The Experts below are selected from a list of 1437 Experts worldwide ranked by ideXlab platform
Reuben Matalon - One of the best experts on this subject based on the ideXlab platform.
-
366 hitting two birds with one stone how efficacious pre clinical gene therapy cures Canavan Disease and sheds light onto the pathomechanism
Molecular Therapy, 2016Co-Authors: Dominic J Gessler, Reuben Matalon, Guangping GaoAbstract:Almost 90 years ago, Canavan Disease (CD) was described for the first time. Since then, the scientific community has unsuccessfully sought to cure this devastating leukodystrophy and understand its pathomechanism. Early hope for gene therapy was fueled with the cloning of the Disease causing gene, Aspartoacylase, in 1993. Unfortunately, the only clinical trial for CD gene therapy failed to show significant clinical improvements in Canavan patients. At that time, animal models for CD were just engineered and comprehensive pre-clinical evaluation of CD gene therapy was missing. Earlier, we reported that our 1st generation IV delivered pre-clinical gene therapy was able to rescue early lethality and partially restored motor function in a mouse model of CD. Now in its 3rd generation, our gene therapy cures the Disease in Canavan mice by a single intravenous injection, shown by behavioral, cognitive, and neuropathology tests. Taking advantage of this complete reversal of the Disease, we used whole brain neurometabolome profiling to closely monitor the molecular efficacy and mechanism(s) in curing Canavan Disease in mouse. Hierarchical cluster analysis (HCA) shows complete restoration of the Disease associated metabolic derangements, including the array of detected myelin lipids. In the next step, we hypothesized that the metabolic nature of Canavan Disease mandates the origin of its pathomechanism in the metabolic regulation. We identified a specific dysregulation in the energy metabolism in vitro and in vivo that suggests the self-digestion of myelin for energetic purposes, calling current hypotheses about the Canavan Disease pathomechanism into question. Currently, we are intensifying our insight into this mechanism by mircoRNAome, transcriptome analyses, a series of in vitro cell culture models, as well as supplementary and alternative strategies for the treatment of Canavan Disease. In summary, our data demonstrates strong evidence that rAAV mediated pre-clinical gene therapy not only cures the Canavan phenotype but also corrects the extensive neurometabolome, which provides meticulous evidence for gene therapy's high efficacy. Furthermore, we revealed a new pathomechanism that supports a paradigm shift in our perception of the function of ASPA and NAA in Canavan Disease and their potential implications in other CNS and metabolic disorders in general.
-
Chapter 62 – Canavan Disease
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 2015Co-Authors: Reuben Matalon, Kimberlee Michals MatalonAbstract:Spongy degeneration of the brain, Canavan Disease, is an autosomal recessive leukodystrophy prevalent among individuals of Ashkenazi Jewish extraction. The Disease is characterized by severe mental retardation, developmental delays, and early death. Deficiency of the enzyme aspartoacylase, causes excessive amounts of N-acetylaspartic acid in the urine, brain and body fluids. High levels of N-acetylaspartic acid in the urine are diagnostic for Canavan Disease. Mild or juvenile cases of Canavan Disease with mild elevation of N-acetylaspartic acid and developmental delay have also been found. The gene for aspartoacylase has been cloned and mutations identified. Ashkenazi Jewish populations have two mutations in 98% of the cases while other ethnic groups have more diverse mutations. A knockout mouse with the same phenotype as Canavan Disease has been generated. Trials in knockout mice and Canavan patients are underway for potential treatment for Canavan Disease.
-
Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan Disease
Molecular genetics and metabolism, 2010Co-Authors: Stephen P. Zano, Reuben Matalon, Radhika Malik, Sylvia Szucs, Ronald E. ViolaAbstract:Abstract Canavan Disease is a fatal neurological Disease without any effective treatments to slow the relentless progress of this disorder. Enzyme replacement therapy has been used effectively to treat a number of metabolic disorders, but the presence of the blood–brain-barrier presents an additional challenge in the treatment of neurological disorders. Studies have begun with the aim of establishing a treatment protocol that can effectively replace the defective enzyme in Canavan Disease patients. The human enzyme, aspartoacylase, has been cloned, expressed and purified, and the surface lysyl groups modified through PEGylation. Fully active modified enzymes were administered to mice that are defective in this enzyme and that show many of the symptoms of Canavan Disease. Statistically significant increases in brain enzyme activity levels have been achieved in this animal model, as well as decreases in the elevated substrate levels that mimic those found in Canavan Disease patients. These results demonstrate that the modified enzyme is gaining access to the brain and functions to correct this metabolic defect. The stage is now set for a long term study to optimize this enzyme replacement approach for the development of a treatment protocol.
