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276

Table9.9 Inhibitors ofGALC.

Compounds GALC, Ki References

190 μM

380 nM

630 nM

52 μM

[171]

130 μM

2.3 mM

7.0μM

450 μM

a) Compound is able to stabilize GALC under thermal denaturation. b) Good inhibitor also for lysosomal βgalactosidase.

[172]

[173]

Table9.10 ERT forPompe disease.

9.6 Glycoproteinoses

277

Enzyme

Disorder Gene

Pompe GAA αglucosidase Lumizyme® (alglucosidase alfa; Sanofi

deficiency ERT

Genzyme, Cambridge, MA, USA) available since 2010

Nexviazyme® (avalglucosidase alfa ngpt; Sanofi Genzyme, Cambridge, MA, USA) available since 2021

Current indication

Infantileonset Pompe disease

Lateonset Pompe disease

that 69 could significantly increase enzyme stability under thermal denaturation, increased enzyme activity and protein levels for different αglu mutants in patient derived fibroblasts and in transiently transfected COS7 cells (the best results are reported in Table 9.11) [176]. Studies on animal models confirmed that DNJ increased the specific activity and lysosomal delivery of mutant αglu and promoted glycogen reduction in tissues[179]. A clinical trial on DNJ showed that total αglu activity and protein in plasma were increased 1.2 to 2.8fold compared to ERT alone in Pompe patients. Moreover, muscle αglu activity was also increased[180]. Unfortunately, based on the serious adverse events of the latest clinical trial (NCT00688597) the administration of 69 on Pompe patients was terminated. Moreover, the DNJ alkylated derivative (Nbutyldeoxynojirimycin, NB DNJ, 3) was also effective in enhancing αglu residual activity in fibroblasts from PD patient carrying specific mutations and in HEK293T cells overexpressing mutated GAA gene (Table9.11)[177]. Even more remarkably, the coincubation of Pompe fibroblasts with recombinant human αgluc and the chaperone 3 resulted in more efficient stabilization of enzyme activity. Improved enzyme correction was also found invivo in a PD mouse model and PD patients treated with coadministra- tion of infusions of recombinant human αgluc and oral NBDNJ[181, 182].  NBDNJ, the unnatural enantiomer of the iminosugar 3, showed αgluc activity rescue, either when administered singularly (1.5fold at 20 μM) in PD fibroblasts bearing L552P/L552P mutation (Table9.11) or when coincubated with the recombinant human αgluc. In addition, different from its NBDNJ, NBDNJ (70) did not act as a glucosidase inhibitor. The lack of inhibition of the deficient enzyme and of other glycosidases further increases the potential of 70, especially compared with its enantiomer[178].

9.6 Glycoproteinoses

9.6.1 Fucosidosis

Fucosidosis is caused by mutations of the αfucosidase (FUCA1) gene, resulting in deficiency of the αlfucosidase enzyme. As a result of the hydrolytic enzyme deficiency, incomplete catabolism of N and Oglycosylproteins results in the accumula- tion of fucosecontaining glycolipids and glycoproteins in various tissues and urine.

 

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278

Table9.11 PCs forPompe disease.

PC IC50 or Ki Mutation

IC50= 1.3 μM, Ki=

530 nM

IVS8+1G>A/ M519V

P545L/P545L 6.4fold

L552P/L552P 17.8fold

L552P/r.spl? 5.1fold

L552P/A445P 4.3fold

G54R/r.0 4.3fold

P545L 4.2fold

L552P 3.9fold

Y575S 8.5fold

E579K 3.5fold

A610V 5.8fold

H612Q 4.5fold

n.d.

L552P/L552P 5.6fold at 20 μM

L552P/abn splic 2.7fold at 20 μM

L552P/A445P 1.8fold at 20

G549R/abn splic 3.7fold at 20 μM

L552P 4fold at 20 μM

G549R 16fold at 20 μM



L552P/L552P 1.5fold at 20 μM

Max. activity enhancement References

Patient fibroblasts

[176]

6.6fold

COS‐7 cells

Patient fibroblasts [177]

μM

HEK293T cells

Patient fibroblasts [178]

a) Compound is able to stabilize αglu under thermal denaturation; b) Cell lines were tested at least three times with DNJ concentrations ranging from 50 nM to 1 mM; c) Cells were treated with 100 μM DNJ; d) n.d.=not determined; e) Compound did not act as a glycosidase inhibitor.

9.7 Conclusions

The clinical features of fucosidosis are progressive mental retardation and neurological deterioration, coarse facies, growth retardation, recurrent infections, dysostosis multiplex, and angiokeratoma. The treatment of fucosidosis is directed toward the specific symptoms that are apparent in each individual[183]. Correction of the enzymatic deficiency by allogeneic bone marrow transplantation has been first experienced on an animal model[184, 185] and then on patients with an amelioration of the clinical signs[186–188]. PCs for fucosidase have not been proposed to date, but several iminosugar derivatives have proved to be effective inhibitors. The discussion of fucosidase inhibitors is not the aim of this work, but a report of the main compounds is reported in the articles[189, 190].

