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Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, 8, 9-25
9
Treatment of Lysosomal Storage Diseases: Recent Patents and Future
Strategies
Saida Ortolano1,*, Irene Viéitez1, Carmen Navarro1 and Carlos Spuch1
1
Neuroscience Research Group, Instituto de Investigación Biomedica de Vigo (IBIV), Xerencia de Xestión Integrada de
Vigo - SERGAS, Vigo, Spain
Received: October 31, 2013; Accepted: January 6, 2014; Revised: January 10, 2014
Abstract: Lysosomal storage diseases (LSDs) are a group of rare genetic multisystemic disorders, resulting in deficient
lysosomal activity. These pathologies are characterized by progressive accumulation of storage material within the
lysosomes, ultimately leading to organ dysfunctions. LSDs patient’s clinical outcomes have significantly improved, since
the advent of enzyme replacement therapy (ERT). ERT is approved worldwide for 6 LSDs: Gaucher disease, Fabry
disease, Mucopolysaccharidosis types I, II, and VI, and Pompe disease. The efficacy and safety of ERT for LSDs has been
confirmed by extensive clinical trials, however therapy with infused protein is life-long and disease progression is still
observed in treated patients. Obstacles to successful ERT, such as immune reactions against the infused enzyme,
miss-targeting of recombinant enzymes, and difficult delivery to crucial tissues (i.e. brain and bone), determine the need
for further research, in order to ameliorate therapeutic strategies. Viral gene therapy, stem cell based therapy, pharmacological chaperones and could be considered essential tools for future improvement of recombinant enzyme trafficking and
targeting. This review will discuss recent patents and new strategic approaches for enzyme delivery to highlight the most
relevant aspects, concerning next generation LSDs treatment.
Keywords: Enzyme replacement therapy, Fabry disease, Gaucher disease, gene therapy, hematopoietic stem cells transplantation, lysosomal storage diseases, pharmacological chaperons, substrate reduction therapy.
INTRODUCTION
Lysosomal Storage Diseases (LSDs) are inherited metabolic multisystemic conditions, affecting lysosomal function.
LSDs comprise a group of more than 50 rare disorders
which are caused by specific mutations in genes encoding
lysosomal enzymes, responsible for the degradation of a
wide variety of glycolipids, oligosaccharides, proteins and
glycoproteins (Table 1). Although often catalytically competent, the mutated enzymes are unable to overcome the efficient quality control of the endoplasmic reticulum, ultimately
causing reduced lysosomal trafficking, substrate accumulation and cellular dysfunction. Storage accumulation in different tissues is thought to underlie the clinical manifestations of LSDs and to eventually be the cause of organ failure
[1]. As a group, many of LSDs are progressive in nature,
share similar clinical evidences and in many cases leads to
premature death. Common signs seen in LSDs include skeletal defects, organomegaly, central nervous system defects
and coarsening of hair and facial features. Nevertheless, each
disease also has unique characteristics marked by its biochemistry and pathophysiology. Phenotypic heterogeneity is
also evident in individuals who share the same disease, due
to multiple organs involvement and differences in symptoms
*Address correspondence to this author at the Neuroscience Research Group
NC-CHUVI, Instituto de Investigación Biomedica de Vigo (IBIV), Biomedical Research Unit, Hospital Rebullón (CHUVI), Puxeiros s/n, 36415
MOS (Pontevedra), Spain; Tel: +34 986824871; Fax: +34 986487516;
E-mail: [email protected]
2212-3334/14 $100.00+.00
severity. For all these reasons, while the variety of therapeutic options for patients has greatly grown, the effective clinical management of these disorders remains an unfulfilled
challenge.
The multisystemic nature of these pathologies determines
that healthcare professionals of different expertise (such as
nephrologists, cardiologists, neurologists, pediatricians,
metabolic physicians, dermatologists, internists and general
practitioners) are involved in medical assistance to LSDs
patients during their lifetime. In order to provide the best
possible management to affected patients, physicians should
be well-aware of the signs and symptoms of individual
LSDs, as well as of their possible evolution and the time of
onset. However, patients’ identification is extremely difficult
during routine consultations, due to the low incidence of
LSDs in the population. Therefore, while collectively the
overall incidence of LSDs is relatively frequent, occurring in
about 1 in 4000 -8000 live births individually the LSDs are
rare with incidences ranging from 1:57000 (Gaucher disease)
to 1:4,200000 (sialidosis) [2].
