Emerging Therapies For the Treatment of Mucopolysaccharidosis Type III
Mucopolysaccharidosis type III (Sanfiippo) is a group of four autosomal recessive lysosomal storage diseases resulting from a failure to degrade glycosaminoglycans. The four biochemical subtypes of Mucopolysaccharidosis type III (MPSIII A–D) are caused by the defiiency of one of the four enzymes required for heparansulfate degradation. Unlike the other MPSs that present with extensive somatic involvement, patients with MPS III typically present with neurological signs and symptoms.Although enzyme replacement therapy is effective to some extent in management ofsomatic pathology of many lysosomal storage diseases, it seems to be of low effiacy in treatment of neurological symptoms because of the blood-brain barrier. In spiteof some treatments for other MPS disorders, which mostly alleviate non-neurologicalsymptoms, no therapy is currently available for MPS III. Treatment of the neurologicalsymptoms of MPS III remains challanging due to blood-brain barrier that restricts thecrossing of therapeutics to the central nervous system (CNS). Intraventricular enzymereplacement, gene therapy, hematopoietic stem cell transplantation, substrate reduction therapy, pharmacological chaperone therapy and stopcodon readthrough therapyare new experimental therapeutic approaches that circumvent this barrier. This reviewdiscusses some of the emerging treatment strategies to treat MPS III, and evaluates theoutcomes of these treatments in animal models and human patients as well as thoseof in vitro.
Mucopolysaccharidosis type III (MPS III) or Sanfilippo syndrome belongs to the group of approximately 50 inherited monogenic lysosomal storagedisorders (LSDs) (1). Currently, there are four autosomal recessive subtypes of MPS III (A, B, C andD) recognized in humans (2); each is caused by thedeficiency of one of four enzyme activities responsible for the degradation of a common glycosaminoglycan (GAG), heparan sulphate: heparan-N-sulfatase (MPS IIIA), N-acetyl-α-glucosaminidase(MPS IIIB), acetyl CoA: α-glucosaminide N-acetyltransferase (MPS IIIC), or N-acetylglucosamine6-sulphatase (MPS IIID) (3). They result from mutations in SGSH (coding for heparan-N-sulfatase),NAGLU (coding for α-N-acetylglucosaminidase),HGSNAT (coding for acetyl-CoA:α-glucosaminideacetyltransferase), and GNS (coding for N-acetylglucosamine-6-sulfatase), respectively (4). MPS IIIA and IIIB are the most prevalent subtypeswith incidences ranging between 0.2 and 1.89 per100,000 live births while the incidence for MPSIIIC is reported to be 0.07-0.21 per 100,000 livebirths. MPS IIID is extremely rare with an incidence of 0.1 per 100,000 live births (3). Characterized by earlier onset, more rapid symptom progression, the clinical course in MPS IIIA is more severethan other subtypes (5).Biochemically, MPS III is characterized by abnormal storage of heparan sulfate (HS) in lysosomesof all tissues and organs and its excretion in urine(6). Heparan sulfate is a negatively charged glycosaminoglycan (GAG) covalently bound to a numberof proteins at the cell surface and in the extracellular matrix and catabolized within lysosome (7). Itsdegradation starts with endolytic cleavage by endoglycosidase and proceeds in a stepwise fashionby three exoglycosidases, at least three sulfatasesand an acetyltransferase. The deficiency in threeof them, α-L-iduronidase, iduronate sulfatase andβ-glucuronidase, results in the lysosomal storagedisorders MPS I, II and VII, respectively. The other four enzymes (SGSH, NAGLU, HGSNAT, GNS)are specific for HS and a deficiency leads to MPSIII (for detailed review see (8). The abnormal storage of GAG affects different signaling pahways byinteracting with molecules such as growth factors(9,10). The injury in neurons activates microgliaand the constant release of inflammatory mediators. The accumulation in storage vesicles has beendetected also in microglial cells in a mouse modelof MPS IIIC (11). These cells play an importantrole in the brain defence and may release different toxic products. Thus, affection of the glial cellstogether with the inflammation may contribute toneuronal degeneration in MPS III (12). Lysosomalstorage of heparan sulfate causes mitochondrialdefects, altered autophagy, and neuronal death inthe mouse model of mucopolysaccharidosis III typeC (13). In addition to HS storage, the secondaryaccumulation of the gangliosides GM2 and GM3 is observed in lysosomes and other organelles suchas mitochondria and Golgi bodies (14,15), eitherby direct GAG-mediated inhibition of lysosomalenzymes responsible for ganglioside degradation(16) or by deregulated trafficking or synthesis ofgangliosides (15).
MOLECULAR GENETIC OF MPS III
MPS III is an autosomal recessive disease withfour substypes according to the four enzymaticdeficiencies caused by multiple mutations. MPSIIIA is caused by mutations in the SGSH generesulting in sulfamidase or heparan N-sulfatasedeficiency. A total of 137 mutations have beendescribed to date (Human Genome Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php);most of these are missense mutations (77.3%);also, nonsense mutations, insertions and deletionshave been reported. The mutation p.R245H is mostcommon in Germany and the Netherlands, p.R74Cin Poland, p.S66W in Sardinia and c.1091delC inSpain (17). The mutations in NAGLU gene encoding α-N-acetylglucosaminidase are responsible forMPS IIIB, where missense mutations outnumbernonsense and deletion mutations (17). Mappingthe positions of known missense mutations ontothe NAGLU protein revealed that they are scattered throughout the protein and only four missense mutations occur at the active site (18). Thesemissense mutations reduce the stability of NAGLU thus resulting in less functional enzyme (19).MPS IIIC is caused by mutations in the HGSNATgene localized in a pericentromeric region in chromosome 8p11.21 (20). Although the spectrum ofmutations in MPS IIIC patients shows substantialheterogeneity, some of the missense mutationshave a high frequency within the patient population such as p.R344C and p.S518F accountingfor 22.0% and 29.3%, respectively, of the allelesin Dutch population (21). MPS IIID is caused bymutations in the GNS gene on chromosome 12q14,which encodes N-acetylglucosamine-6-sulfatase MPS III is an autosomal recessive disease withfour substypes according to the four enzymaticdeficiencies caused by multiple mutations. MPSIIIA is caused by mutations in the SGSH generesulting in sulfamidase or heparan N-sulfatasedeficiency. A total of 137 mutations have beendescribed to date (Human Genome Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php);most of these are missense mutations (77.3%);also, nonsense mutations, insertions and deletionshave been reported. The mutation p.R245H is mostcommon in Germany and the Netherlands, p.R74Cin Poland, p.S66W in Sardinia and c.1091delC inSpain (17). The mutations in NAGLU gene encoding α-N-acetylglucosaminidase are responsible forMPS IIIB, where missense mutations outnumbernonsense and deletion mutations (17). Mappingthe positions of known missense mutations ontothe NAGLU protein revealed that they are scattered throughout the protein and only four missense mutations occur at the active site (18). Thesemissense mutations reduce the stability of NAGLU thus resulting in less functional enzyme (19).MPS IIIC is caused by mutations in the HGSNATgene localized in a pericentromeric region in chromosome 8p11.21 (20). Although the spectrum ofmutations in MPS IIIC patients shows substantialheterogeneity, some of the missense mutationshave a high frequency within the patient population such as p.R344C and p.S518F accountingfor 22.0% and 29.3%, respectively, of the allelesin Dutch population (21). MPS IIID is caused bymutations in the GNS gene on chromosome 12q14,which encodes N-acetylglucosamine-6-sulfatase.
