The Experts below are selected from a list of 477 Experts worldwide ranked by ideXlab platform
Ichizo Nishino - One of the best experts on this subject based on the ideXlab platform.
-
Phase I clinical trial results of aceneuramic acid for GNE myopathy in Japan
'Springer Science and Business Media LLC', 2018Co-Authors: Naoki Suzuki, Masaaki Kato, Hitoshi Warita, Rumiko Izumi, Maki Tateyama, Hiroshi Kuroda, Ryuta Asada, Akifumi Suzuki, Takuhiro Yamaguchi, Ichizo NishinoAbstract:Abstract Background GNE myopathy (distal myopathy with rimmed vacuoles) is a rare intractable muscle disease caused by the mutations in GNE Gene, with no therapeutic agents at present. The mutations in GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene result in a deficiency of the biosynthesis of aceneuramic acid. Aceneuramic acid improves the phenotype of GNE myopathy model mice. We examined the pharmacokinetics and safety of aceneuramic acid therapy in a nonrandomized manner for patients with GNE myopathy for the first time in humans. Methods This article was based on the world’s first Phase I trial and the additional Phase I trial that began at a time when the intermediate results of an overseas Phase II trial were ascertained. In the first trial, conventional tablets without controlled release were administered orally in a single dose of 800 mg, in 800 mg/doses given three times in 1 day, and in 800 mg/doses given three times per day for 5 days. Serum and urinary concentrations of total aceneuramic acid including aceneuramic acid bound to proteins and lipids were measured. Subsequently, administering extended-release tablets to patients with GNE myopathy, we investigated the pharmacokinetics and safety of a single 2000 mg dose, three doses given for 1 day, and three doses per day for 7 days. Results The results of the first trial showed no obvious increase in serum concentration after administration. Whereas the amount of aceneuramic acid excreted in the urine Generally increased with all given doses, although there were variations among trial subjects. In the second trial, we measured free serum aceneuramic acid levels, and with all doses given there were obvious increases in the levels observed after administration. The degrees of increase were comparable with other studies conducted overseas, and there was no difference based on ethnicity. With regards to urinary excretion, free aceneuramic acid levels showed elevated levels in all patients, and total aceneuramic acid also increased in General, thus we could confirm the absorption of the investigational drug. In respect to safety, while some adverse events including abnormal laboratory test findings were observed, all events were mild and the causal relationship with the investigational drug was ruled out or unlikely. Conclusion The elevated serum concentration of aceneuramic acid and safety were confirmed. We decided that the trial could shift to the next level to examine the long-term efficacy and safety for Japanese patients as well. Trial registration NCT01236898, UMIN000011532. Registered 9 November 2010
-
phenotypic stratification and genotype phenotype correlation in a heteroGeneous international cohort of GNE myopathy patients first report from the GNE myopathy disease monitoring program registry portion
Neuromuscular Disorders, 2017Co-Authors: Oksana Pogoryelova, Ichizo Nishino, Alison Skrinar, Zohar Argov, Phillip Cammish, Hank Mansbach, Yiumo Chan, Shahriar Nafissi, Hosein Shamshiri, Emil D KakkisAbstract:GNE myopathy is a rare distal myopathy, caused by mutations in the GNE Gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of Genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.
-
sialic acid replacement therapy for distal myopathy with rimmed vacuoles
Brain and nerve, 2015Co-Authors: Madoka Moriyoshimura, Ichizo NishinoAbstract:: Distal myopathy with rimmed vacuoles or GNE myopathy, is an early adult-onset myopathy with slow progression that preferentially affects the tibialis anterior muscle. Severely affected patients show marked limb muscle atrophy together with respiratory dysfunction. The disease is caused by a mutation in the GNE Gene that catalyzes two rate-limiting reactions in cytosolic sialic acid synthesis. Oral treatment with sialic acid metabolite prevents muscle atrophy and weakness in a mouse GNE myopathy model and a global Phase III study is currently underway. In addition, a global patient registry of neuromuscular cases is widely accepted as a useful tool to obtain epidemiological data and bolster patient recruitment for further development of this treatment strategy.