-
Canavan Disease: Studies on the knockout mouse
Advances in Experimental Medicine and Biology, 2006Co-Authors: Reuben Matalon, Sankar Surendran, Kimberlee Michals-matalon, S. K. TyringAbstract:Canavan Disease (CD) is an autosomal recessive disorder, characterized by spongy degeneration of the brain. Patients with CD have aspartoacylase (ASPA) deficiency, which results accumulation of N-acetylaspartic acid (NAA) in the brain and elevated excretion of urinary NAA. Clinically, patients with CD have macrocephaly, mental retardation and hypotonia. A knockout mouse for CD which was engineered, also has ASPA deficiency and elevated NAA. Molecular studies of the mouse brain showed abnormal expression of multiple genes in addition to ASPA deficiency. Adenoassociated virus mediated gene transfer and stem cell therapy in the knockout mouse are the latest attempts to alter pathophysiology in the CD mouse.
-
Canavan Disease prenatal diagnosis and genetic counseling.
Obstetrics and Gynecology Clinics of North America, 2002Co-Authors: Reuben Matalon, Kimberlee Michals MatalonAbstract:Canavan Disease, also known as spongy degeneration of the brain, is a severe neurodegenerative Disease that leads to early death. The Disease is caused by deficiency of the enzyme aspartoacylase (ASPA), which causes increased levels of N-acetylaspartic acid (NAA) in brain and excessive excretion in urine. There is no treatment for Canavan Disease. Recent developments in carrier identification have led to two major findings: 1) that Canavan is not a rare Disease among Ashkenazi Jews and 2) molecular diagnosis of carriers among Ashkenazi Jews can be determined in about 98% of the cases, which makes prenatal diagnosis for Canavan Disease in the risk population possible.
Rajinder Kaul - One of the best experts on this subject based on the ideXlab platform.
-
Identification and expression of eight novel mutations among non-Jewish patients with Canavan Disease.
American journal of human genetics, 1996Co-Authors: Rajinder Kaul, Reuben Matalon, Anne B. Johnson, Guangping Gao, M. Aloya, M. Jin, R. B H Schutgens, Jennifer ClarkeAbstract:Canavan Disease is inherited as an autosomal recessive trait that is caused by the deficiency of aspartoacylase (ASPA). The majority of patients with Canavan Disease are from an Ashkenazi Jewish background. Mutations in ASPA that lead to loss of enzymatic activity have been identified, and E285A and Y231X are the two predominant mutations that account for 97% of the mutant chromosomes in Ashkenazi Jewish patients. The current study was aimed at finding the molecular basis of Canavan Disease in 25 independent patients of non-Jewish background. Eight novel and three previously characterized mutations accounted for 80% (40/50) of mutant chromosomes. The A305E missense mutation accounted for 48% (24/50) of mutant chromosomes in patients of western European descent, while the two predominant Jewish mutations each accounted for a single mutant chromosome. The eight novel mutations identified included 1- and 4-bp deletions (32 deltaT and 876 deltaAGAA, respectively) and I16T, G27R, D114E, G123E, C152Y, and R168C missense mutations. The homozygous 32 deltaT deletion was identified in the only known patient of African-American origin with Canavan Disease. The heterozygosity for 876 deltaAGAA mutation was identified in three independent patients from England. Six single-base changes leading to missense mutations were identified in patients from Turkey (D114E, R168C), The Netherlands (I16T), Germany (G27R), Ireland (C152Y), and Canada (G123E). A PCR-based protocol is described that was used to introduce mutations in wild-type cDNA. In vitro expression of mutant cDNA clones demonstrated that all of these mutations led to a deficiency of ASPA and should therefore result in Canavan Disease.