Generally, MPS III manifests at 2 to 3 years of agewith developmental delays, initially appearing aslanguage deficits followed by behavioral problems,sleep difficulties, progressive cognitive and motorfunction regression (26). Somatic symptoms in humans can include coarse facial features with broadeyebrows, dark eyelashes, dry and rough hair, andskeletal pathology that affects growth and causesdegenerative joint disease, hepatosplenomegaly,macrocephaly, and hearing loss. Unlike other MPStypes, major clinical characteristic of MPS III ishowever degeneration of the central nervous system (CNS), resulting in mental retardation andhyperactivity (7). Although four MPS III subtypesare assumed to be clinically indistinguishable, theclinical course in type A is more severe with earlieronset, rapid progression and shorter survival (27).It was reported that MPS IIIA patients lost theirabilities to speak and walk earlier than the MPCIIIC patients. Median age at death is 15.22 ± 4.22years in MPS IIIA patients, 18.91 ± 7. 33 years inMPS IIIB patients and 23.43 ± 9.47 years in MPSIIIC patients according to the data obtained fromthe Society of Mucopolysaccharide Diseases (UK)(2). Pneumonia was reported as the leading causeof death for both MPS IIIA and IIIB, accountingfor more than 50% and 38%, respectively. Othercauses of death include cardiorespiratory failure,gastrointestinal complications and central nervous systemcomplications according to the dataobtained from the Society of MucopolysaccharideDiseases (UK) (2).
PATHOLOGY OF MPS III
The storage of heparan sulfate, secondary accumulation of GM2 and GM3 gangliosides and neuroinflammation events were shown in the brainsof MPS IIIA and IIIB mouse brains (12,28-31). Ina study to compare neuropathology in mouse models of MPS I, IIIA and IIIB, quantitative immunohistochemistry showed significantly increasedlysosomal compartment, GM2 ganglioside storage,neuroinflammation, decreased and mislocalisedsynaptic vesicle associated membrane protein,(VAMP2), and decreased post-synaptic proteinHomer-1 in layers II/III-VI of the primary motor,somatosensory and parietal cortex. In addition,increased HS, abnormally N-, 6-O and 2-O sulphated compared to WT, neuroinflammation, dystrophic axons, axonal storage, and extensive lipidwere observed (31). Substantial >30% reduction ofneuronal density in somatosensory cortex and substantial loss of purkinje cells in cerebellar cortexhave been demonstrated in homozygous HgsnatGeo MPS IIIC mice. Neurons of MPS IIIA, IIIBand IIIC mouse models contain SCMAS (subunitC of mitochondrial ATP synthase) aggregates, increased levels of ubiquitin and protein markers ofAlzheimer disease and other tauopathies such aslysozyme, hyperphosphorylated tau (Ptau), Ptaukinase, Gsk3β, and β amyloid suggestive of mitophagy and a general impairment of proteolysis(32,33).Post-mortem studies carried out on brain tissuefrom children with MPS IIIB revealed the accumulation of phosphorylated α-synuclein in spheroidalstructures in the temporal cerebral cortex, hippocampus, periaqueductal gray, substantia nigraand anteroventral nucleus of the thalamus (34). Inaddition to post-mortem studies carried on braintissues of patients and animal models, inducedpluripotent stem cells (iPSCs) derived from fibroblasts of patients provide access to affected neurons and offer a good opportunity to model humanneurodegenerative diseases. In a study to model MPS IIIB disease, patient iPSC and neuronalprogeny of these cells expressed MPS IIIB diseasethat not apparent in parantel fibroblasts includingstorage vesicles and severe disorganization of Golgi ribbons associated with modified expression ofthe Golgi matrix protein GM130 (35).
Currently there is no treatment for MPS III. Thecognitive and neurological problems are majorclinical characteristics of MPS III. Managementconsists of supportive care and treatment of specific complications. The neurological nature of thedisease makes treatment problematic due to theblood-brain barrier (BBB). There are numerouspre-clinical research projects examining varioustreatment strategies for MPS III. These recenttreatment strategies are summarized and discussed in this review.
Enzyme replacement therapy
Although enzyme replacement therapy (ERT) hasbeen shown to have a positive effect on systemicsymptoms of the disease in many MPS types (MPSI, II, IVA, and VI), the main problem with this therapy is delivery of the enzyme to central nervoussystem (CNS) due to blood brain barrier (BBB)(36). This limits the utility of enzyme ERT for thetreatment of neurological symptoms of MPSs. Recombinant caprine GNS enzyme was shown to correct liver pathology of a goat affected by MPS IIID,but it did not result in improvement in the encephalon due to fractional delievery of the enzyme tothe CNS (37). A possible strategy to circumventBBB is direct delivery of the enzyme in the cerebrospinal fluid (CSF) through either intracerebroventricular (ICV) injection into the lateral ventricle, or intrathecal injection into the lumbar spineor subarachnoid space at the cisterna manga (38).A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIAappeared generally safe and well tolerated, and resulted in consistent declines in cerebrospinal fluid(CSF) heparan sulfate (39). However, immune responses of patients to recombinant enzyme, highcost of the enzyme, requirement of regular enzymeinfusions in a hospital setting are other limitationsof ERT. A recent ERT clinical trial for MPS II hasshown the inconveniences about the implantationof such devices for periodic delivery of proteins tothe CNS (40).