-
sialic acid replacement therapy for distal myopathy with rimmed vacuoles
Brain and nerve, 2015Co-Authors: Madoka Moriyoshimura, Ichizo NishinoAbstract:: Distal myopathy with rimmed vacuoles or GNE myopathy, is an early adult-onset myopathy with slow progression that preferentially affects the tibialis anterior muscle. Severely affected patients show marked limb muscle atrophy together with respiratory dysfunction. The disease is caused by a mutation in the GNE Gene that catalyzes two rate-limiting reactions in cytosolic sialic acid synthesis. Oral treatment with sialic acid metabolite prevents muscle atrophy and weakness in a mouse GNE myopathy model and a global Phase III study is currently underway. In addition, a global patient registry of neuromuscular cases is widely accepted as a useful tool to obtain epidemiological data and bolster patient recruitment for further development of this treatment strategy.
-
GNE myopathy current update and future therapy
Journal of Neurology Neurosurgery and Psychiatry, 2015Co-Authors: Ichizo Nishino, Nuria Carrillocarrasco, Zohar ArgovAbstract:GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a Gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE Gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early Gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.
Marjan Huizing - One of the best experts on this subject based on the ideXlab platform.
-
Hereditary inclusion body myopathy: single patient response to GNE Gene Lipoplex therapy
2020Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Chris Jay, Cynthia BedellAbstract:Abstract Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle
-
Genetic analysis reveals that GNE myopathy is an underdiagnosed neuromuscular disorder p2 044
Neurology, 2015Co-Authors: Marjan Huizing, William A. Gahl, Carla Ciccone, May Christine V Malicdan, Frank Celeste, Thierry Vilboux, Nuria CarrillocarrascoAbstract:OBJECTIVE: To support our GNE myopathy natural history study and subject recruitment for clinical trials, we analyzed all reported GNE variants associated with GNE myopathy and estimated world-wide prevalence of the disease. BACKGROUND: GNE myopathy (also called HIBM, DMRV, IBM-2, Nonaka myopathy, QSM) is an adult-onset progressive myopathy, caused by bi-allelic GNE Gene variants. GNE encodes the key enzyme in sialic acid synthesis. The pathomechanism of GNE myopathy likely involves aberrant muscle sialylation. Clinical trials with sialylation-increasing compounds are ongoing. DESIGN/METHODS: We gathered all known GNE myopathy-associated GNE variants and used next-Generation databases to estimate the prevalence of the disease. RESULTS: We identified 154 GNE myopathy-associated GNE variants and assessed their predicted effects on protein function. Exome sequence database analysis revealed three frequently occurring, unreported GNE missense variants/polymorphisms, important for sequence interpretations. Based on allele frequencies, the estimate world-wide prevalence of GNE myopathy was estimated to be at least 6/1,000,000. CONCLUSIONS: The unrecognized high prevalence of GNE myopathy (~ 40,000 patients worldwide; ~3000 patients in USA, instead of previously estimated ~ 400) confirms suspicions that many patients escape diagnosis. Indeed, our ongoing natural history study revealed significant diagnostic delay (~10 years) after initial symptoms in most patients, due to the rare nature of the disease and the lack of conclusive, inexpensive diagnostic tests. Genetic testing for pathogenic, bi-allelic GNE variants ultimately confirms the diagnosis. GNE myopathy should be considered in any young adult with distal, lower extremity muscle weakness. Delayed diagnosis causes emotional hardship for the patient, delays proper disease-management, and influences eligibility to enroll in clinical trials. Awareness among physicians and Geneticists for GNE myopathy is essential for the identification of new patients, preferably in early stages of disease. This will support understanding of the disorder’s pathomechanism and success of ongoing treatment trials. Support: NHGRI and NCATS Intramural Programs, NIH, Bethesda, USA Disclosure: Dr. Huizing has nothing to disclose. Dr. Malicdan has nothing to disclose. Dr. Celeste has nothing to disclose. Dr. Vilboux has nothing to disclose. Dr. Ciccone has nothing to disclose. Dr. Gahl has nothing to disclose. Dr. Carrillo-Carrasco has nothing to disclose.
