α-and β-Acetylnaphthalenes condensed with dimethyl β,β-dimethyl glutarate in the presence of sodium hydride to give the corresponding half-esters,the E-isomers 2a and 2b being predominant. The structure and config...α-and β-Acetylnaphthalenes condensed with dimethyl β,β-dimethyl glutarate in the presence of sodium hydride to give the corresponding half-esters,the E-isomers 2a and 2b being predominant. The structure and configuration of the half-esters were characterized by chemical and spectroscopic means.展开更多
The enzyme-mediated highly enantioselective hydrolysis of aliphatic dicarboxylic acid diesters has been developed. The racemic diesters were easily prepared by the coupling of racemic alcohols with dicarboxylic anhydr...The enzyme-mediated highly enantioselective hydrolysis of aliphatic dicarboxylic acid diesters has been developed. The racemic diesters were easily prepared by the coupling of racemic alcohols with dicarboxylic anhydrides followed by esterification or with dicarboxylic acids. In the cases of bis(1-phenylethyl) glutarate and bis(1-phenylethyl) adipate, the diesters which contained the dl- and meso-form diastereomers, were enantioselectively hydrolyzed by lipase from Candida antarctica (Novozym 435) in buffer at 30°C to afford the almost optically pure (R)-1-phenylethanol. On the other hand, the following chemical hydrolysis of the remaining (S, S)-diesters and (S)-monoesters gave the (S)-alcohol. Finally, both enantiomers were stoichiometrically obtained in about 100% isolated yield based on the racemic diesters. The enzymatic reaction was also applicable for the preparation of several optically active alcohols. In some cases, both the reactivities and enantioselectivities were quite different from those in the case of the corresponding simple acetates.展开更多
By using the laser-monitoring technique,solid-liquid equilibrium data of glutaric acid in cyclohexanol,cyclohexanone,their five mixed solvents and acetic acid were measured within the temperature range from 292.15K to...By using the laser-monitoring technique,solid-liquid equilibrium data of glutaric acid in cyclohexanol,cyclohexanone,their five mixed solvents and acetic acid were measured within the temperature range from 292.15K to 354.60K by dynamic method.Empirical formula and λh equation were used to correlate the solubilities of glutaric acid in eight solvents.The maximal average relative deviations were 1.15% and 2.20% by using the em-pirical formula and λh equation to correlate the solubility data.The results showed that the empirical formula and λh model could correlate the solubility data of glutaric acid in eight solvents.In addition,the solubility data of glutaric acid in five mixtures(cyclohexanone+cyclohexanol)could be predicted with the NRTL equation utilizing the pa-rameters of the binary systems.The total average relative deviation was 3.60%.The results indicate that the NRTL equation could well predict the solubilities of glutaric acid in the mixed solvents of cyclohexanone and cyclohexanol.展开更多
The bis(tributyltin) ester of succinic acid was synthesized by the reaction of disodium salt of succinic acid with tributyltin chloride in a molar ratio of 1:2. The crystal structure was determined by X-ray single-cry...The bis(tributyltin) ester of succinic acid was synthesized by the reaction of disodium salt of succinic acid with tributyltin chloride in a molar ratio of 1:2. The crystal structure was determined by X-ray single-crystal diffraction. It belongs to orthorhombic with space group Pccn, a = 20.949(3), b = 17.470(3), c = 20.345(3) Angstrom, V = 7446(2) Angstrom(3), Z = 8, D-c = 1.242 g/cm(3), mu = 1.365 mm(-1), F(000) = 2864, R = 0.0544 and wR = 0.1417. The tin atom is of five-coordination in a trigonal bipyramidal structure by bridging two carboxylate groups in different directions and the resulting structure which contains straight twist large ring channels along the axes of a, b and c is a three-dimensional framework polymer containing two different tin atoms.展开更多
In previous study,glutaric acid (GA) induced apoptosis of primary striatal neuron in vitro.In order to investigate the neurotoxic effects of GA on neonatal rat corpus striatum and the possible mechanism,34 male pups w...In previous study,glutaric acid (GA) induced apoptosis of primary striatal neuron in vitro.In order to investigate the neurotoxic effects of GA on neonatal rat corpus striatum and the possible mechanism,34 male pups were randomly assigned to NS group,low dose GA (LGA,5 μmol GA/g body weight) group and high dose GA (HGA,10 μmol GA/g body weight) group.These pups were subcutaneously administered with three injections from postnatal day 3 to 22 at 7:30 am,15:00 pm and 22:30 pm and killed 12 h after the last injection.Microscopic pathology in corpus striatum was evalu-ated by HE staining.The apoptotic cells were identified by TUNEL staining.The transcript levels of caspase-3,8,9,Bax,Bcl-2 were detected by using real-time PCR and the protein levels of procaspase-3 and the active fraction were evaluated by Western blotting.In LGA and HGA groups,ventricle collapse,cortical atrophy by a macroscope and interstitial edema,vacuolations,widened perivascular space of bi-lateral striatum by a microscope were observed.TUNEL assay revealed that the apoptotic cells were in-creased in LGA and HGA groups.The transcript of caspase-3 was up-regulated to 2.5 fold,accompanied by the up-regulation of caspase-9,Bax and down-regulation of Bcl-2.The protein levels of procaspase-3 and the active fraction were up-regulated in LGA and HGA groups.The rat model for GA Ⅰ showed mitochondrial apoptotic pathway may be involved in the GA-induced striatal lesion.Further studies should be taken to investigate the underlying mechanisms.展开更多
Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electro...Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electron transfer flavoprotein （ETF）-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicityon the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicat-ing glutaric acidemia type Ⅱ in newborn screening analysis. Urinary organic acids were evaluated for the confrmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, ribofavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor developmentwas normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.展开更多
The fixation of leaves of Tanacetum vulgare L. in glutaraldehyde makes it possible to isolate chloroplasts without sacrificing an electron dense substance in the thylakoid lumen. The extraction of lipids from the chlo...The fixation of leaves of Tanacetum vulgare L. in glutaraldehyde makes it possible to isolate chloroplasts without sacrificing an electron dense substance in the thylakoid lumen. The extraction of lipids from the chloroplasts isolated from the leaves preliminarily fixed in glutaraldehyde has demonstrated that glycerolipids (galactolipids and phospholipids) are not manifested in TLC, whereas isoprenoid lipids (chlorophyll, carotenoids) are manifested. Presumably, isoprenoid lipids are not fixed with glutaraldehyde and are extracted from the thylakoid membrane. The ultrastructural control demonstrates that the electron dense substance from the thylakoid lumen is also extracted. It is possible that this substance is of isoprenoid nature.展开更多
Objectives:The purpose of this study was to evaluate the potential of three medium-chain dicarboxylic acids(MCDAs),specifically glutaric acid(GLA),succinic acid(SUA),and azelaic acid(AZA),as alternatives for sulphites...Objectives:The purpose of this study was to evaluate the potential of three medium-chain dicarboxylic acids(MCDAs),specifically glutaric acid(GLA),succinic acid(SUA),and azelaic acid(AZA),as alternatives for sulphites in extending the shelf life of fresh salmon.While previous studies have demonstrated the antibacterial effects of MCDAs against oral microbes,their application as food preservatives has yet to be explored.Materials and Methods:This study investigated the potential of MCDAs to suppress microbial growth and maintain the quality of salmon during refrigerated storage,using salmon slices and minced salmon as models.Results:The findings showed that these MCDAs,especially AZA,exhibited promising antibacterial effects despite their limited antioxidant activity.Coating salmon slices with these MCDAs significantly(P<0.05)extended their shelf life by preserving colour and pH while reducing total volatile basic nitrogen,microbial counts,and weight loss.Furthermore,these MCDAs also had promising effects on maintaining the freshness of minced salmon.Conclusions:The results suggest that AZA,SUA,and GLA could serve as promising alternatives to sulphites in extending the shelf life of salmon slices and minced salmon.展开更多
Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabol...Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabolic pathways and signaling cascades.1 In the realm of cancer immunotherapy,metabolic interventions in immune cells have demon-strated potential to enhance therapeutic efficacy.For instance,Minogue et al.2 found that glutaric acid from tryptophan metabolism can mod-ulate the antitumor T cell response by affecting pyruvate metabolism and𝛼-ketoglutarate-dependent dioxygenases.The adjustment of glutaric acid levels in CD8^(+)T cells has been shown to promote central memory T cell development,reduce exhaustion markers,and enhance cell death.展开更多
Being the most abundant non-macromolecular organic component of bone,the role of citrate(Cit)in hydroxyapatite(HA)crystallization is of high relevance.In this work we have investigated the influence of hydroxycitrate(...Being the most abundant non-macromolecular organic component of bone,the role of citrate(Cit)in hydroxyapatite(HA)crystallization is of high relevance.In this work we have investigated the influence of hydroxycitrate(CitOH)and glutarate(Glr)on HA crystallization in terms of particle growth,composition,and morphology in comparison to Cit.CitOH and Glr have been selected for this work because they share the same backbone structure of Cit but bear different functional groups in the central region.Our data has revealed that CitOH strongly inhibits HA