-
Canavan Disease: From spongy degeneration to molecular analysis
The Journal of Pediatrics, 1995Co-Authors: Reuben Matalon, K. Michals, Rajinder KaulAbstract:Establishing the basic defect in Canavan Disease has led to reliable biochemical methods for the diagnosis of this Disease. The isolation of the gene and identification of mutations causing Canavan Disease have led to the possibility of using DNA methods for the diagnosis of Canavan Disease and for carrier detection. A surprising finding is the high carrier frequency of this gene defect among Ashkenazi Jewish people. Analysis for two mutations leads to the identification of 97% of Jewish patients with Canavan Disease, and screening of Ashkenazi Jews is possible. N-Acetylaspartic acid has been considered to be an inert compound. The pathophysiology of Canavan Disease links lack of NAA hydrolysis to a severe, debilitating white matter Disease. Currently, NAA is being studied in many other brain disorders, such as Alzheimer Disease, Huntington Disease, and stroke. However, the only Disease with a specific defect in the metabolism of NAA is Canavan Disease. An animal model for Canavan Disease is needed to study some of the questions regarding the role of NAA in brain tissue, and for the study of therapeutic modalities, including gene therapy.
-
Canavan Disease: Genomic Organization and Localization of Human ASPA to 17p13-ter and Conservation of the ASPA Gene during Evolution
Genomics, 1994Co-Authors: Rajinder Kaul, Kuppareddi Balamurugan, Guang P. Gao, Reuben MatalonAbstract:Canavan Disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan Disease. The human ASPA gene has been cloned and found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon III) to 514 (exon VI) bases. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey. The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution. It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan Disease and to study the regulation of ASPA.
-
Canavan Disease: molecular basis of aspartoacylase deficiency.
Journal of Inherited Metabolic Disease, 1994Co-Authors: Rajinder Kaul, Kuppareddi Balamurugan, Guangping Gao, Reuben MatalonAbstract:The biochemical deficiency of aspartoacylase (ASPA; EC 3.5.1.15) was established as the basic defect in Canavan Disease (CD; McKusick 271900) by Matalon et al (1988). Deficiency of ASPA and accumulation of N-acetylaspartic acid (NAA) in the leukodystrophic brain of CD is unique, and has not been observed in any other nonCanavan leukodystrophies such as Alexander and Krabbe Disease, metachromatic leukodystrophy, adrenoleukodystrophy or other andiagnosed leukodystrophies (Matalon et al 1989). The spongy degeneration of brain in CD is accompanied by mental retardation, megalencephaly, hypotonia and early death. The CD is inherited as a Mendelian recessive trait and is more prevalent among Ashkenazi Jews, although patients from other ethnic groups have also been reported
-
Canavan Disease: mutations among Jewish and non-Jewish patients.
American journal of human genetics, 1994Co-Authors: Rajinder Kaul, K. Michals, Kuppareddi Balamurugan, M. Aloya, Guang P. Gao, Arlene Petrosky, Reuben MatalonAbstract:Canavan Disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene. Three point mutations--693C-->A, 854A-->C, and 914C-->A--were identified in the coding sequence. The 693C-->A and 914C-->A base changes, resulting in nonsense tyr231-->ter and missense ala305-->glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A-->C transversion converted glu to ala in codon 285. The glu285-->ala mutant ASPA has 2.5% of the activity expressed by the wild-type enzyme. A fourth mutation, 433 --2(A-->G) transition, was identified at the splice-acceptor site in intron 2. The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285-->ala mutation was predominant (82.9%) in this population, followed by the tyr231-->ter (14.8%) and 433 --2(A-->G) (1.1%) mutations. The three mutations account for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305-->glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes. Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan Disease would suggest a founding-father effect in propagation of these mutant chromosomes.
Aziza Chedrawi - One of the best experts on this subject based on the ideXlab platform.