-
identification tissue distribution and molecular modeling of novel human isoforms of the key enzyme in sialic acid synthesis udp glcnac 2 epimerase mannac kinase
Biochemistry, 2011Co-Authors: Tal Yardeni, William A. Gahl, Carla Ciccone, Tsering Choekyi, Katherine Jacobs, Katherine Patzel, Yair Anikster, Natalya Kurochkina, Marjan HuizingAbstract:The bifunctional enzyme uridine diphosphate (UDP)1-N-acetylglucosamine (GlcNAc) 2- epimerase/N-acetylmannosamine (ManNAc) kinase (GNE), encoded by the GNE Gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid (Neu5Ac) (1, 2). Neu5Ac is the most abundant mammalian sialic acid and the precursor of most naturally existing sialic acids (3). Sialic acids are negatively charged, terminal residues on glycoconjugates, and assist in many cellular functions including cell-cell interactions, proliferation, and viral or bacterial infections (3, 4). The GNE enzyme consists of two enzymatic domains. The N-terminal domain carries out UDP-GlcNAc epimerase function, whereas the Cterminal domain is responsible for ManNAc kinase activity. In mammals, the end product of sialic acid synthesis, CMP-Neu5Ac, feedback-inhibits UDP-GlcNAc 2-epimerase activity of GNE by binding to its allosteric site (5). Two distinct human disorders, sialuria (OMIM 269921) and hereditary inclusion body myopathy (HIBM; OMIM 600737), are associated with predominantly missense mutations in GNE. Sialuria is an autosomal dominant disorder characterized by coarse facies, variable developmental delay, hepatomegaly and recurrent infections. To date, only seven sialuria patients are described worldwide. All patients have a heterozygous missense mutation affecting the allosteric site of GNE, leading to loss of feedback-inhibition of GNE-epimerase activity by CMP-Neu5Ac, resulting in excessive sialic acid production (6, 7). HIBM and its allelic Japanese disorder, distal myopathy with rimmed vacuoles, or DMRV (OMIM 605820), is an autosomal recessive neuromuscular disorder of adult onset, characterized by slowly progressive muscle weakness and atrophy. More than 500 HIBM\DMRV patients exist worldwide, harboring over 60 GNE mutations. HIBM\DMRV patients have recessive (predominantly missense) mutations in either enzymatic domain of GNE, leading to decreased enzyme activity and, presumably, decreased sialic acid production (2, 8, 9). Whether hyposialylation is the main cause of the neuromuscular symptoms in HIBM\DMRV patients remains unknown. In prokaryotes, GNE epimerase and kinase functions are carried out by two separate enzymes, and prokaryotic 2-epimerases have no allosteric feedback inhibition. In mammals, a bifunctional enzyme might have evolved by Gene fusion of the two independent enzymes responsible for epimerase/kinase activity. Similarities between mammalian GNE N-terminal regions with prokaryotic UDP-GlcNAc 2-epimerases and mammalian GNE C-terminal regions with members of the sugar kinase superfamily previously assisted in identifying characteristic motifs of the GNE epimerase and kinase enzymatic domains (10, 11). Bacterial 2-epimerases are allosterically regulated by its substrate UDP-GlcNAc. A structural basis for allosteric activation was demonstrated by a crystallographic analysis of the B. subtilis 2 2-epimerase in complex with the reaction intermediate UDP (12). In addition, the crystallographic structures of the E. coli GNE enzyme unbound and in complex with UDP-N-acetylglucosamine (pdb code 1f6d, 1vgv), and the V. cholera (pdb code 1dzc) and B. anthracis (pdb code 3beo) enzymes in complex with UDP-N-acetylglucosamine were solved. Similarity of the N-terminal domain of the H. sapiens GNE to V. cholera (27% homology), E. coli (20% homology) and B. anthracis (18% homology) 2-epimerases was used to model its three-dimensional structure. In previous studies, structural elements and important ATP, ADP, Mg2+ and substrate-binding amino acids were assiGNEd on the basis of these similarities (10, 11). The N-terminal epimerase domain of the human GNE enzyme contains two α/β domains (domains I and II) that form a cleft at the domain interface harboring the active site. Topology of both domains is similar to the Rossmann dinucleotide binding fold (13). Rossmann fold domains are conserved among mammalian and bacterial 2- epimerases. The human N-terminal GNE epimerase domain has a 7-stranded parallel β-sheet sandwiched between a total of 7 α-helices. The C-terminus of the GNE epimerase domain contains a 6-stranded β-sheet surrounded by a total of 7 α-helices (11). Other carriers of the Rossmann fold, including glycosyltransferases and the epimerase domains of 2-epimerases, have similar N-terminal and C-terminal domains (14, 15). The crystallographic structure of the ManNAc kinase domain of human GNE is solved at 2.84 A resolution (pdb code 3eo3) (16). Residues 409–431 of the mammalian GNE ManNAc kinase domain showed similarities with the phosphate 1 motif of the ATP-binding domain of eukaryotic hexokinases (10). Similar to hexokinases (17), mammalian GNE ManNAc kinase contains a 5-stranded β-sheet β3β2β1β4β5 with β2 being anti-parallel to four other parallel strands with a pair of parallel alpha-helices located on each side of the β-sheet (Domain I). Another 5-stranded β-sheet β8β7β6β9β1 with β7 being anti-parallel to four other parallel strands is surrounded by a pair of parallel α-helices on each side (Domain II). The structure of two similar domains involved in ATP binding is a common feature of the ASKHA (Acetate and Sugar Kinase/Hsp70/Actin) superfamily, described in detail for the bacterial poly(P)/ATP-glucomannokinase (18, 19). Recently, different human GNE mRNA splice variants and three predicted translated proteins, hGNE1, hGNE2 and hGNE3 were described (20, 21). Subsequently, two different mouse GNE mRNA splice variants were described, GNE1 and GNE2, together with their expression in selected tissues (22). In the current study we identified additional human isoforms hGNE4-8, and demonstrate expression of hGNE isoform transcripts in a wide variety of tissues. It is unknown which role these isoforms play in GNE regulation, or GNE-related disease pathology. Based on our previous modeling results of the hGNE1 isoform (11), we now analyze and compare the structural features, with respect to catalytic activity, ligand binding and allosteric regulation, of all eight human GNE isoforms.