crystallization more efficiently than Cit.CitOH-HA nanoparticles are composed of platy,elongated particles similar to those of Cit-HA but they are ca.twice smaller and have a lower crystal order.On the other hand,Glr does not inhibit HA crystallization as Cit,but leads to the formation of OCP platelets that convert with maturation time to HA nanorods with larger aspect ratio than Cit-HA.In comparison to Cit-HA samples,Glr-HA nanoparticles have bigger dimensions,and higher structural order.Overall,our data reveal that the central carboxyl group of Cit is involved in the selective binding with HA crystal surface and in regulating HA crystal growth.The results of this work highlight new possibilities to control the formation of HA for designing advanced bioactive materials and give new insights on the role of the structure of Cit in regulating the HA morphology.展开更多
Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a c...Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a child with recurrent rhabdomyolysis and undiagnosed glutaric acidemia type I(GA-I).And a literature review was performed.Results:A 4.5-year-old girl was admitted to our hospital due to recurrent rhabdomyolysis for 3 times within three years.At the third admission,she was diagnosed with GA-I by biochemical testing and mutation analysis.The girl was found to have a serine to leucine replacement mutation of the GCDH gene in exon 8 at position 764.Other three patients with rhabdomyolysis and GA-I were discovered by literature searching.Conclusion:This report highlights that patients with GA-I may have an increased risk of rhabdomyolysis.展开更多
Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisi...Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisis.Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine.A mouse model of Gcdh^(c.422_428del/c.422_428del)(Gcdh^(−/−))was generated in our laboratory using CRISPR/Cas9.Gcdh^(−/−)mice had significantly higher levels of glutaric acid(GA)in the plasma,liver,and brain than those in wild-type C57BL/6 mice.When given a high-protein diet(HPD)for two days,approximately 60%of Gcdh^(−/−)mice did not survive the metabolic stress.To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1,we prepared a recombinant adeno-associated virus(rAAV)carrying a human GCDH expression cassette and injected it into Gcdh^(−/−)neonates for a proof-of-concept(PoC)study.Our study demonstrated that delivering rAAV to the central nervous system(CNS),but not the peripheral system,significantly increased the survival rate under HPD exposure.Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate.Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels.Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.展开更多
文摘α-and β-Acetylnaphthalenes condensed with dimethyl β,β-dimethyl glutarate in the presence of sodium hydride to give the corresponding half-esters,the E-isomers 2a and 2b being predominant. The structure and configuration of the half-esters were characterized by chemical and spectroscopic means.
文摘The enzyme-mediated highly enantioselective hydrolysis of aliphatic dicarboxylic acid diesters has been developed. The racemic diesters were easily prepared by the coupling of racemic alcohols with dicarboxylic anhydrides followed by esterification or with dicarboxylic acids. In the cases of bis(1-phenylethyl) glutarate and bis(1-phenylethyl) adipate, the diesters which contained the dl- and meso-form diastereomers, were enantioselectively hydrolyzed by lipase from Candida antarctica (Novozym 435) in buffer at 30°C to afford the almost optically pure (R)-1-phenylethanol. On the other hand, the following chemical hydrolysis of the remaining (S, S)-diesters and (S)-monoesters gave the (S)-alcohol. Finally, both enantiomers were stoichiometrically obtained in about 100% isolated yield based on the racemic diesters. The enzymatic reaction was also applicable for the preparation of several optically active alcohols. In some cases, both the reactivities and enantioselectivities were quite different from those in the case of the corresponding simple acetates.
文摘By using the laser-monitoring technique,solid-liquid equilibrium data of glutaric acid in cyclohexanol,cyclohexanone,their five mixed solvents and acetic acid were measured within the temperature range from 292.15K to 354.60K by dynamic method.Empirical formula and λh equation were used to correlate the solubilities of glutaric acid in eight solvents.The maximal average relative deviations were 1.15% and 2.20% by using the em-pirical formula and λh equation to correlate the solubility data.The results showed that the empirical formula and λh model could correlate the solubility data of glutaric acid in eight solvents.In addition,the solubility data of glutaric acid in five mixtures(cyclohexanone+cyclohexanol)could be predicted with the NRTL equation utilizing the pa-rameters of the binary systems.The total average relative deviation was 3.60%.The results indicate that the NRTL equation could well predict the solubilities of glutaric acid in the mixed solvents of cyclohexanone and cyclohexanol.
