Emerging Therapies For the Treatment of Mucopolysaccharidosis Type III
ABSTRACT
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.
INTRODUCTION
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.
CLINICAL ASPECTS
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).
THERAPY
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
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).
CONCLUSION
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.
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