Hematopoietic stem cell transplantation
Although hematopoietic stem cell transplantation(HSCT) was shown to be effective for MPS I-Hurler with improvement of clinical parameters andincreased life expectancy, it is not considered aneffective method for MPS III because of concernsregarding neurological aspects (41). Patients canbenefit HSCT if transplation is performed beforesomatic and intellectual development are severelyaffected (42). In this approach, HSCs repopulatethe recipient and secrete enzyme which cross-corrects cells in the periphery but cannot cross BBB.However, monocytes traffic from the blood intothe brain where they differentiate into microglial cells and mediate crosscorrection in the central nervous system (43). Allogeneic bone marrowtransplantation was performed for children withMPS IIIA (44) and IIIB (45) but their neurologicalconditions were not prevented. Although lentiviral (LV)-transduced wild-type cells improved neuropathology in MPS IIIA mice, lentiviral-transduced autologous MPS IIIA cells were unable tomediate neurological correction, possibly due toinsufficient enzyme production in brain (46). However, when transplanted into MPS IIIA mice, autologous HSCs expressing codon optimized SGSunder myeloid-specific promoters CD11b (CD11bcoSGSH vector) normalized MPS IIIA behavior,brain HS, GM2 ganglioside, and neuroinflammation to WT levels (47).
Gene therapy attempts to introduce the coding sequence of the protein (cDNA) into the cells of patients via the use of a viral vector. Manipulatedcells synthesize and secrete the enzyme of interestinto circulation, which is taken up by unalteredcells (7). Intracerebral, intrathecal (IT), or intracerebroventricular (ICV) injection of adeno-associated viruses (AAV) and lentiviral vectors successfully treated brain disease in MPS I, IIIA, IIIB,and VII animal models, inducing stable expressionof the vector and enzyme (48-53). Co-delivery ofSGSH or sulfamidase and SUMF1 via intraventricular injection of a recombinant AAV vectorresulted in increased sulfamidase activity in themouse brain, decrease in lysosomal storage andmicroglial activation and enhancement of motorand cognitive capabilities (48). A clinical trial evaluating intracerebral injection of an AAVrh10hMPS3A vector, an AVV vector encoding both SGSand the sulfatase modifying factor SUMF-1, incombination with immunosuppressive treatmentshowed moderate improvements in behavior, attention, and sleep (54). A similar gene therapy approach based on AAV-mediated NAGLU deliveryfor treating MPS IIIB mice resulted in a significantly prolonged lifespan and improved behavioralperformences compared to untreated MPS III mice(55). An AAV-based vector designed to target liver,which included sulfamidase engineered to be fusedto both the signal peptide of iduronate-2-sulfataseprotein and the BBB binding domain of apolipoprotein B resulted in reduction of neuropathology andrestoration of behavior in MPS IIIA mice, whereBBB binding domain permitted rescue of sulfamidase in the brain (56).Finally, a recent study showed that treatment ofa new MPS IIID mouse model with adeno-associated viral (AAV) vectors of serotype 9 delivered tothe cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionalityin the CNS and somatic tissues, resolved neuroinflammation, restored normal behaviour andextended lifespan of treated mice (57).
Substrate reduction therapy
Substrate reduction therapy (SRT) uses small molecules such as the isoflavone compound genisteinto decrease the synthesis of HS and hence to improve the balance between the synthesis anddegradation. Genistein is thought to impair GAGsymthesis by inhibiting tyrosine autophosphorylation of the epidermal growth factor receptor(EGFR), which reduces the expression of factorsresponsible for GAG synthesis (58,59). Genisteintreatment of cultured fibroblasts derived fromMPS I, MPS II, MPS III, and MPS VII patients wasshown to reduce GAG storage (58,60). GAG storagewas also reduced in MPS II and MPS III mice after oral genistein administration (61,62). Although8 weeks of daily genistein treatment reduced thetotal GAG content and the size of the lysosomalcompartment significantly in the livers of maleMPS IIIB mice, no change in total GAGs, lysosomal size or reactive astrogliosis in the brain cortexwere observed despite evidence that genistein cancross BBB (61). However, genistein treatment overa 9 month period significantly reduced lysosomalstorage, HS and neuroinflammation in the cerebral cortex and hippocampus in MPS IIIB mice,resulting in correction of the behavioural defectsobserved (63).In clinical trials that administered genistein toMPS III patients orally in a soy isoflavone extract,mixed results were obtained. Patients treated with5-10 mg/kg genistein for 12 months did not exhibitcognitive improvements (64,65); however, longer36-month treatment improved cognitive function(66). In addition, in MPS IIIA mice treated withrhodamine B ((9-(2-carboxyphenyl)-6-diethylamino-3-xanthenylidene)-diethylammonium chloride),GAG levels decreased both in somatic tissues andbrain with an improvement in animal behavior(67,68). However, rhodamine was never tested at aclinical trial since its adverse effect on humans hadalready been reported (69). N-butyldeoxynojirimycin (miglustat), an inhibitor of ceramide glucosyltransferase and therefore of ganglioside synthesis,approved for the treatment for Niemann-Pick typeC, has been shown to improve learning and restorethe innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity(70).