基金the National Natural Science Foundation of China (No. 20271025)the Natural Science Foundation of Shandong province (No. Z2001B02)the State Key Laboratory of Crystal Materials,Shandong University
文摘The bis(tributyltin) ester of succinic acid was synthesized by the reaction of disodium salt of succinic acid with tributyltin chloride in a molar ratio of 1:2. The crystal structure was determined by X-ray single-crystal diffraction. It belongs to orthorhombic with space group Pccn, a = 20.949(3), b = 17.470(3), c = 20.345(3) Angstrom, V = 7446(2) Angstrom(3), Z = 8, D-c = 1.242 g/cm(3), mu = 1.365 mm(-1), F(000) = 2864, R = 0.0544 and wR = 0.1417. The tin atom is of five-coordination in a trigonal bipyramidal structure by bridging two carboxylate groups in different directions and the resulting structure which contains straight twist large ring channels along the axes of a, b and c is a three-dimensional framework polymer containing two different tin atoms.
基金supported grants from the National Natural Science Foundation of China (No. 81070699)the 11th Five-Year Plan of National Science and Technology Supporting Project (No. 2006BAI05A07)+1 种基金Sector Fund of Ministry of Health of China (No. 201002006)Key Construction Project of Clinical Subjects from the Ministry of Health of China(No. 2011-2014)
文摘In previous study,glutaric acid (GA) induced apoptosis of primary striatal neuron in vitro.In order to investigate the neurotoxic effects of GA on neonatal rat corpus striatum and the possible mechanism,34 male pups were randomly assigned to NS group,low dose GA (LGA,5 μmol GA/g body weight) group and high dose GA (HGA,10 μmol GA/g body weight) group.These pups were subcutaneously administered with three injections from postnatal day 3 to 22 at 7:30 am,15:00 pm and 22:30 pm and killed 12 h after the last injection.Microscopic pathology in corpus striatum was evalu-ated by HE staining.The apoptotic cells were identified by TUNEL staining.The transcript levels of caspase-3,8,9,Bax,Bcl-2 were detected by using real-time PCR and the protein levels of procaspase-3 and the active fraction were evaluated by Western blotting.In LGA and HGA groups,ventricle collapse,cortical atrophy by a macroscope and interstitial edema,vacuolations,widened perivascular space of bi-lateral striatum by a microscope were observed.TUNEL assay revealed that the apoptotic cells were in-creased in LGA and HGA groups.The transcript of caspase-3 was up-regulated to 2.5 fold,accompanied by the up-regulation of caspase-9,Bax and down-regulation of Bcl-2.The protein levels of procaspase-3 and the active fraction were up-regulated in LGA and HGA groups.The rat model for GA Ⅰ showed mitochondrial apoptotic pathway may be involved in the GA-induced striatal lesion.Further studies should be taken to investigate the underlying mechanisms.
文摘Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electron transfer flavoprotein （ETF）-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicityon the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicat-ing glutaric acidemia type Ⅱ in newborn screening analysis. Urinary organic acids were evaluated for the confrmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, ribofavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor developmentwas normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.
文摘The fixation of leaves of Tanacetum vulgare L. in glutaraldehyde makes it possible to isolate chloroplasts without sacrificing an electron dense substance in the thylakoid lumen. The extraction of lipids from the chloroplasts isolated from the leaves preliminarily fixed in glutaraldehyde has demonstrated that glycerolipids (galactolipids and phospholipids) are not manifested in TLC, whereas isoprenoid lipids (chlorophyll, carotenoids) are manifested. Presumably, isoprenoid lipids are not fixed with glutaraldehyde and are extracted from the thylakoid membrane. The ultrastructural control demonstrates that the electron dense substance from the thylakoid lumen is also extracted. It is possible that this substance is of isoprenoid nature.
基金funded by the Researchers Supporting Project(No.RSP2025R502)King Saud University,Riyadh,Saudi Arabia.
文摘Objectives:The purpose of this study was to evaluate the potential of three medium-chain dicarboxylic acids(MCDAs),specifically glutaric acid(GLA),succinic acid(SUA),and azelaic acid(AZA),as alternatives for sulphites in extending the shelf life of fresh salmon.While previous studies have demonstrated the antibacterial effects of MCDAs against oral microbes,their application as food preservatives has yet to be explored.Materials and Methods:This study investigated the potential of MCDAs to suppress microbial growth and maintain the quality of salmon during refrigerated storage,using salmon slices and minced salmon as models.Results:The findings showed that these MCDAs,especially AZA,exhibited promising antibacterial effects despite their limited antioxidant activity.Coating salmon slices with these MCDAs significantly(P<0.05)extended their shelf life by preserving colour and pH while reducing total volatile basic nitrogen,microbial counts,and weight loss.Furthermore,these MCDAs also had promising effects on maintaining the freshness of minced salmon.Conclusions:The results suggest that AZA,SUA,and GLA could serve as promising alternatives to sulphites in extending the shelf life of salmon slices and minced salmon.