-
hereditary inclusion body myopathy single patient response to intravenous dosing of GNE Gene lipoplex
Human Gene Therapy, 2011Co-Authors: Gregory Nemunaitis, William A. Gahl, Tal Yardeni, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Cynthia BedellAbstract:Abstract Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE Gene function through liposomal delivery of the wild-type GNE Gene. Results were verified in a single patient treated by intravenous infusion of GNE Gene lipoplex. A single patient (patient 001) with severe HIBM treated with a compassionate investigational new drug received seven doses of GNE Gene lipoplex via intravenous infusion at the following doses: 0.4, 0.4, 1.0, 4.0, 5.0, 6.0, and 7.0 mg of DNA. GNE transGene expression, downstream induction of sialic acid, safety, and muscle function were evaluated. Transient low-grade fever, myalgia, tachycardia, transaminase elevation, hyponatremia, and hypotension were observed after infusion of each dose of GNE Gene lipoplex. Quadric...
-
hereditary inclusion body myopathy single patient response to GNE Gene lipoplex therapy
Journal of Gene Medicine, 2010Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Cynthia BedellAbstract:Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle. Methods A single patient (subject #001) with severe HIBM treated by compassionate investigational new drug received four doses of GNE Gene Lipoplex via intramuscular injection. GNE transGene expression, downstream induction of sialic acid, safety and muscle function were evaluated. Results Significant durable improvement in locoregional skeletal muscle function was observed in the injected left extensor carpi radialis longus of #001 in correlation with GNE transGene upregulation and local induction of sialic acid. Other than transient low grade fever and pain at the injection site, no significant toxicity was observed. Conclusions Proof of principle for manufacturing of ‘clinical grade’ GNE Gene Lipoplex, clinical safety and activity are demonstrated with GNE Gene Lipoplex. Further assessment will involve intravenous administration and subsequent phase I trial involving additional but less severely afflicted HIBM patients. Copyright 2010 John Wiley & Sons, Ltd.
Gregory Nemunaitis - One of the best experts on this subject based on the ideXlab platform.
