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236
Figure8.5 (a) Metabolic incorporation of Ac5ManNTGc in the sialic acid pathway; (b)
thiol-modified analogs. Source: Adapted from Du etal.[136].
Current approaches to MGE for regenerative medicine applications are mostly
focused on the replacement or modulation of cell surface glycosignature. MGE
approaches have been performed in vitro using different polyacetylated ManNAc
analogs in which the Nacetyl group was replaced by a thiolated acyl moiety. The
thiolated and polyacetylated ManNAc analogs were metabolized, generating cell
surface glycans in which Neu5Ac was replaced by a thiolated analog (see Figure8.5).
Neu5(2′thiolAc), for example, was able to induce clustering of nonadhesive Jurkat
cells and morphological neuronal differentiation of human embryoid bodyderived
(hEBD) stem cells[137]. Other Neu5Acthiolated analogs showed interesting bioactivity in human stemcell modulation, including the induction of neuronal differentiation in human Neuronal Stem Cells (hNSCs) and the suppression of adipogenic
differentiation in human adipose stem cells (hASCs)[136].
Gutmann et al. proposed a MGE approach employing tetraacylated
monosaccharides containing an azido group, such as 1,3,4,6tetraOacetylN
azidoacetylgalactosamine (Ac4GlcNAz), to obtain ECMs suitable for subsequent
click chemistry protocols in order to conjugate different functional biomolecules in
NIH 3T3 fibroblasts[138]. Also, fibroblast cellderived ECM was modified with
azido groups by MGE introducing Ac4GalNAz in the culture medium [139].
Another MGE approach was developed by Nellinger etal.[140] by the incorporation of alkenefunctionalized monosaccharides in the ECM, able to chemoselectively react with dienophiles as reporter groups. The alkenefunctionalized
monosaccharides showed good cytocompatibility, ensuring the correct exposition
of unnatural sugar on the ECM.
References
8.5 Future Opportunities and Major Challenges
The role of carbohydrates in medical device and tissue engineering applications is
undoubtedly impressive and merits being studied and implemented. Mimicking
nature, scientists have exploited polysaccharides as scaffolds to generate artificial
tissues, often in combination with proteins, and shorter glycans as signaling molecules to induce cell fate. Where the structural role ends and the biological signal
begins is not entirely clear. It will have to be thoroughly investigated. The possibility
to synthetically generate human tissues and even organs is a big challenge, requiring multiple expertise to control structural, mechanical, and biomolecular properties, in all of which even carbohydrates play their role. Polysaccharides and
glycosylated proteins, derived from human and nonhuman sources, are already
widely used as scaffolds to generate medical devices, but there is still room for significant improvements. The clinical translation of glycoengineered materials able to
restore damaged tissues by exploiting the glycosignature as modulators of tissue
morphogenesis is still in its infancy. The advancement in manufacturing technologies, like 3D printing and 3D bioprinting, will have a significant impact on the generation of polysaccharidebased materials with advanced micrometric physical and
morphological properties. The high structural variability of glycans in ECM and cell
surfaces and the large number of physiological and pathological events that they
can specifically induce require the collection of a lot of information to have a complete picture of their role. The research, therefore, requires robotic platforms for the
synthesis and artificial intelligence approaches to elaborate on the multitude of data
and develop predictive programs. Once the picture is sufficiently clear, the gap
between glycoscience and clinical translation will be covered, revealing the complex
mosaic in which glycans are related to age, health, or pathological states. A big challenge for glycoscientists.
237
Conflict ofInterest
LR and FN are partners and members of the Advisory Scientific Board of
Biocompatibility Innovation srl (BCI).
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9
Carbohydrate-Based Therapeutics forLysosomal
Storage Disorders
Camilla Matassini, Francesca Clemente, and Francesca Cardona
Department of Chemistry “U. Schiff” (DICUS), University of Florence, via della Lastruccia 3-13, 50019 Sesto F.no
(FI), Italy
9.1 An Introduction to Lysosomal Storage
Disorders (LSDs)
Lysosomal Storage Disorders (LSDs) are a group of 70 inherited metabolic
disorders[1] that affect the function of the lysosome, a membranebound organelle
with a key role in processes involved in degrading and recycling cellular waste, cellular signaling, and energy metabolism[2]. LSDs are monogenic disorders caused
by the mutation in a gene encoding for a lysosomal protein (such as lysosomal glycosidases, proteases, integral membrane proteins, transporters, enzyme modifiers,
or activators), resulting in lysosomal failure and subsequent accumulation of non
metabolized substrates. This steady accumulation of substrates in the lysosome, the
“storage,” hence the name of these disorders, ultimately leads to cell dysfunction
and cell death (Figure9.1).
LSDs are considered a class of genetically and clinically heterogeneous disorders,
even though some common clinical features, such as a pediatric onset and the
enlargement of abdominal organs, mainly liver and spleen (visceromegaly), can be
identified. Other frequent symptoms, related to the specific genetic mutation and
the consequent stored substrate, are skeletal dysmorphia, developmental delay, or
other central nervous system (CNS) deficits. Diagnosis of LSDs is based on clinical
symptoms and subsequent confirmation with biochemical and genetic tests, such as
enzymatic dosage and gene sequencing[3]. Unfortunately, especially for the less
severe forms with longer survival, the overlapping clinical features that are not specific for LSDs lead to considerable diagnostic delay and missed cases, while early
diagnosis is a priority for the application of new diseasemodifying therapies.
245
Carbohydrate-Based Therapeutics, First Edition. Edited by Roberto Adamo and Luigi Lay.
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