基金supported by Zhejiang Provincial Natural Science Foundation of China(grant number:LGD22H090003).
文摘Metabolic reprogramming is a critical process in the activation and function of immune cells,wherein changes in metabolites and enzymes regulate the phenotype and function of immune cells by modulating en-ergy metabolic pathways and signaling cascades.1 In the realm of cancer immunotherapy,metabolic interventions in immune cells have demon-strated potential to enhance therapeutic efficacy.For instance,Minogue et al.2 found that glutaric acid from tryptophan metabolism can mod-ulate the antitumor T cell response by affecting pyruvate metabolism and𝛼-ketoglutarate-dependent dioxygenases.The adjustment of glutaric acid levels in CD8^(+)T cells has been shown to promote central memory T cell development,reduce exhaustion markers,and enhance cell death.
基金supported by the CERIC-ERIC Consortium for financial support and for giving access to ELETTRA SAXS beamline(proposal CERIC-ERIC-20175403).
文摘Being the most abundant non-macromolecular organic component of bone,the role of citrate(Cit)in hydroxyapatite(HA)crystallization is of high relevance.In this work we have investigated the influence of hydroxycitrate(CitOH)and glutarate(Glr)on HA crystallization in terms of particle growth,composition,and morphology in comparison to Cit.CitOH and Glr have been selected for this work because they share the same backbone structure of Cit but bear different functional groups in the central region.Our data has revealed that CitOH strongly inhibits HA crystallization more efficiently than Cit.CitOH-HA nanoparticles are composed of platy,elongated particles similar to those of Cit-HA but they are ca.twice smaller and have a lower crystal order.On the other hand,Glr does not inhibit HA crystallization as Cit,but leads to the formation of OCP platelets that convert with maturation time to HA nanorods with larger aspect ratio than Cit-HA.In comparison to Cit-HA samples,Glr-HA nanoparticles have bigger dimensions,and higher structural order.Overall,our data reveal that the central carboxyl group of Cit is involved in the selective binding with HA crystal surface and in regulating HA crystal growth.The results of this work highlight new possibilities to control the formation of HA for designing advanced bioactive materials and give new insights on the role of the structure of Cit in regulating the HA morphology.
基金This study was supported by the National Natural Science Foundation of China(81170664).
文摘Background:Glutaric acidemia type I(GA-I)is a rare metabolic disorder caused by mutation of the glutaryl-CoA dehydrogenase(GCDH)gene.The occurrence of rhabdomyolysis with GA-I is extremely rare.Methods:We reported a child with recurrent rhabdomyolysis and undiagnosed glutaric acidemia type I(GA-I).And a literature review was performed.Results:A 4.5-year-old girl was admitted to our hospital due to recurrent rhabdomyolysis for 3 times within three years.At the third admission,she was diagnosed with GA-I by biochemical testing and mutation analysis.The girl was found to have a serine to leucine replacement mutation of the GCDH gene in exon 8 at position 764.Other three patients with rhabdomyolysis and GA-I were discovered by literature searching.Conclusion:This report highlights that patients with GA-I may have an increased risk of rhabdomyolysis.
基金the National Key Research and Development Program(2019YFA0110800 and 2020YFA0707900 to W.L.,and 2018YFA0108400 and 2019YFA0903800 to Q.Z.)Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030403 to W.L.)+1 种基金National Natural Science Foundation of China(31621004 to Q.Z.and W.L.)CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.).
文摘Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisis.Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine.A mouse model of Gcdh^(c.422_428del/c.422_428del)(Gcdh^(−/−))was generated in our laboratory using CRISPR/Cas9.Gcdh^(−/−)mice had significantly higher levels of glutaric acid(GA)in the plasma,liver,and brain than those in wild-type C57BL/6 mice.When given a high-protein diet(HPD)for two days,approximately 60%of Gcdh^(−/−)mice did not survive the metabolic stress.To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1,we prepared a recombinant adeno-associated virus(rAAV)carrying a human GCDH expression cassette and injected it into Gcdh^(−/−)neonates for a proof-of-concept(PoC)study.Our study demonstrated that delivering rAAV to the central nervous system(CNS),but not the peripheral system,significantly increased the survival rate under HPD exposure.Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate.Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels.Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.