-
Hereditary inclusion body myopathy: single patient response to GNE Gene Lipoplex therapy
2020Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Chris Jay, Cynthia BedellAbstract:Abstract Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle
-
Safety and in vivo Expression of a GNE-TransGene: A Novel Treatment Approach for Hereditary Inclusion Body Myopathy-2
2016Co-Authors: Anagha P Phadke, Gregory Nemunaitis, Chris Jay, Salina J. Chen, Courtney Haddock, Zhaohui Wang, Derek Nemunaitis, Nancy S. Templeton, Neil SenzerAbstract:Abstract: Hereditary inclusion body myopathy-2 (HIBM2) is an adult-onset, muscular disease caused by mutations in the GNE Gene. HIBM2-associated GNE mutations causing hyposialyation have been proposed to contribute to reduced muscle function in patients with HIBM2, though the exact cause of this disease is unknown. In the current studies we examined pre-clinical in vivo toxicity, and expression of the plasmid-based, CMV driven wild-type GNE plasmid vector. The plasmid vector was injected intramuscularly (IM) or systemically (IV) into BALB/c mice, following encapsulation in a cationic liposome (DOTAP:Cholesterol). Single IM injections of the GNE-lipoplex at 40 μg did not produce overt toxicity or deaths, indicating that the no observable adverse effect level (NOAEL) dose for IM injection was 40 μg. Single intravenous (IV) infusion of GNE-lipoplex was lethal in 33 % of animals at 100 μg dose, with a small proportion of animals in the 40 μg cohort demonstrating transient toxicity. Thus the NOAEL dose by the IV route was greater than 10 μg and less than or equal to 40 μg. Real-time RT-qPCR analysis demonstrated recombinant human GNE mRNA expression in 100 % of muscle tissues that received IM injection of 40 μg GNE-lipoplex, at 2 weeks. These results indicate that GNE-lipoplex Gene transfer i
-
Preclinical Assessment of wt GNE Gene Plasmid for Management of Hereditary Inclusion Body Myopathy 2 (HIBM2)
2016Co-Authors: Chris Jay, Daniel Darvish, Gregory Nemunaitis, John Nemunaitis, Neil Senzer, Julie Ogden, John Eager, Alex Tong, Phillip B MaplesAbstract:Abstract: Hereditary Inclusion Body Myopathy (HIBM2) is a chronic progressive skeletal muscle wasting disorder which Generally leads to complete disability before the age of 50 years. There is currently no effective therapeutic treatment for HIBM2. Development of this disease is related to expression in family members of an autosomal recessive mutation of the GNE Gene, which encodes the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK). This is the rate limiting bifunctional enzyme that catalyzes the fi rst 2 steps of sialic acid biosynthesis. Decreased sialic acid production, consequently leads to decreased sialyation of a variety of glycoproteins including the critical muscle protein alpha-dystroglycan (α-DG). This in turn severely cripples muscle function and leads to the onset of the syndrome. We hypothesize that replac-ing the mutated GNE Gene with the wildtype Gene may restore functional capacity of GNE/MNK and therefore production of sialic acid, allowing for improvement in muscle function and/or delay in rate of muscle deterioration. We have constructed three GNE Gene/CMV promoter plasmids (encoding the wildtype, HIBM2, and Sialuria forms of GNE) and demonstrated enhanced GNE Gene activity following delivery to GNE-defi cient CHO-Lec3 cells. GNE/MNK enzyme function was sig
-
hereditary inclusion body myopathy single patient response to intravenous dosing of GNE Gene lipoplex
Human Gene Therapy, 2011Co-Authors: Gregory Nemunaitis, William A. Gahl, Tal Yardeni, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Cynthia BedellAbstract:Abstract Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE Gene function through liposomal delivery of the wild-type GNE Gene. Results were verified in a single patient treated by intravenous infusion of GNE Gene lipoplex. A single patient (patient 001) with severe HIBM treated with a compassionate investigational new drug received seven doses of GNE Gene lipoplex via intravenous infusion at the following doses: 0.4, 0.4, 1.0, 4.0, 5.0, 6.0, and 7.0 mg of DNA. GNE transGene expression, downstream induction of sialic acid, safety, and muscle function were evaluated. Transient low-grade fever, myalgia, tachycardia, transaminase elevation, hyponatremia, and hypotension were observed after infusion of each dose of GNE Gene lipoplex. Quadric...
-
hereditary inclusion body myopathy single patient response to GNE Gene lipoplex therapy
Journal of Gene Medicine, 2010Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Cynthia BedellAbstract:Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle. Methods A single patient (subject #001) with severe HIBM treated by compassionate investigational new drug received four doses of GNE Gene Lipoplex via intramuscular injection. GNE transGene expression, downstream induction of sialic acid, safety and muscle function were evaluated. Results Significant durable improvement in locoregional skeletal muscle function was observed in the injected left extensor carpi radialis longus of #001 in correlation with GNE transGene upregulation and local induction of sialic acid. Other than transient low grade fever and pain at the injection site, no significant toxicity was observed. Conclusions Proof of principle for manufacturing of ‘clinical grade’ GNE Gene Lipoplex, clinical safety and activity are demonstrated with GNE Gene Lipoplex. Further assessment will involve intravenous administration and subsequent phase I trial involving additional but less severely afflicted HIBM patients. Copyright 2010 John Wiley & Sons, Ltd.
William A. Gahl - One of the best experts on this subject based on the ideXlab platform.