Stopcodon readthrough therapy
Premature termination codons (PTCs), also calledas nonsense or stop mutations, represent a minorportion of the all mutations responsible for MPSIII and cause neglible enzyme activity. In MPS III,they comprise about 10% in Type A, somewherebetween 20-30% in Type B, somewhere between10-20% in Type C and 8% in Type D, of all mutations. Since translation termination is not 100%efficient, a low level of translational read-throughof termination codons occur, which results in theincorporation of an amino acid in place of a PTC(71). Some aminoglycosides combine with A siteoligonucleotides of ribosome, thus reducing the fidelity of normal translation and promote stopcodon readthrough according to the results obtainedfrom crystallographic and modelling studies (72).Gentamicin, amikacin, paromomycin, G418 (geneticin), lividomycin, tobramycin, and streptomycinwere shown to suppress permature terminationcodons (PTCs) in mammalian cells and result intranslation of full-lenght protein protein that isfunctional when the PTC is not at a crucial position (73). Glutamine (Gln) and tryptophan (Trp)are the most common amino acid insertions; UAGor UAA miscode Gln, whereas UGA miscodes Trp(74). In addition the identitiy of PTC itself andthe sequence context around the PTC are crucialfactors determining the efficiency of readthrough,with the highest readthrough efficiency observedfor UGA codon, followed by UAG, and to a lesserextent, UAA (75).The first demonstration that aminoglycosidescould suppress PTC in a defective gene was carried out in cystic fibrosis (76,77). Since then PTC readthrough has been documented in vitro and in celland animal models of different disorders includingmuscular dystrophy (78), methylmalonic-aciduria(79), Stüve-Wiedemann syndrome (80), propionic acidemia (81), phenylketonuria (82), xeroderma pigmentosum (83), mucopolysaccharidosis VI(84), Rett syndrome (85), mucopolysaccharidosistype I-Hurler (86). The toxicity of aminoglycosidesin mammals has greatly restricted their potential for successful readthrough therapy and led tosearching for better aminoglycoside derivativeswith reduced toxicity and enhanced activity (87).A luciferase-based high-throughput screening byPTC Therapeutics identified a non-aminoglycosidereadthrough drug, PTC124(88). PTC124 has notadverse effects in contrast to aminoglycosides andhas a great potential for treating genetic diseasescaused by PTCs. Clinical trials of this drug are underway for patients with cystic fibrosis (phase III),Duchenne muscular dystrophy (DMD) (phase II),and other diseases (89).The first readthrough study on MPS III disease wascarried out on NAGLU and HGSNAT mutations(90), where fibroblasts bearing the p.W168X (NAGLU), p.Q566X (NAGLU), and p.R384X (HGSNAT)mutations were treated with gentamicin, geneticinand five non-aminoglycoside (PTC124, RTC13,RTC14, BZ6 and BZ16) readthrough compounds.Neither of the tested drugs resulted in any recovery at the enzyme acitivity levels for all three mutations. However, a two-fold increase (75-90% ofWT) in mRNA recovery for MPS IIIB fibroblaststreated with G418 and about 1.5 fold increase (45-50% of WT levels) in mRNA recovery for MPS IIICfibroblasts treated with RTC14 and PTC124 wasobserved. Although no increase in enzyme activity was observed, G418 treatment resulted in highrecovery of NAGLU mRNA for p.W168X/p.Q566Xgenotype, suggesting that the readthrough productwas not active (90).
Pharmacological chaperone therapy
In the last last decade, protein misfolding due tomissense mutations was demonstrated to be causative for increasing number of inborn errors ofmetabolism. Missense mutations tend to be morecommon although insertions, large deletions, premature stop codons and splicing mutations havebeen identified in many LSDs (91). They occurmostly outside the enzyme’s active site and havenegative effects on protein folding efficiency, thermodynamic stability, and lysosomal trafficking, although the mutant enzymes retain their catalyticproperties (92). Misfolding of proteins due to mutations results in aggregations and hence a widerange of deleterious effects or a lack of catalyticactivity. Misfolded proteins are recognized and retained in endoplasmic reticulum (ER) by a proteinquality control system that relies on unfolded protein response (UPR) to recover from ER stres (93)and eventually routed for endoplasmic reticulumassociated degradation (ERAD). Even in wild-type(WT) proteins, a significant fraction is misfolded oraggregated and degraded by the UPS within minutes of their synthesis despite chaperones (94). Ifprolonged ER stress continues and misfolded protein cannot be refolded or degraded, UPR causesthe cells to undergo apoptosis (95). Another defense mechanism evolved by cells to cope with protein misfolding is chaperone machinery for properprotein folding and their trafficking to organelles.Both these machineries closely coordinate to maintain the proteome in soluble and functional state indifferent cellular compartments. Proteostasis regulators, chemical chaperones and pharmacologicalchaperones are small molecular weight compoundsto rehabilitate misfolded proteins and thereforerestore protein homeostasis in misfolding diseases (92). Chemical chaperones are low molecularweight and membrane-permeable molecules ableto nonselectively stabilize mutant proteins, facilitate their folding, and rescue their physiologicalfunctionality. Various substances such as glycerol, polyols, dimethylsulfoxide (DMSO) or sodium4-phenylbutyrate (4-PBA) represent chemicalchaperones which also improve the folding of mutant proteins (96-100). From a functional point ofview, chemical chaperones can be subgrouped intoosmolytes and hydrophobic compounds. Osmolytesare uncharged or zwitterionic molecules that canchange solvent properties, hence forcing thermodynamically unstable proteins to fold and stabilize(93). Polyols (glycerol, trehalose, sucrose), trimethylamine N-oxide (TMAO), taurine, β-alanin, glycin may act as osmolytes. Hydrophobic chaperonesact as protectors by interacting with the exposedhydrophobic segments of unfolded proteins, thuspreventing protein aggregation. 4-PBA is one ofthe most well-known chemical chaperones and ithas been shown to reverse misfolding of variousmutant proteins (101,102).Pharmacological chaperones are small moleculesthat bind to proteins specifically via electrostaticforces, van der Waals forces, or hydrogen bonding,thus inducing thermodynamic stabilization andcontributing to recover protein function. They areprotein specific, and some are mutation specific(103). Pharmacological chaperones are competetive inhibitors of enzymes where weaker inhibitorsshows minimum enhancement of mutant enzymeactivity while more potent inhibitors act as moreeffective chaperones (104). Enzyme cofactors mayact as another type pharmacological chaperones.An increase in the amount of the natural cofactormight stabilize misfolded proteins. A well knownexample is tetrahydrobiopterin (BH4), the natural cofactor of phenylalanine hydroxylase, thedefective enzyme in phenylketonuria (PKU). BH4treatment is effective in almost half of PKU patients (92). Many chaperone approaches have beenassayed at different levels for LSDs such as Fabry (105), GM1-gangliosidosis (106), Pompe (107),Gaucher (108), Krabbe (109), and Niemann-Picktype C (110) diseases. Iminosugars and azasugars represent a specialclass of small molecules for pharmacological chaperone therapy with high solubility and low toxicity(111,112). 1-deoxy-galactonojirimycin (DGJ) is animinosugar used as a pharmacological chaperonefor the treatment of Fabry disease and has beenapproved for use in the European union underthe brand name GalafoldTM (migalastat). Phase 3studies conducted with patients whose mutationswere responsive to migalastat monotherapy showed≥50% reduction in the storage of globotriaosylceramide (GL-3) in the interstitial capilleries of thekidney following 6 months treatment (113). It wasshown that even treatment of wild-type α-galactosidase with 1-deoxy-galactonojirimycin enhancesits stabilization as shown by using scanning calorimetry (114), so that this effect of migalastat onα-galactosidase can be benefited for Fabry patientswho do not have responsive mutation. By formulating with ERT with intravenous migalastat, the stability of the active form of the enzyme in circulationcan be increased. Similarly, improved enzyme activity upon co-incubation of α-glucosidase and thechaperone N-butyldeoxynojirimycin (NB-DNJ) wasshown both in vitro and in a mouse model of Pompedisease (107). In the case of type 1 Gaucher disease, pre-inbubation of glucocerebrosidase (GLA)with isofagomine significantluy increased stabilityof the enzyme to heat, neutral pH, and denaturingagents in vitro, thus resulted in increased intracellular enzyme activity (115).Since the mutations that cause misfolding are relatively prevalent in MPS III disease, pharmacological chaperone therapy has the potential to bea suitable treatment strategy for the majority ofaffected patients. It is known that for these diseases, an enzyme activity above 10-20% is sufficientto preclude the development of clinical symptoms.The fact that pharmacological chaperones can bedesigned to cross the BBB make them candidatesfor the treatment of neurodegenerative damages ofMPS III. A comprehensive evaluation of MPS IIIA mutations via a novel multiparametric algorithmdemonstrated that the majority of the SGSH mutations impair proper folding of the three-dimensionalconformation of the enzyme (116). This is especially relavant within the context of pharmacologicalchaperones, a highly promising therapy for thetreatment of protein folding diseases. In addition,most of HGSNAT mutations results in misfoldingof the enzyme, which is abnormally glycosylatedand not targeted to the lysosome, but retained inthe endoplasmic reticulum. Glucosamine, whichis a competitive inhibitor of HGSNAT enzyme resulted in significant increases HGSNAT activity ineight out of nine patients’ fibroblasts, indicating itstherapeutic potential (117). Using CpGH89 fromClostridium perfringens, a close bacterial homologof NAGLU, 2-acetamido-1,2-dideoxynojirimycin(2AcDNJ) and 6-acetamido-6-deoxycastanospermine (6AcCAS) were shown as potential inhibitorsto act as pharmacologic chaperones by isothermaltitration calorimetry (ITC) and kinetic methods(18).