9.6.2 α-Mannosidosis

αmannosidosis is an ultrarare autosomal recessive genetic disorder caused by mutations in the MAN2B1 gene encoding for αmannosidase, a lysosomal enzyme involved in glycoprotein catabolism. The result of αmannosidase deficiency is blockage of the degradation of glycoproteins, leading to an accumulation of mannoserich oligosaccharides in all tissues[191]. Accumulation of mannoserich oligosaccharides manifests in a broad variety of symptoms including skeletal abnormalities, motor function impairment, intellectual disability, hearing loss, respiratory dysfunction, recurrent infections, and cellular and humoral immune defects usually presenting in early childhood[192, 193].

Currently, intravenous ERT, Lamzede (Velmanase alfa, Chiesi Italia S.p.A.), is available since 2021 for the treatment of mild–moderate forms of αmannosidosis in adults, adolescents, and children, but it is not effective treatment for neurological involvement. Preliminary studies demonstrated the ability of HSCT to partially preserve neurocognitive function, stabilize skeletal abnormalities, and prevent early death[194–196].

Recently, a series of PCs combining the 5N,6Ooxomethylidenemannonojirimycin (OMJ) in either mono (71–76, Table9.12) or multivalent (βcyclodextrins as scaffold) fashion (77–79, Table9.12) were reported. Multivalent derivatives exhibited potent enzyme inhibition that prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives proved effective as activity enhancers for several mutant alfaman forms in patient fibroblasts and/or transfected MAN2B1KO cells[197].

279

9.7 Conclusions

The chapter summarizes the invitro screening, preclinical, and clinical results of carbohydratebased compounds in the currently available therapeutic approaches (ERT, SRT, and PCT) for LSDs, organized accordingly to LSD classification into MPS, sphingolipidoses, glycogen storage disorders, and glycoproteinoses.

 

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280

Table9.12 PCs forα-mannosidosis

PC IC

IC50=

μM

26.8

IC50= 116 μM

IC50=

19.3 μM

IC50=

30.7 μM

IC50=

17.3 μM

Mutation

Max. activity enhancement

Patient fibroblasts

H72L/H72L 8.2fold at 20 μM

P356R/P356R 6.4fold at 2

R750W/

1.35fold at 20

μM

R750W

Patient fibroblasts

H72L/H72L 8.0fold at 20 μM

P356R/P356R 4.5fold at 20 μM

R750W/

1.3fold at 20 μM

R750W

Patient fibroblasts

H72L/H72L 7.8fold at 20 μM

P356R/P356R 5.7fold at 20 μM

R750W/

1.35fold at 20 μM

R750W

Patient fibroblasts

H72L/H72L 11fold at 20 μM

P356R/P356R 5fold at 20 μM

R750W/

1.6fold at 2 μM

R750W

MAN21B‐KO HAP1 cells

C55F 51% increase at 2

μM

H71L 34% increase at 2 μM

L352P 8% increase at 2 μM

L565P 14% increase at 2 μM

R916C 26% increase at 2 μM

Patient fibroblasts

H72L/H72L 4fold at 0.2 μM

R750W/ R750W

1.7fold at 20 and 2 nM

Table9.12 (Continued)

9.7 Conclusions

281

PC IC

IC50=

2.2 μM

IC50=

0.44 μM

IC50=

0.45 μM

Mutation

Max. activity enhancement

Patient fibroblasts

H72L/H72L 7.8fold at 0.2 μM

R750W/

1.7fold at 2 nM

R750W

MAN21B‐KO HAP1 cells

C55F 111% increase at 20 μM

H71L 68% increase at 20 μM

L352P 10% increase at 0.2 μM

L565P 8% increase at 2 μM

R916C 63% increase at 20 μM

Patient fibroblasts

R750W/

1.5fold at 2 nM

R750W

Patient fibroblasts

R750W/

1.3fold at 2 nM

R750W

a) Ref.[197].

IC50= 55 μM

R750W/ R750W

Patient fibroblasts

1.4fold at 2 nM

 

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282

Within the field of MPS, a sulfated disaccharide derived from heparin was reported as a good PC for MPS II (almost 40fold activity enhancement at 10 but only for a specific mutation, demonstrating that often PCT lacks general applicability. In addition, when searching for MPS enzyme stabilizers to be employed both in PCT and ERT/PC, multivalent sugars and iminosugars emerged as valuable candidates due to their strong affinity toward GALNS and IDS enzymes, paving the way for future investigations in this field. Probably due to the multimeric nature of the deficient enzyme (αmannosidase), multivalent PCs were developed also for αmannosidosis, a glycoproteinosis. However, in this case, the strong inhibitory activity of the compounds prevailed over the PC effect. Among sphingolipidoses, FD represents an excellent example of the potential use of iminosugars in all three therapeutic approaches. Indeed, several pyrrolidine and piperidine iminosugars are currently under investigation to stabilize and prolong the ERT enzyme activity (ERT/PC). The iminosugar analog of galactose (DGJ) is the only PC, which became a drug to date (Galafold), and further investigations are ongoing to address the few mutations that are not responsive to DGJ. Finally, the Nbutyl DGJ analog is currently under Phase 3 of clinical trials for SRT. Conversely, for GD, an