-
Hereditary inclusion body myopathy: single patient response to GNE Gene Lipoplex therapy
2020Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Chris Jay, Cynthia BedellAbstract:Abstract Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle
-
Genetic analysis reveals that GNE myopathy is an underdiagnosed neuromuscular disorder p2 044
Neurology, 2015Co-Authors: Marjan Huizing, William A. Gahl, Carla Ciccone, May Christine V Malicdan, Frank Celeste, Thierry Vilboux, Nuria CarrillocarrascoAbstract:OBJECTIVE: To support our GNE myopathy natural history study and subject recruitment for clinical trials, we analyzed all reported GNE variants associated with GNE myopathy and estimated world-wide prevalence of the disease. BACKGROUND: GNE myopathy (also called HIBM, DMRV, IBM-2, Nonaka myopathy, QSM) is an adult-onset progressive myopathy, caused by bi-allelic GNE Gene variants. GNE encodes the key enzyme in sialic acid synthesis. The pathomechanism of GNE myopathy likely involves aberrant muscle sialylation. Clinical trials with sialylation-increasing compounds are ongoing. DESIGN/METHODS: We gathered all known GNE myopathy-associated GNE variants and used next-Generation databases to estimate the prevalence of the disease. RESULTS: We identified 154 GNE myopathy-associated GNE variants and assessed their predicted effects on protein function. Exome sequence database analysis revealed three frequently occurring, unreported GNE missense variants/polymorphisms, important for sequence interpretations. Based on allele frequencies, the estimate world-wide prevalence of GNE myopathy was estimated to be at least 6/1,000,000. CONCLUSIONS: The unrecognized high prevalence of GNE myopathy (~ 40,000 patients worldwide; ~3000 patients in USA, instead of previously estimated ~ 400) confirms suspicions that many patients escape diagnosis. Indeed, our ongoing natural history study revealed significant diagnostic delay (~10 years) after initial symptoms in most patients, due to the rare nature of the disease and the lack of conclusive, inexpensive diagnostic tests. Genetic testing for pathogenic, bi-allelic GNE variants ultimately confirms the diagnosis. GNE myopathy should be considered in any young adult with distal, lower extremity muscle weakness. Delayed diagnosis causes emotional hardship for the patient, delays proper disease-management, and influences eligibility to enroll in clinical trials. Awareness among physicians and Geneticists for GNE myopathy is essential for the identification of new patients, preferably in early stages of disease. This will support understanding of the disorder’s pathomechanism and success of ongoing treatment trials. Support: NHGRI and NCATS Intramural Programs, NIH, Bethesda, USA Disclosure: Dr. Huizing has nothing to disclose. Dr. Malicdan has nothing to disclose. Dr. Celeste has nothing to disclose. Dr. Vilboux has nothing to disclose. Dr. Ciccone has nothing to disclose. Dr. Gahl has nothing to disclose. Dr. Carrillo-Carrasco has nothing to disclose.
-
identification tissue distribution and molecular modeling of novel human isoforms of the key enzyme in sialic acid synthesis udp glcnac 2 epimerase mannac kinase
Biochemistry, 2011Co-Authors: Tal Yardeni, William A. Gahl, Carla Ciccone, Tsering Choekyi, Katherine Jacobs, Katherine Patzel, Yair Anikster, Natalya Kurochkina, Marjan HuizingAbstract:The bifunctional enzyme uridine diphosphate (UDP)1-N-acetylglucosamine (GlcNAc) 2- epimerase/N-acetylmannosamine (ManNAc) kinase (GNE), encoded by the GNE Gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid (Neu5Ac) (1, 2). Neu5Ac is the most abundant mammalian sialic acid and the precursor of most naturally existing sialic acids (3). Sialic acids are negatively charged, terminal residues on glycoconjugates, and assist in many cellular functions including cell-cell interactions, proliferation, and viral or bacterial infections (3, 4). The GNE enzyme consists of two enzymatic domains. The N-terminal domain carries out UDP-GlcNAc epimerase function, whereas the Cterminal domain is responsible for ManNAc kinase activity. In mammals, the end product of sialic acid synthesis, CMP-Neu5Ac, feedback-inhibits UDP-GlcNAc 2-epimerase activity of GNE by binding to its allosteric site (5). Two distinct human disorders, sialuria (OMIM 269921) and hereditary inclusion body myopathy (HIBM; OMIM 600737), are associated with predominantly missense mutations in GNE. Sialuria is an autosomal dominant disorder characterized by coarse facies, variable developmental delay, hepatomegaly and recurrent infections. To date, only seven sialuria patients are described worldwide. All patients have a heterozygous missense mutation affecting