MPS III are presented with serious neurodegeneration which does not have a cure. While otherMPS diseases (MPS I, II, IVA and VI) can be treated by ERT and HSCT, there is no such an available therapy for MPS III. Although substrate reduction therapy was shown to be effective in MPSIIIA and IIIB mice, mix results were obtained inhuman clinical trials. There is not much researchin the field of pharmacological chaperone therapyfor MPS III except for few studies. Actually, thefact that the majority of disease causing mutationsare missense variations that result in misfoldingdefects and the serious neurodegenerative natureof the disease hold great hopes for therapeutic application of pharmacological chaperones. Nonsensesupression or stopcodon readthrough therapy isalso an emerging therapy but it is feasible only for the diseases mostly caused by PTCs such as MPSI-Hurler syndrome. In addition, the discovery of induced pluripotent stem cell (iPSC) technology is arevolution for the drug discovery and modelling ofgenetic diseases. While the existing animal models for MPS III and other LSDs are valuable, theysuffer from partially mimicking the human phenotype. Furthermore, most in vitro studies focusingon pharmacological chaperone screening (and also screening of other small molecules for stopcodonreadthrough and substrate reduction therapies) forLSDs have been performed on patient fibroblasts, acell type not primarily affected in patients. Modelling of relevant neuronal defects using patient-specific iPSC obtained by re-programming of their fibroblasts provides access to human neurons andhence a drug screening platform for screeening ofsmall molecules for therapy.
1. Parenti G, Andria G, Ballabio A. Lysosomal storage diseases:from pathophysiology to therapy. Annu Rev Med 2015; 66471-86.
2. Lavery C, Hendriksz C, Jones SA. Mortality in patients withSanfilippo syndrome. Orphanet J Rare Dis 2017; 12:168.
3. Shapiro EG, Jones SA, Escolard ML. Developmental and behavioral aspects of mucopolysaccharidoses with brain manifestations-Neurological signs and symptoms. Mol Genet Metab 2017; 122:1-7.
4. Gaffke L, Pierzynowska K, Piotrowska E et al. How close arewe to therapies for Sanfilippo disease?. Metab Brain Dis2018; 33:1-10.
5. Garbuzova-Davis S, Mirtyl S, Sallot SA et al. Blood-brain barrierimpairment in MPS III patients. BMC Neurology 2013; 13:174.
6. Andrade F, Aldámiz-Echevarría L, Llarena M et al. Sanfilipposyndrome: overall review. Pediatr Int 2015; 57:331-38.
7. Fedele AO. Sanfilippo syndrome: causes, consequences, andtreatments. Appl Clin Genet 2015; 8:269-81.
8. Valstar MJ, Rijter GJG, van Diggelen OP et al. Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008; 31:240-52.
9. Gallagher JT Multiprotein signalling complexes: regional assembly on heparan sulphate. Biochem Soc Trans 2006;34:438-41.
10. Yamaguchi Y, Inatani M, Matsumoto Y et al. Roles of heparansulfate in mammalian brain development current views basedon thefindings from Ext1 conditional knockout studies. ProgMol Biol Transl Sci 2010; 93:133-52.
11. Li HH, Yu WH, Rozengurt N et al. Mouse model of Sanfilipposyndrome type B produced by targeted disruption of the geneencoding α-N-acetylglucosaminidase. Prot Natl Acad Sci U S A1999; 96:14505-10
12. Ohmi K, Greenberg DS, Rajavel KS et al. Activated microglia incortex of mouse models of mucopolysaccharidoses I and IIIB.Prot Natl Acad Sci U S A 2003; 100:1902-7.
13. Pshezhetsky AV. Lysosomal storage of heparan sulfate causesmitochondrial defects, altered autophagy, and neuronal deathin the mouse model of mucopolysaccharidosis III type C. Autophagy 2016; 12:1059-60.
14. Martins C, Hu° lková H, Dridi L et al. Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model. Brain 2015; 138:336-55.
15. McGlynn R, Dobrenis K, Walkley SU. Differential subcellularlocalization of cholesterol, gangliosides, and glycosaminoglycans in murine models of mucopolysaccharide storage disorders. J Comp Neurol 2004; 480:415-26.
16. Avila JL, Convit J. Inhibition of leucocytic lysosomal enzymesby glycosaminoglycans in vitro. Biochem J 1975; 152:57-64.
17. Yogalingam G, Hopwood JJ Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 2001; 18:264-81.
18. Ficko-Blean E, Stubbs KA, Nemirovsky O et al. Structural andmechanistic insight into the basis of mucopolysaccharidosisIIIB. Proc Natl Acad Sci U S A 2008; 105: 6560-5.
