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Table 2. (Continued)
Therapeutic
strategy
Drug/compound
Sanfilippo
disease subtype
Used model
Results
Reference
Enzyme
replacement
therapy
CM-rhSulfamidase
A
mouse
reduction in HS levels in CNS and improvement of the
cognitive, motor and social activity (after intravenous
administration)
[83]
rhHNS
A
Cynomolgus
monkeys
biodistribution of the enzyme for CNF cells is more
effective after intrathecal compare to intravenous
administration
[84]
cTfRMAb-SGSH
A
mouse
reduction in HS levels in the brain and liver, increase
of latency in rotarod test of motor activity (after
intraperitoneal injections)
[85]
rhHNS
(delivered by IDDD)
A
patients
well-toleration rhHNS administered via IDDD,
reduction on HS levels in CSF
[86]
rhHNS
(delivered by IDDD)
A
patients
reduction in HS levels in CSF and urine, lack of
improvement in cognitive abilities
[87]
BMN 250
B
patients’ cell lines
improvement in enzyme uptake efficiency in neurons
and astrocytes
[88]
BMN 250
B
mouse
high efficiency enzyme uptake, reduction in HS levels,
improvement of lysosome functions (after
intracerebroventricular administration)
[89]
BMN 250
B
mouse
limited benefits of intravenous administration
compared to simultaneous intravenous and
intracerebroventricular administration
[90]
SBC 103
B
patients
well-toleration therapy for patients, insignificant
reduction of HS in CSF
[92]
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Therapeutic
strategy
Drug/compound
Sanfilippo
disease subtype
Used model
Results
Reference
Hematopoietic
stem cell
therapy
HCT
B
mouse
improved disease outcomes
[93]
combination of
HSCT and UCBT
(early therapy)
A and B (case
reports)
patients
lack of reduction of HS levels in CSF, lack of
improvement of neurological function and behavior
[94]
HCT
unknown
patients
preferred donor for HCT is matched unrelated cord
blood donor, reduction of HCT-related toxicity in
young age patients
[95]
Gene Therapy
Intra-CSF administration
rAAV9-NAGLU
B
mouse
reduction in HS levels, NAGLU or GNS enzyme
activity and lysosomal pathology, also
neuroinflammation was normalized
[103]
rAAV9-NAGLU
B
dogs with/without
preexisting
immunity
levels of enzymatic activity in CSF were similar in
dogs with/without preexisting immunity
[103]
rAAV9-NAGLU
D
mouse
reduction in HS levels, GNS enzyme activity and
lysosomal pathology, also neuroinflammation was
normalized
[104]
Intravenous injection
AAV2/8- SGSH
A
mouse
improved behavior of mice
[76]
AAV9- SGSH
A
mouse
reduction in GAG levels in CNS and peripheral tissues
[97]
rAAV9-hNAGLU
B
nonhuman primates
safety of gene therapy
[99]
rAAV9-CMV-
hNAGLU
B
mouse
no adverse signs were observed nor toxicity
[106]
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Table 2. (Continued)
Therapeutic
strategy
Drug/compound
Sanfilippo
disease
subtype
Used
model
Results
Reference
Gene therapy
rAAV9-CMV-hNAGLU
B
mouse
metabolite abnormalities were corrected
[107]
scAAVrh74-hSGSH
A
mouse
restoration of SGSH activity and GAG storage,
improved behavioral performance, extended
survival
[108]
scAAV9
A
mouse
improved GAG storage in CNS, normalized
lifespan
[109]
lentiviral vector and the
myeloid-specific CD11b
promoter with NAGLU
expression
B
mouse
behavioral correction, normalization of HS
level, reduced inflammatory cytokine
expression, reduced neuroinflammatory and
lysosomal compartment size
[117]
scAAV9
A
clinical
trial phase
I/II
Trial is ongoing, no results available yet
NCT02716246,
www.clinicaltrials.