the allosteric site of GNE, leading to loss of feedback-inhibition of GNE-epimerase activity by CMP-Neu5Ac, resulting in excessive sialic acid production (6, 7). HIBM and its allelic Japanese disorder, distal myopathy with rimmed vacuoles, or DMRV (OMIM 605820), is an autosomal recessive neuromuscular disorder of adult onset, characterized by slowly progressive muscle weakness and atrophy. More than 500 HIBM\DMRV patients exist worldwide, harboring over 60 GNE mutations. HIBM\DMRV patients have recessive (predominantly missense) mutations in either enzymatic domain of GNE, leading to decreased enzyme activity and, presumably, decreased sialic acid production (2, 8, 9). Whether hyposialylation is the main cause of the neuromuscular symptoms in HIBM\DMRV patients remains unknown. In prokaryotes, GNE epimerase and kinase functions are carried out by two separate enzymes, and prokaryotic 2-epimerases have no allosteric feedback inhibition. In mammals, a bifunctional enzyme might have evolved by Gene fusion of the two independent enzymes responsible for epimerase/kinase activity. Similarities between mammalian GNE N-terminal regions with prokaryotic UDP-GlcNAc 2-epimerases and mammalian GNE C-terminal regions with members of the sugar kinase superfamily previously assisted in identifying characteristic motifs of the GNE epimerase and kinase enzymatic domains (10, 11). Bacterial 2-epimerases are allosterically regulated by its substrate UDP-GlcNAc. A structural basis for allosteric activation was demonstrated by a crystallographic analysis of the B. subtilis 2 2-epimerase in complex with the reaction intermediate UDP (12). In addition, the crystallographic structures of the E. coli GNE enzyme unbound and in complex with UDP-N-acetylglucosamine (pdb code 1f6d, 1vgv), and the V. cholera (pdb code 1dzc) and B. anthracis (pdb code 3beo) enzymes in complex with UDP-N-acetylglucosamine were solved. Similarity of the N-terminal domain of the H. sapiens GNE to V. cholera (27% homology), E. coli (20% homology) and B. anthracis (18% homology) 2-epimerases was used to model its three-dimensional structure. In previous studies, structural elements and important ATP, ADP, Mg2+ and substrate-binding amino acids were assiGNEd on the basis of these similarities (10, 11). The N-terminal epimerase domain of the human GNE enzyme contains two α/β domains (domains I and II) that form a cleft at the domain interface harboring the active site. Topology of both domains is similar to the Rossmann dinucleotide binding fold (13). Rossmann fold domains are conserved among mammalian and bacterial 2- epimerases. The human N-terminal GNE epimerase domain has a 7-stranded parallel β-sheet sandwiched between a total of 7 α-helices. The C-terminus of the GNE epimerase domain contains a 6-stranded β-sheet surrounded by a total of 7 α-helices (11). Other carriers of the Rossmann fold, including glycosyltransferases and the epimerase domains of 2-epimerases, have similar N-terminal and C-terminal domains (14, 15). The crystallographic structure of the ManNAc kinase domain of human GNE is solved at 2.84 A resolution (pdb code 3eo3) (16). Residues 409–431 of the mammalian GNE ManNAc kinase domain showed similarities with the phosphate 1 motif of the ATP-binding domain of eukaryotic hexokinases (10). Similar to hexokinases (17), mammalian GNE ManNAc kinase contains a 5-stranded β-sheet β3β2β1β4β5 with β2 being anti-parallel to four other parallel strands with a pair of parallel alpha-helices located on each side of the β-sheet (Domain I). Another 5-stranded β-sheet β8β7β6β9β1 with β7 being anti-parallel to four other parallel strands is surrounded by a pair of parallel α-helices on each side (Domain II). The structure of two similar domains involved in ATP binding is a common feature of the ASKHA (Acetate and Sugar Kinase/Hsp70/Actin) superfamily, described in detail for the bacterial poly(P)/ATP-glucomannokinase (18, 19). Recently, different human GNE mRNA splice variants and three predicted translated proteins, hGNE1, hGNE2 and hGNE3 were described (20, 21). Subsequently, two different mouse GNE mRNA splice variants were described, GNE1 and GNE2, together with their expression in selected tissues (22). In the current study we identified additional human isoforms hGNE4-8, and demonstrate expression of hGNE isoform transcripts in a wide variety of tissues. It is unknown which role these isoforms play in GNE regulation, or GNE-related disease pathology. Based on our previous modeling results of the hGNE1 isoform (11), we now analyze and compare the structural features, with respect to catalytic activity, ligand binding and allosteric regulation, of all eight human GNE isoforms.