19. Yogalingam G, Weber B, Meehan J et al. Mucopolysaccharidosis type IIIB: characterisation and expression of wild-type andmutant recombinant α-N-acetylglucosaminidase and relationship with Sanfilippo phenotype in an attenuated patient. Biochim Biophys Acta 2000; 1502:415-25.
20. Fan X1, ZhangH, Zhang S et al. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC(Sanfilippo disease type C). Am J Hum Genet 2006; 79:738-44.
21. Ruijter GJ, Valstar MJ, van de Kamp JM et al. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in TheNetherlands. Mol Genet Metab 2008; 93:104-11.
22. Jansen AC, Cao H, Kaplan P et al. Sanfilippo syndrome type D:natural history and identification of 3 novel mutations in theGNS gene. Arch Neurol 2007; 64:1629-34.
23. Beesley CE, Burke D, Jackson M et al. Sanfilippo syndrometype D: identification of thefirst mutation in the N-acetylglucosamine-6sulphatase gene. J Med Genet 2003; 40:192-94.
24. Mok A, Cao H, Hegele RA. Genomic basis of mucopolysaccharidosis type IIID (MIM 252940) revealed by sequencing of GNSencoding N-acetylglucosamine-6sulfatase. Genomics 2003;81:1-5.
25. Beesley CE, Concolino D, Filocamo M et al. Identification andcharacterisation of an 8.7 kb deletion and a novel nonsensemutation in two Italian families with Sanfilippo syndrometype D (mucopolysaccharidosis IIID). Mol Genet Metab 2007;90:77-80.
26. Knottnerus SJG, Nijmeijer SCM, IJlst L et al. Prediction of phenotypic severity in mucopolysaccharidosis type IIIA. Ann Neurol2017; 82:686-96.
27. van de Kamp JJ, Niermeijer MF, von Figura K et al. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome(types A, B, and C). Clin Genet 1981; 20:152-60.
28. Ausseil J, Desmaris N, Bigou S et al. Early neurodegenerationprogresses independently of microglial activation by heparansulfate in the brain of mucopolysaccharidosis IIIB mice. PLoSOne 2008; 3:e2296.
29. Crawley AC, Gliddon BL, Auclair D et al. Characterization ofa C57BL/6 congenic mouse strain of mucopolysaccharidosistype IIIA. Brain Res 2006; 1104:1-17.
30. DiRosario J, Divers E, Wang C, Etter J, Charrier A, et al. Innateand adaptive immune activation in the brain of MPS IIIB mousemodel. J Neurosci Res 2009; 87:978-90.
31. Wilkinson FL, Holley RJ, Langford-Smith KJ et al. Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA andIIIB. PLoS One 2012; 7:e35787.
32. Ohmi K, Zhao HZ, Neufeld EF. Defects in the medial entorhinalcortex and dentate gyrus in the mouse model of Sanfilipposyndrome type B. PLoS One 2011; 6:e27461.
33. Pshezhetsky AV. Crosstalk between 2 organelles: Lysosomalstorage of heparan sulfate causes mitochondrial defects andneuronal death in mucopolysaccharidosis III type C. Rare Dis2015; 3:e1049793.
34. Beard H, Hassiotis S, Gai WP et al. Axonal dystrophy in thebrain of mice with Sanfilippo syndrome. Exp Neurol 2017;295:243-55.
35. Lemonnier T, Blanchard S, Toli D et al. Modeling neuronal defects associated with a lysosomal disorder using patient-derived induced pluripotent stem cells. Hum Mol Genet 2011;20:3653-66.
36. Maccari F, Sorrentino NC, Mantovani V et al. Glycosaminoglycan levels and structure in a mucopolysaccharidosis IIIA miceand the effect of a highly secreted sulfamidase engineered tocross the blood-brain barrier. Metab Brain Dis 2017; 32:203-10.
37. Downs-Kelly E, Jones MZ, Alroy J et al. Caprine mucopolysaccharidosis IIID: a preliminary trial of enzyme replacement therapy. J Mol Neurosci 2000; 15:251-62.
38. Scarpaa M, Orchard PJ, Schulz A et al. Treatment of brain disease in the mucopolysaccharidoses. Mol Genet Metab 2017;122:25-34.
39. Jones SA, Breen C, Heap F et al. A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab 2016; 118:198-205.
40. Muenzer J, Hendriksz CJ, Fan Z et al. A phase I/II study ofintrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet Med 2016; 18:73-81.
41. Boelens JJ, Prasad VK, Tolar J et al. Current internationalperspectives on hematopoietic stem cell transplantation forinherited metabolic disorders. Pediatr Clin North Am 2010;57:123-45.
42. Muenzer J. The mucopolysaccharidoses: A heterogeneousgroup of disorders with variable pediatric presentations. J Pediatr 2004; 144:27-34.
43. Krivit, W, Sung, JH, Shapiro, EG et al. Microglia: the effectorcell for reconstitution of the central nervous system followingbone marrow transplantation for lysosomal and peroxisomalstorage diseases. Cell Transplant 1995; 4:385-92.
44. Sivakumur P, Wraith JE. Bone marrow transplantation in mucopolysaccharidosis type IIIA: a comparison of an early treatedpatient with his untreated sibling. J Inherit Metab Dis 1999;22:849-50.
45. Vellodi A, Young E, New M et al. Bone marrow transplantation for Sanfilippo disease type B. J Inherit Metab Dis 1992;15:911-18.
46. Langford-Smith A, Wilkinson FL, Langford-Smith KJ et al. Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice.Mol Ther 2012; 20:1610-21.
47. Sergijenko A, Langford-Smith A, Liao AY et al. Myeloid/Microglial driven autologous hematopoietic stem cell gene therapycorrects a neuronopathic lysosomal disease. Mol Ther 2013;21:1938-49.
48. Fraldi A, Hemsley K, Crawley A et al. Functional correctionof CNS lesions in an MPS-IIIA mouse model by intracerebralAAV-mediated delivery of sulfamidase and SUMF1 genes. HumMol Genet 2007; 16:2693-2702.
49. Heldermon CD, Ohlemiller KK, Herzog ED et al. Therapeuticefficacy of bone marrow transplant, intracranial AAV-mediatedgene therapy, or both in the mouse model of MPS IIIB. MolTher 2010; 18:873-80.
50. McIntyre C, Byers S, Anson DS. Correction of mucopolysaccharidosis type IIIA somatic and central nervous system pathology by lentiviral-mediated gene transfer. J Gene Med 2010;12:717-28.
51. Fu H, DiRosario J, Kang L et al. Restoration of central nervoussystem α-N-acetylglucosaminidase activity and therapeuticbenefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adenoassociated viral type 2 vector delivery. J Gene Med 2010; 12:624-33.
