until several months after transplant. We developed the cell product DUOC-01 to provide therapeutic effects in the early post-transplant period.Methods
DUOC-01 cultures initiated from banked CB units were characterized by use of time-lapse photomicroscopy during the 21-day manufacturing process. Antigen expression was measured by means of flow cytometry and immunocytochemistry; transcripts for cytokines and enzymes by quantitative real-time polymerase chain reaction; activities of lysosomal enzymes by direct biochemical analysis; alloreactivity of DUOC-01 and of peripheral blood (PB) mononuclear cells (MNC) to DUOC-01 by mixed lymphocyte culture methods; and cytokine secretion by Bioplex assays.Results
DUOC-01 cultures contained highly active, attached, motile, slowly proliferating cells that expressed common (cluster of differentiation [CD]11b, CD14 and Iba1), M1 type (CD16, inducible nitric oxide synthase), and M2-type (CD163, CD206) macrophage or microglia markers. Activities of 11 disease-relevant lysosomal enzymes in DUOC-01 products were similar to those of normal PB cells. All DUOC-01 products secreted interleukin (IL)-6 and IL-10. Accumulation of transforming growth factor-β, IL-1β, interferon-γ and TNF-α in supernatants was variable. IL-12, IL-2, IL-4, IL-5 and IL-13 were not detected at significant concentrations. Galactocerebrosidase, transforming growth factor-β and IL-10 transcripts were specifically enriched in DUOC-01 relative to CB cells. PB MNCs proliferated and released cytokines in response to DUOC-01. DUOC-01 did not proliferate in response to mismatched MNC.Conclusions
DUOC-01 has potential as an adjunctive cell therapy to myeloablative CB transplant for treatment of inherited metabolic diseases.Item Open Access Reprint of: Preclinical characterization of DUOC-01, a cell therapy product derived from banked umbilical cord blood for use as an adjuvant to umbilical cord blood transplantation for treatment of inherited metabolic diseases.(Cytotherapy, 2015-09) Kurtzberg, Joanne; Buntz, Susan; Gentry, Tracy; Noeldner, Pamela; Ozamiz, April; Rusche, Benjamin; Storms, Robert W; Wollish, Amy; Wenger, David A; Balber, Andrew EBackground aims
Cord blood (CB) transplantation slows neurodegeneration during certain inherited metabolic diseases. However, the number of donor cells in the brain of patients does not appear to be sufficient to provide benefit until several months after transplant. We developed the cell product DUOC-01 to provide therapeutic effects in the early post-transplant period.Methods
DUOC-01 cultures initiated from banked CB units were characterized by use of time-lapse photomicroscopy during the 21-day manufacturing process. Antigen expression was measured by means of flow cytometry and immunocytochemistry; transcripts for cytokines and enzymes by quantitative real-time polymerase chain reaction; activities of lysosomal enzymes by direct biochemical analysis; alloreactivity of DUOC-01 and of peripheral blood (PB) mononuclear cells (MNC) to DUOC-01 by mixed lymphocyte culture methods; and cytokine secretion by Bioplex assays.Results
DUOC-01 cultures contained highly active, attached, motile, slowly proliferating cells that expressed common (cluster of differentiation [CD]11b, CD14 and Iba1), M1 type (CD16, inducible nitric oxide synthase), and M2-type (CD163, CD206) macrophage or microglia markers. Activities of 11 disease-relevant lysosomal enzymes in DUOC-01 products were similar to those of normal PB cells. All DUOC-01 products secreted interleukin (IL)-6 and IL-10. Accumulation of transforming growth factor-β, IL-1β, interferon-γ and TNF-α in supernatants was variable. IL-12, IL-2, IL-4, IL-5 and IL-13 were not detected at significant concentrations. Galactocerebrosidase, transforming growth factor-β and IL-10 transcripts were specifically enriched in DUOC-01 relative to CB cells. PB MNCs proliferated and released cytokines in response to DUOC-01. DUOC-01 did not proliferate in response to mismatched MNC.Conclusions
DUOC-01 has potential as an adjunctive cell therapy to myeloablative CB transplant for treatment of inherited metabolic diseases.