-
hereditary inclusion body myopathy single patient response to intravenous dosing of GNE Gene lipoplex
Human Gene Therapy, 2011Co-Authors: Gregory Nemunaitis, William A. Gahl, Tal Yardeni, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Cynthia BedellAbstract:Abstract Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE Gene function through liposomal delivery of the wild-type GNE Gene. Results were verified in a single patient treated by intravenous infusion of GNE Gene lipoplex. A single patient (patient 001) with severe HIBM treated with a compassionate investigational new drug received seven doses of GNE Gene lipoplex via intravenous infusion at the following doses: 0.4, 0.4, 1.0, 4.0, 5.0, 6.0, and 7.0 mg of DNA. GNE transGene expression, downstream induction of sialic acid, safety, and muscle function were evaluated. Transient low-grade fever, myalgia, tachycardia, transaminase elevation, hyponatremia, and hypotension were observed after infusion of each dose of GNE Gene lipoplex. Quadric...
-
hereditary inclusion body myopathy single patient response to GNE Gene lipoplex therapy
Journal of Gene Medicine, 2010Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Cynthia BedellAbstract:Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle. Methods A single patient (subject #001) with severe HIBM treated by compassionate investigational new drug received four doses of GNE Gene Lipoplex via intramuscular injection. GNE transGene expression, downstream induction of sialic acid, safety and muscle function were evaluated. Results Significant durable improvement in locoregional skeletal muscle function was observed in the injected left extensor carpi radialis longus of #001 in correlation with GNE transGene upregulation and local induction of sialic acid. Other than transient low grade fever and pain at the injection site, no significant toxicity was observed. Conclusions Proof of principle for manufacturing of ‘clinical grade’ GNE Gene Lipoplex, clinical safety and activity are demonstrated with GNE Gene Lipoplex. Further assessment will involve intravenous administration and subsequent phase I trial involving additional but less severely afflicted HIBM patients. Copyright 2010 John Wiley & Sons, Ltd.
Cynthia Bedell - One of the best experts on this subject based on the ideXlab platform.
-
Hereditary inclusion body myopathy: single patient response to GNE Gene Lipoplex therapy
2020Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Chris Jay, Cynthia BedellAbstract:Abstract Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle
-
hereditary inclusion body myopathy single patient response to intravenous dosing of GNE Gene lipoplex
Human Gene Therapy, 2011Co-Authors: Gregory Nemunaitis, William A. Gahl, Tal Yardeni, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Cynthia BedellAbstract:Abstract Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE Gene function through liposomal delivery of the wild-type GNE Gene. Results were verified in a single patient treated by intravenous infusion of GNE Gene lipoplex. A single patient (patient 001) with severe HIBM treated with a compassionate investigational new drug received seven doses of GNE Gene lipoplex via intravenous infusion at the following doses: 0.4, 0.4, 1.0, 4.0, 5.0, 6.0, and 7.0 mg of DNA. GNE transGene expression, downstream induction of sialic acid, safety, and muscle function were evaluated. Transient low-grade fever, myalgia, tachycardia, transaminase elevation, hyponatremia, and hypotension were observed after infusion of each dose of GNE Gene lipoplex. Quadric...
-
hereditary inclusion body myopathy single patient response to GNE Gene lipoplex therapy
Journal of Gene Medicine, 2010Co-Authors: Gregory Nemunaitis, William A. Gahl, Marjan Huizing, Chris M Jay, Phillip B Maples, Alex W Tong, Anagha P Phadke, Beena O Pappen, Justin Poling, Cynthia BedellAbstract:Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) Gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE Gene function and the safety of delivery of wild type GNE Gene using a liposomal delivery vehicle. Methods A single patient (subject #001) with severe HIBM treated by compassionate investigational new drug received four doses of GNE Gene Lipoplex via intramuscular injection. GNE transGene expression, downstream induction of sialic acid, safety and muscle function were evaluated. Results Significant durable improvement in locoregional skeletal muscle function was observed in the injected left extensor carpi radialis longus of #001 in correlation with GNE transGene upregulation and local induction of sialic acid. Other than transient low grade fever and pain at the injection site, no significant toxicity was observed. Conclusions Proof of principle for manufacturing of ‘clinical grade’ GNE Gene Lipoplex, clinical safety and activity are demonstrated with GNE Gene Lipoplex. Further assessment will involve intravenous administration and subsequent phase I trial involving additional but less severely afflicted HIBM patients. Copyright 2010 John Wiley & Sons, Ltd.