52. Haurigot V, Marcó S, Ribera A et al. Whole body correctionof mucopolysaccharidosis IIIA by intracerebrospinal fluid genetherapy. J Clin Invest 2013; 123:3254-71.
53. Ribera A, Haurigot V, Garcia M et al. Biochemical, histological and functional correction of mucopolysaccharidosis typeIIIB by intra-cerebrospinal fluid gene therapy. Hum Mol Genet2015; 24:2078-95.
54. Tardieu M, Zérah M, Husson B, et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carryinghuman SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial.Hum Gene Ther 2014; 25:506-16.
55. Fu H, Kang L, Jennings JS et al. Significantly increased lifespan and improved behavioral performances by rAAV genedelivery in adult mucopolysaccharidosis IIIB mice. Gene Ther2007; 14:1065-77.
56. Sorrentino NC, D’Orsi L, Sambri I, et al. A highly secretedsulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses typeIIIA. EMBO Mol Med 2013; 5:675-90.
57. Roca C, Motas S, Marcó S et al. Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID. Hum Mol Genet 2017; 26:1535-51
58. Piotrowska E, Jakobkiewicz-Banecka J, Baranska S et al.Genistein-mediated inhibition of glycosaminoglycan synthesisas a basis for gene expression-targeted isoflavone therapy formucopolysaccharidoses. Eur J Hum Genet 2006; 14:846-52.
59. Wegrzyn G, Jakobkiewicz-Banecka J, Gabig-Ciminska M et al.Genistein: a natural isoflavone with a potential for treatmentof genetic diseases. Biochem Soc Trans 2010; 38:695-701.
60. Jakobkiewicz-Banecka J, Piotrowska E, Narajczyk M et al.Genistein-mediated inhibition of glycosaminoglycan synthesis,which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growthfactor-dependent pathway, J Biomed Sci 2009; 16:26.
61. Malinowska M, Wilkinson FL, Bennett W et al. Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice. Mol Genet Metab 2009; 98:235-42.
62. Friso A, Tomanin R, Salvalaio M et al. Genistein reduces glycosaminoglycan levels in a mouse model of mucopolysaccharidosis type II. Br J Pharmacol 2010; 159:1082-91.
63. Malinowska M, Wilkinson FL, Langford-Smith KJ et al.Genistein improves neuropathology and corrects behaviour ina mouse model of neurodegenerative metabolic disease. PloSOne 2010; 5:e14192.
64. Delgadillo V, O’Callaghan Mdel M, Artuch R et al. Genisteinsupplementation in patients affected by Sanfilippo disease. JInherit Metab Dis 2011; 34:1039-44.
65. de Ruijter J, Valstar MJ, Narajczyk M et al. Genistein in Sanfilippo disease: a randomized controlled crossover trial, AnnNeurol 2012; 71:110-20.
66. Piotrowska E, Jakobkiewicz-Banecka J, Maryniak A et al. Twoyear follow-up of Sanfilippo Disease patients treated with agenistein-rich isoflavone extract: Assessment of effects oncognitive functions and general status of patients. Med SciMonit 2011; 17:CR196-202.
67. Roberts AL, Rees MH, Klebe S et al. Improvement in behaviour after substrate deprivation therapy with rhodamineB in a mouse model of MPS IIIA. Mol Genet Metab 2007;92:115-21.
68. Roberts AL,Thomas BJ, Wilkinson AS et al. Inhibition of glycosaminoglycan synthesis using rhodamine B in a mousemodel of mucopolysaccharidosis type IIIA. Pediatr Res 2006;60:309-14.
69. Dire DJ, Wilkinson JA. Acute exposure to rhodamine B. J Toxicol Clin Toxicol 1987; 25:603-7.
70. Kaidonis X, Byers S, Ranieri E et al. N-butyldeoxynojirimycintreatment restores the innate fear response and improveslearning in mucopolysaccharidosis IIIA mice. Mol Genet Metab2016; 118:100-110.
71. Karijolich J, Yu YT. Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review). Int J Mol Med 2014; 34:355-62.
72. Fronçois B, Russell RJ, Murray JB et al. Crystal structuresof complexes between aminoglycosides and decoding A siteoligonucleotides: role of the number of rings and positivecharges in the specific binding leading to miscoding. NucleicAcids Res 2005; 33:5677-90.
73. Keeling KM, Bedwell DM. Suppression of nonsense mutationsas a therapeutic approach to treat genetic diseases. WileyInterdiscip Rev RNA 2011; 2:837-52.
74. Brooks DA, Muller VJ, Hopwood JJ. 2006. Stop-codon readthrough for patients affected by a lysosomal storage disorder.Trends Mol Med 2006; 12:367-73.
75. Manuvakhova M, Keeling K, Bedwell DM. Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA 2000;6:1044-55.
76. Bedwell DM, Kaenjak A, Benos DJ et al. Suppression of aCFTR premature stop mutation in a bronchial epithelial cellline. Nat Med 1997; 3:1280-4.
77. Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibioticsrestore CFTR function by overcoming premature stop mutations. Nat Med 1996; 2:467-69.
78. Bidou L, Hatin I, Perez N et al. 2004. Premature stop codonsinvolved in muscular dystrophies show a broad spectrum ofreadthrough efficiencies in response to gentamicin treatment.Gene Ther 2004; 11:619-27.
79. Buck NE, Wood L, Hu R et al. Stop codon read-through of amethylmalonic-aciduria mutation. Mol Genet Metab 2009;97:244-49.
80. Bellais S, Le Goff C, Dagoneau N et al. In vitro readthroughof termination codons by gentamycin in the Stüve-WiedemannSyndrome. Eur J Hum Genet 2010; 18:130-32.
81. Sánchez-Alcudia R, Pérez B, Ugarte M et al. Feasibility ofnonsense mutation readthrough as a novel therapeutical approach in propionic acidemia. Hum Mutat 2012; 33:973-80.
82. Ho G, Reichardt J, Christodoulou J. In vitro read-through ofphenylalanine hydroxylase (PAH) nonsense mutations usingaminoglycosides: a potential therapy for phenylketonuria. JInherit Metab Dis 2013; 36:955-59.
83. Kuschala C, DiGiovannaa JJ, Khana SG et al. Repair of UV photolesions in xeroderma pigmentosum group C cells inducedby translational readthrough of premature termination codons.Proc Natl Acad Sci U S A 2013; 110:19483-88.