-
Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan Disease
Genetics in Medicine, 2008Co-Authors: Namik Kaya, Faiqa Imtiaz, Dilek Colak, Moeenaldeen Al-sayed, Ali Al-odaib, Fatma Al-zahrani, Bashayer R. Al-mubarak, Mohammad Al-owain, Hesham Al-dhalaan, Aziza ChedrawiAbstract:Purpose: Canavan Disease, caused by a deficiency of aspartoacylase, is one of the most common cerebral degenerative Diseases of infancy. The aims of this study were to identify the mutations associated with Canavan Disease in Saudi Arabia and to identify differentially expressed genes likely to contribute to the development of this Disease. Methods: Polymerase chain reaction, long polymerase chain reaction, multiplex ligation-dependent probe amplification, sequencing, array comparative genomic hybridization (aCGH), and global gene expression profiling were used to determine putative mutations and likely gene signatures in cultured fibroblasts of patients from Saudi Arabia. Results: One novel and one known large deletion and two previously known mutations (IVS4 + 1G>T and G27R) were identified. Compared with controls, 1440 genes were significantly modulated in Canavan patients (absolute fold change [FC] ≥4). Genome-wide gene expression profiling results indicated that some genes, involved in apoptosis, muscle contraction and development, mitochondrial oxidation, inflammation and glutamate, and aspartate metabolism, were significantly dysregulated. Conclusions: Our findings indicate that the presence of muscle weakness and hypotonia in patients may be associated with the dysregulated gene activities of cell motility, muscle contraction and development, actin binding, and cytoskeletal-related activities. Overall, these observations are in accordance with previous studies performed in a knockout mouse model.
-
Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan Disease.
Genetics in medicine : official journal of the American College of Medical Genetics, 2008Co-Authors: Namik Kaya, Faiqa Imtiaz, Dilek Colak, Moeenaldeen Al-sayed, Ali Al-odaib, Fatma Al-zahrani, Bashayer R. Al-mubarak, Mohammad Al-owain, Hesham Aldhalaan, Aziza ChedrawiAbstract:Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan Disease
Namik Kaya - One of the best experts on this subject based on the ideXlab platform.
-
Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan Disease
Genetics in Medicine, 2008Co-Authors: Namik Kaya, Faiqa Imtiaz, Dilek Colak, Moeenaldeen Al-sayed, Ali Al-odaib, Fatma Al-zahrani, Bashayer R. Al-mubarak, Mohammad Al-owain, Hesham Al-dhalaan, Aziza ChedrawiAbstract:Purpose: Canavan Disease, caused by a deficiency of aspartoacylase, is one of the most common cerebral degenerative Diseases of infancy. The aims of this study were to identify the mutations associated with Canavan Disease in Saudi Arabia and to identify differentially expressed genes likely to contribute to the development of this Disease. Methods: Polymerase chain reaction, long polymerase chain reaction, multiplex ligation-dependent probe amplification, sequencing, array comparative genomic hybridization (aCGH), and global gene expression profiling were used to determine putative mutations and likely gene signatures in cultured fibroblasts of patients from Saudi Arabia. Results: One novel and one known large deletion and two previously known mutations (IVS4 + 1G>T and G27R) were identified. Compared with controls, 1440 genes were significantly modulated in Canavan patients (absolute fold change [FC] ≥4). Genome-wide gene expression profiling results indicated that some genes, involved in apoptosis, muscle contraction and development, mitochondrial oxidation, inflammation and glutamate, and aspartate metabolism, were significantly dysregulated. Conclusions: Our findings indicate that the presence of muscle weakness and hypotonia in patients may be associated with the dysregulated gene activities of cell motility, muscle contraction and development, actin binding, and cytoskeletal-related activities. Overall, these observations are in accordance with previous studies performed in a knockout mouse model.
-
Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan Disease.
Genetics in medicine : official journal of the American College of Medical Genetics, 2008Co-Authors: Namik Kaya, Faiqa Imtiaz, Dilek Colak, Moeenaldeen Al-sayed, Ali Al-odaib, Fatma Al-zahrani, Bashayer R. Al-mubarak, Mohammad Al-owain, Hesham Aldhalaan, Aziza ChedrawiAbstract:Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan Disease
K. Michals - One of the best experts on this subject based on the ideXlab platform.
-
Canavan Disease: From spongy degeneration to molecular analysis
The Journal of Pediatrics, 1995Co-Authors: Reuben Matalon, K. Michals, Rajinder KaulAbstract:Establishing the basic defect in Canavan Disease has led to reliable biochemical methods for the diagnosis of this Disease. The isolation of the gene and identification of mutations causing Canavan Disease have led to the possibility of using DNA methods for the diagnosis of Canavan Disease and for carrier detection. A surprising finding is the high carrier frequency of this gene defect among Ashkenazi Jewish people. Analysis for two mutations leads to the identification of 97% of Jewish patients with Canavan Disease, and screening of Ashkenazi Jews is possible. N-Acetylaspartic acid has been considered to be an inert compound. The pathophysiology of Canavan Disease links lack of NAA hydrolysis to a severe, debilitating white matter Disease. Currently, NAA is being studied in many other brain disorders, such as Alzheimer Disease, Huntington Disease, and stroke. However, the only Disease with a specific defect in the metabolism of NAA is Canavan Disease. An animal model for Canavan Disease is needed to study some of the questions regarding the role of NAA in brain tissue, and for the study of therapeutic modalities, including gene therapy.