iminosugarbased SRT (Zavesca

) is available from 2002, while no PC has reached the drug market yet, even though the IFG iminosugar reached Phase 2 of clinical trials. For this reason, many efforts have been devoted to identifying novel PCs for GD, by preparing multivalent compounds, introducing alkyl chains (both on sugars and iminosugars skeleton) to improve cellpermeability and by developing pH sensitive systems or noncompetitive inhibitors with the aim of favoring the enhancer activity with respect to the inhibitory one. In the last few years, the search for PCs for GD attracted even higher attention due to link between Gaucher and Parkinson disease, suggesting that effective PCs can be potentially applied to all protein misfolded diseases, including neurodegenerative disorders. DGJ analogs, IFG analogs, and aminocyclitols (e.g. valienamine derivatives) were investigated as PCs for GM1gangliosidosis and MBD, but all studies are at most at a preclinical level (mouse models). Regarding the glycogen storage disorder Pompe disease, the serious adverse effects caused in patients by coadministration of ERT with the natural iminosugar 1deoxynojirimycin (DNJ) stopped the ER/PC therapy clinical trial, despite the remarkable increase in enzyme activity observed. Lower side effects might be obtained with the Nbutyl enantiomer of the natural DNJ, which is a modest PC but does not act at all as enzyme inhibitor. The latter case suggests that noninhibitory chaperones, although more difficult to be identified, might represent a valuable alternative for a faster development of safe and efficient PCs for LSDs, in general.

μM),

Acknowledgments

The authors thank Regione Toscana (Bando Salute 2018, project: “Late onset Lysosomal Storage Disorders” [LSDs] in the differential diagnosis of neurodegenerative diseases: development of new diagnostic procedures and focus on potential

pharmacological chaperones [PCs], Acronym: Lysolate) and by Università di Firenze and Fondazione CR Firenze (Bando congiunto per il finanziamento di progetti competitivi sulle malattie neurodegenerative 2018, project: A multidisciplinary approach to target Parkinson’s disease in Gaucher related population, Acronym: MuTaParGa).

Abbreviations and Acronyms

Lysosomal storage disorders LSDs Central nervous system CNS Orphan drug act ODA Haematopoietic stem cell transplantation HSCT Antisense oligonucleotide ASO Adenoassociated virus AAV Enzyme replacement therapy ERT Blood brain barrier BBB Substrate reduction therapy SRT Pharmacological chaperone therapy PCT Highthroughput screening HTS Chinese hamster ovary CHO Active sitespecific chaperone ASSC Endoplasmic reticulum ER Endoplasmic reticulumassociated degradation ERAD Deoxynojirimycin DNJ Niemann–Pick type C disease NPC Deoxygalactonojirimycin DGJ Food and drugs administration FDA European medicines agency EMA Isofagomine IFG Mucopolysaccharidoses MPS Glycosaminoglycans GAGs Heparan sulfate HS Dermatan sulfate DS Keratan sulfate KS Chondroitin sulfate CS acidβglucosidase (or glucocerebrosidase) GCase NAcetylglucosaminidase NAGLU Iduronate2sulfatase IDS Nacetylglucosamine6sulfatase sulfatase GALNS gold glyconanoparticles AuGNPs Fabry Disease FD αgalactosidase A αGal A globotriaosylceramide Gb3 polyethylene glycol PEG

283Abbreviations and Acronyms

 

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284

Gaucher disease GD 1,5Dideoxy1,5iminoxylitol Nojirimycin

NJ) 1,4dideoxy1,4iminoarabinitol βcyclodextrin

βCD

DIX

DAB1

coppercatalyzed azidealkyne cycloaddition Niemann–Pick acid sphingomyelinase GM1gangliosidosis Morquio B disease N‐octyl4epibetavalienamine βHexosaminidases Tay–Sachs disease Sandhoff disease glucosylceramide synthase

NAcetylgalactosamine NAcetylglucosaminethiazoline

6Acetamido6deoxycastanospermine 2Acetamido2deoxynojirimycin 2Acetamido1,2dideoxynojirimycin 2,5dideoxy2,5iminomannitol rabbe disease

βgalactocerebrosidase βgalactocerebroside

Pompe disease 5N,6Ooxomethylidenemannonojirimycin

ASM

GM1

MBD

NOEV

HEX

TSD

GCS

GalNAc

NGT

ACAS

ADNJ

AdDNJ

DMDP

GALC

GalCer

OMJ

CuAAC

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