84. Bartolomeo R, Polishchuk EV, Volpi N et al. Pharmacologicalread-through of nonsense ARSB mutations as a potential therapeutic approach for mucopolysaccharidosis VI. J Inherit Metab Dis 2013; 36:363-71.
85. Brendel C, Belakhov V, Werner H et al. 2011. Readthroughof nonsense mutations in Rett syndrome: evaluation of novelaminoglycosides and generation of a new mouse model. J MolMed 2011; 89:389-98
86. Gunn G, Dai Y, Du M et al. Long-term nonsense suppressiontherapy moderates MPS I-H disease progression. Mol GenetMetab 2014; 111:374-81.
87. Nudelman I, Glikin D, Smolkin B et al. Repairing faulty genesby aminoglycosides: development of new derivatives of geneticin (G418) with enhancd suppression of diseases-causingnonsense mutation. Bioorg Med Chem 2010; 18:3735-46.
88. Welch EM, Barton ER, Zhuo J et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007;447:87-91.
89. Peltz SW, Morsy M,Welch EM et al. Ataluren as an agent fortherapeutic nonsense suppression. Annu Rev Med 2013;64:407-25.
90. Gómez-Grau M, Garrido E, Cozar M et al. Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codonreadthrough therapy in four lysosomal storage diseases. PLoSOne 2015; 10:e0135873.
91. Valenzano KJ, Khanna R, Powe AC et al. Identification andcharacterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. Assay DrugDev Technol 2011; 9:213-35
92. Muntau AC, Leandro J, Staudigl M et al. Innovative strategiesto treat protein misfolding in inborn errors of metabolism:pharmacological chaperones and proteostasis regulators. JInherit Metab Dis 2014; 37:505-23.
93. Pereira M, Tomé D, Domingues AS et al. Afluorescence-basedsensor assay that monitors general protein aggregation in human cells. Biotechnol J 2018; 13:e1700676.
94. Tao YX, Conn PM. Pharmacoperones as novel therapeutics fordiverse protein conformational diseases. Physiol Rev 2018;98:697-725.
95. Hughes D, Malluci GR. 2018. The unfolded protein responsein neurodegenerative disorders-therapeutic modulation of thePERK pathway. FEBS J doi:10.1111/febs.14422.[Epub aheadof print].
96. Kim BE, Smith K, Meagher CK et al. A conditional mutationaffecting localization of the Menkes disease copper ATPase.Suppression by copper supplementation. J Biol Chem 2002;277:44079-84.
97. Perlmutter DH. Chemical chaperones: a pharmacological strategy for disorders of protein folding and trafficking. Pediatr Res2002; 52:832-36.
98. Yoshida H, Yoshizawa T, Shibasaki F et al. Chemical chaperones reduce aggregate formation and cell death caused bythe truncated Machado-Joseph disease gene product with anexpanded polyglutamine stretch. Neurobiol Dis 2002; 10:88-99.
99. Cohen FE, Kelly JW. Therapeutic approaches to protein-misfolding diseases. Nature 2003; 426:905-09.
100.Forny P, Froese DS, Suormala T et al. Functional characterization and categorization of missense mutations that causemethylmalonyl-CoA mutase (MUT) deficiency. Hum Mutat2014; 35:1449-58.
101.Burrows JAJ, Willis LK, Perlmutter DH. Chemical chaperonesmediate increased secretion of mutant a 1-antitrypsin ( a 1-AT)Z: A potential pharmacological strategy for prevention of liverinjury and emphysema in a α1-AT deficiency. Proc Natl AcadSci U S A 2000; 97:1796-1801.
102.Yam GH, Gaplovska-Kysela K, Zuber C et al. Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilinto rescue cells from endoplasmic reticulum stress and apoptosis. Invest Ophtalmol Vis Sci 2007; 48:1683-90.
103.Gámez A, Yuste-Checa P, Brasil S et al. 2018. Protein misfolding diseases: Prospects of pharmacological treatment.Clin Genet 2018; 93:450-58.
104.Asano N, Ishii S, Kizu H et al. In vitro inhibition and intracellular enhancement of lysosomal α-galactosidase A activity inFabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. Eur J Biochem 2000; 267, 4179-4186.
105.Andreotti G., Citro V., De Crescenzo A et al. Therapy of Fabrydisease with pharmacological chaperones: from in silico predictions to in vitro tests. Orphanet J. Rare Dis 2011; 6:66.
106.Matsuda J, Suzuki O, Oshima A et al. Chemical chaperonetherapy for brain pathology in GM1-gangliosidosis. Proc NatlAcad Sci U S A 2003; 100:15912-17.
107.Porto C, Cardone M, Fontana F et al. The pharmacologicalchaperone N-butyldeoxynojirimycin enhances enzyme replacement therapy in Pompe diseasefibroblasts. Mol Ther 2009;17:964-71.
108.Zheng W., Padia J., Urban D.J. Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughputscreening are chaperone leads for Gaucher disease. Proc NatlAcad Sci U S A 2007; 104:13192-97.
109.Hill CH, Viuff AH, Spratley SJ et al. Azasugar inhibitors as pharmacological chaperones for Krabbe disease. Chem Sci 2015;6:3075-86.
110.Fukuda H, Karaki F, Dodo K. Phenanthridin-6-one derivativesas thefirst class of non-steroidal pharmacological chaperonesfor Niemann-Pick disease type C1 protein. Bioorg Med ChemLett 2017; 27:2781-87.
111.Mellor HR, Neville DC, Harvey DJ et al. Cellular effects of deoxynojirimycin analogues: inhibition of N-linked oligosaccharide processing and generation of free glucsylated oligosaccharides. Biochem J 2004; 381:867-75.
112.Horne G, Wilson FX, Tinsley J et al. Iminosugars past, presentand future: medicines for tomorrow. Drug Discov Today 2011;16:107-18.
114.Lieberman RL, D’Aquino JA, Ringe D et al. Effects of pH andiminosugar pharmacological chaperones on lysosomal glycosidase structure and stability. Biochemistry 2009; 48:4816-27.
115.Shen JS, Edwards NJ, Hong YB et al. Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase. NiochemBiophs Res Commun 2008; 369:1071-5.
116.Ugrinov KG, Freed SD, Thomas CL et al. A multiparametriccomputational algorithm for comprehensive assessment of genetic mutationsin mucopolysaccharidosis type IIIA (SanfilippoSyndrome) PLoS One 2015; 10:e0121511117.Feldhammer M, Durand S, Pshezhetsky AV. 2009. Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C. PLoS One 2009; 4:e7434.