-
Canavan Disease: mutations among Jewish and non-Jewish patients.
American journal of human genetics, 1994Co-Authors: Rajinder Kaul, K. Michals, Kuppareddi Balamurugan, M. Aloya, Guang P. Gao, Arlene Petrosky, Reuben MatalonAbstract:Canavan Disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene. Three point mutations--693C-->A, 854A-->C, and 914C-->A--were identified in the coding sequence. The 693C-->A and 914C-->A base changes, resulting in nonsense tyr231-->ter and missense ala305-->glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A-->C transversion converted glu to ala in codon 285. The glu285-->ala mutant ASPA has 2.5% of the activity expressed by the wild-type enzyme. A fourth mutation, 433 --2(A-->G) transition, was identified at the splice-acceptor site in intron 2. The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285-->ala mutation was predominant (82.9%) in this population, followed by the tyr231-->ter (14.8%) and 433 --2(A-->G) (1.1%) mutations. The three mutations account for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305-->glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes. Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan Disease would suggest a founding-father effect in propagation of these mutant chromosomes.
-
Canavan Disease: Biochemical and molecular studies
Journal of Inherited Metabolic Disease, 1993Co-Authors: Reuben Matalon, R. Kaul, K. MichalsAbstract:Deficiency of the enzyme aspartoacylase and the accumulation of N -acetylaspartic acid lead to a severe leukodystrophy and spongy degeneration of the brain, Canavan Disease (McKusick 271900). Since our discovery in 1988 of the defect in Canavan Disease, 144 patients with Canavan Disease have been diagnosed in our laboratory. Most of these children are of Ashkenazi Jewish extraction. The level of enzyme activity can be used for carrier testing. Prenatal diagnosis has been difficult using the enzyme assay owing to the low activity of aspartoacylase in cultured chorionic villus samples or amniocytes. The determination of N -acetylaspartic acid in the amniotic fluid is another parameter for diagnosis; however, the levels may not always be elevated. Bovine and human aspartoacylase have been purified in our laboratory. Bovine and human cDNA and genomic clones have been isolated and six exons have been localized. This information is being used for the study of Canavan Disease at the molecular level.
-
Canavan Disease: Biochemical and Molecular Studies
Journal of inherited metabolic disease, 1993Co-Authors: Reuben Matalon, Rajinder Kaul, K. MichalsAbstract:Deficiency of the enzyme aspartoacylase and the accumulation ofN-acetylaspartic acid lead to a severe leukodystrophy and spongy degeneration of the brain, Canavan Disease (McKusick 271900). Since our discovery in 1988 of the defect in Canavan Disease, 144 patients with Canavan Disease have been diagnosed in our laboratory. Most of these children are of Ashkenazi Jewish extraction. The level of enzyme activity can be used for carrier testing. Prenatal diagnosis has been difficult using the enzyme assay owing to the low activity of aspartoacylase in cultured chorionic villus samples or amniocytes. The determination ofN-acetylaspartic acid in the amniotic fluid is another parameter for diagnosis; however, the levels may not always be elevated.
-
Prenatal diagnosis of Canavan Disease.
Journal of inherited metabolic disease, 1992Co-Authors: Reuben Matalon, K. Michals, P. Gashkoff, Rajinder KaulAbstract:Spongy degeneration of the brain, Canavan Disease (CD; McKusick 271900), is an autosomal recessive disorder prevalent among Ashkenazi Jews. The Disease is a leukodystrophy manifested by macrocephaly, mental retardation and early death (Canavan 1931; van Bogaert and Bertrand 1967). Patients with Canavan Disease excrete large amounts of β-acetylaspartic acid (NAA) in their urine and have a profound deficiency of aspartoacylase (EC 3.5.1.15) in their cultured skin fibroblasts and other tissues (Matalon et al 1988, 1989)