Gov
Intra-brain injection
combined neonatal
intracranial AAV and
systemic lentiviral gene
therapy
B
mouse
significant improvement of symptoms, including
longer life span
[98]
AAVrh-SGSH
A
clinical
trial phase
I/II
well tolerated, but improvement in symptoms
was negligible
[100]
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Therapeutic
strategy
Drug/compound
Sanfilippo
disease
subtype
Used model
Results
Reference
Gene therapy
Intra-brain injection
rAAV serotypes, -5, -8, -9
and -rh10, administered
bilaterally into the thalamus
B
mouse
AAV8 and -9 superior in biodistribution
and transduction efficiency profiles
[110]
AVV serotypes -5, -8, -9 and
-rh10 intraparenchymal
injected
B
mouse
AAV8 more efficient than others for gene
delivery to most brain structures and
improved transduction in NAGLU
[111]
AAVrh10-SGSH-IRES-
SUMF1, Intracerebral
injections
A
mouse
improved catabolism of HS, reduced
neuroinflammatory activation of microglia
and secondary subtracted storage
accumulation
[113]
lentiviral vector with NAGLU
overexpression
B
mouse embryonic
fibroblasts have been
reprogrammed into iPSC
cells
reduction in HS levels, no microglia
activation, reduced astrocyte activation
[116]
AAV-TT, Intracranial
injections
C
mouse
administrated at low doses is able to correct
neurological phenotype and lysosomal
storage
[112]
Three modified AAVrh10
vectors intracranial injection
A
mouse
promotor exchange has increased the
amount of SGSH expressed in the brain
[115]
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Table 2. (Continued)
Therapeutic
strategy
Drug/compound
Sanfilippo
disease subtype
Used model
Results
Reference
Substrate
reduction
therapy
siRNA for EXTL2 and EXTL3
C
patients’ cell lines
inhibition of GAG synthesis, reduction in the
level of HS storage
[121]
rhodamine B
A
patients’ cell lines
impaired HS synthesis
[122]
rhodamine B
A
mouse
decrease in HS storage and improved animal
behavior
[123]
rhodamine B
A
mouse
safe treatment
[124]
rhodamine B
-
chondrocyte
monolayer cell
culture
down-regulation of expression of GAG
synthesis-related genes
[125]
genistein
A, B
patients’ cell lines
GAG synthesis inhibition
[126]
genistein
A, B
patients’ cell lines
blocking epidermal growth factor receptor
[127]
genistein
A, B
patients’ cell lines
impaired GAG synthesis
[129,
130]
genistein
-
Cell lines
stimulating expression of genes coding for
lysosomal enzymes through activation of
transcription factor EB
[135]
cyclodextrin encapsulation of
genistein and daidzein
unknown
patients’ cell lines
reduction of GAG levels by both pure
isoflavones and their co-ground cyclodextrin
complexes
[136]
genistein
B
mouse
reduction of GAG storage in somatic organs
and the brain
[137,
138]
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Therapeutic
strategy
Drug/compound
Sanfilippo
disease subtype
Used model
Results
Reference
Substrate
reduction
therapy
genistein
B
mouse
behavior of animals was completely corrected
[138]
genistein
A, B
preliminary clinical
studies
decreasd GAG storage
[143,
144]
genistein
all
patients
lack of positive effects with low dose
[145]
genistein
all
randomized
controlled crossover
trial
decrease in GAG levels in urine and plasma, no effects
on total behavior scores
[146]
genistein
all
patients
high dose is safe in a long-term treatment
[147]
Other
therapies
miglustat
A
mouse
improved learning and some biochemical parameters
[150]
miglustat
A
patients
no improvement
[151]
Coenzyme Q
10
A, B
cell lines
Reduced GAG levels and enhanced exocytosis is some
cell lines
[152]
U1 snRNAs
cell lines
increased activity of the deficient enzyme
[153]
five non-
aminoglycoside
compounds
B, C
patients’ cell lines
some compounds causing an increase in the deficient
enzyme activities
[154]
trehalose
B
mouse
prolonged life span, reduced hyperactivity and anxiety,
reduction of neuroinflammation in the brain and retina
[156]
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Karolina Pierzynowska, Estera Rintz, Lidia Gaffke et al.
78
5.5. Other Therapies
There were also other therapeutic approaches tested for Sanfilippo
syndrome. An inhibitor of glycosphingolipid synthesis, miglustat (N-1-
butyl-2-(hydroxymethyl) piperidine-3,4,5-triol or N-butyldeoxynojiri-
mycin), which is a drug registered for therapy of Gaucher disease and
Niemann-Pick disease type C [148, 149], was assessed. MPS IIIA mice
treated with this compound revealed improved learning and some
biochemical parameters [150], but no improvement was observed in MPS
III patients [151].
Coenzyme Q
10
(CoQ
10
) was tested in experiments with MPS IIIA and
MPS IIIB fibroblasts, and some positive effects were reported, though the
results were different for different cell lines [152]. This research line needs
further studies to assess CoQ10 supplementation as a putative treatment
option in Sanfilippo disease.
Since in patients suffering from MPS IIIC, many mutations have been
mapped to conserved donor or acceptor splice sites, it was suggested that
medication of the splicing process might have therapeutic effects [153].
Therefore, modified U1 snRNAs which can recognize mutated donor sites
have been designed and tested in cellular models to assess their potential to
re-establish normal splicing. In fact, correctly spliced molecules could be
detected in this system, suggesting that modified U1 snRNAs might have a
therapeutic potential [153]. In the case of a mutation in the acceptor splice
site, a molecular chaperone – glucosamine – has been used, and increased
activity of the deficient enzyme could be detected relative to non-treated
cells [153]. These approaches indicate that the use of modified U1 snRNAs
and molecular chaperones might be considered in further works on
developing drugs for MPS III where splice site mutations occur.
If non-sense mutation is responsible for a disease, one of potential
therapeutic options is the use of compounds which are able to cause stop
codon read through. Different kinds of such molecules, including
gentamycin, geneticin and five non-aminoglycoside compounds, were
tested in experiments of cells derived from patients suffering from
Sanfilippo disease types B and C [154]. The obtained results were different
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Mucopolysaccharidosis Type III (Sanfilippo Disease) …
79
from different compounds, some causing an increase in the deficient
enzyme activities by 1.5-2-fold, while some showing no significant effects
[154]. Thus, this type of therapy has some potential in treatment of MPS
III, but improvement of efficiency is necessary before it can be considered
for clinical use.
Finally, it was suggested recently that stimulation of autophagy, a
cellular process devoted to degradation of damaged or unwanted
macromolecules and organelles, might be a potential therapeutic approach
for MPS [155]. Indeed, one of autophagy inducers, trehalose, has been
tested in MPS IIIB mice, and the results were encouraging. Namely, life
span of animals was prolonged, hyperactivity was reduced, as was anxiety,
and reduction of neuroinflammation in the brain and retina was evident
[156]. This work indicated a novel opportunity is searching for effective
therapy of Sanfilippo disease.
CONCLUSION
Sanfilippo syndrome (or MPS III) is a severe disease caused be HS
storage resulting from mutations in one of genes (SGSH, NAGLU,
HGSNAT or GNS) coding enzymes involved in degradation of this GAG.
Diagnostics of MPS III is based on assessment of clinical phenotypes,
determination of GAG levels in urine and/or plasma, measurement of the
activities of relevant enzymes, and identification of mutations in
corresponding genes. No therapy is currently available for this disease, but
there are various approaches to find effective treatment. The therapeutic
strategies for MPS III, and results of recent studies, are summarized in
Table 2.
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Karolina Pierzynowska, Estera Rintz, Lidia Gaffke et al.
80
ACKNOWLEDGMENTS
This work was supported by Fundacja Sanfilippo (Poland) and
National Science Center (Poland) (grants no 2017/25/B/NZ2/00414 and
2018/29/N/NZ2/00802).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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