Even though the incidence of LSDs is probably underestimated, as shown in recent screening studies enrolling newborns [3], delayed diagnosis is a commonplace in their
LSDs, due to the non-specific nature of disease manifestations arising during childhood. To provide patient an early
diagnosis, which is strictly related to efficacy of the available
treatments, is hence another partially unmet goal for clinicians.
© 2014 Bentham Science Publishers
10 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
Table 1.
Ortolano et al.
Molecular Basis of Frequent LSDs.
DISEASE
GENE
ENZYME
STORAGE PRODUCT
Tay-Sachs
HEX A
-Hexosaminidase A
GM2, Condroitin sulfate
Sandhoff
HEX B
-Hexosaminidase A/B
GL4, GA2, GM2
Fabry
GLA
-Galactosidase A
Gb3 LysoGb3
Gaucher
GBA
-Glucosidase
Glucocerebrosidase
GM1 Gangliosidosis
GLB1
-Galactosidase
GM1
Krabbe
GALC
Galactosylcerebrosidase
GalCer, Psychosine
Pompe
GAA
-Glucosidase
Glycogen
MPS I
IDUA
Iduronidase
Dermatin sulfate, Heparin sulfate
MPS II
IDS
Iduronate sulfatase
Dermatin sulfate, Heparin sulfate
MPS III A
SGSH
N-Sulfoglucosamine sulfohydrolase
Heparan sulfate
MPS III B
NAGLU
-N-Acetylglucosaminidase
Heparan sulfate
MPS III C
HGSNAT
Heparan--glucosaminide N-acetyltransferase
Heparan sulfate
MPS III D
GNS
Glucosamine (N-acetyl)-6-sulfatase
Heparan sulfate
MPS IVA
GALNS
N-Acetylglucosamine 6 sulfatase
Keratan sulfate, Chontroitin sulfate,
Keratin sulfate
MPS IV B
GALB1
-Galactosidase
GM1-ganglioside and Keratan
sulfate
MPS VI
ARSB
N-Acetylgalactosamine 4-Sulfatase
Dermatan sulfate
MPS VII
GUSB
-Glucoronidase
Chondroitin sulfate
Niemann-Pick A-B
SMPD1
Acid sphingomyelin phosphodiesterase 1
Sphingomyelin
Niemann-Pick C
NPC1-2
NPC-1 and NPC-2
Cholesterol, lipids
Infantile NCL
CLN1(PPT1)
Palmitoyl-protein thioesterase 1
Lipopigments
Late infantile NCL (CLN2)
CLN2 (TTP1)
Tripeptiyl-peptidase 1
Lipopigments
MLD
ARSA
Arylsulfatase A
Sulfatides
(CLN1)
Most of the lysosomal enzymes involved in LSDs are
glycoproteins that are synthesized in the endoplasmic reticulum and are transported via Golgi to the lysosome, although
a number of molecules are secreted from the cell. This proportion of secreted enzyme is available for recapture by the
same cell or neighboring cells that internalize and deliver the
protein into the lysosome. This characteristic of most of the
LSDs has allowed the development of therapeutic strategies
based on the exogenous administration of the enzyme (native
or recombinant) to the cells. Moreover, newer approaches
include the use of small molecules to enhance enzyme folding and stabilization of the active site (pharmacological
chaperon therapy) or to reduce the substrate synthesis [4].
Gene delivery and cell based therapy are also being evaluated for LSDs therapy in a considerable number of clinical
trials. These two approaches, aim to provide enough functional enzymes at surrounding tissues, through infection of a
few cells with viral vectors or by transfering a small amount
of donor cells to the organism in order to obtain significant
therapeutic effects Fig. (1) [5].
The aim of this review is to describe recent patents and
new strategic approaches for enzyme delivery to highlight
the most relevant aspects, concerning next generation LSDs
treatment.
ENZYME REPLACEMENT THERAPY
Enzyme replacement therapy (ERT) is based on the intravenous infusion of a recombinant wild type enzyme,
which is taken up into the cell through membrane receptors
(typically the mannose-6-phosphate receptor) and replaces
the catalytic action of the mutated lysosomal enzyme [6, 7].
ERT is available since 1996 [8] and is the sole kind of treatment approved for LSD patients, with the only exception of
a drug based on substrate reduction therapy (SRT) [9]. Efficacy and safety of ERT have been confirmed by extensive
Lysosomal Storage Diseases Treatment
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
11
A
ER
Lysosome
B
Stem cell
Golgi
D
Differentiated cell
Substrate
Viral Vector
C
Active enzyme
Synthetase
Inhibitor
Growth factor
Mutated enzyme
E
Chaperon
Fig. (1). Schematic view of the possible approaches for LSDs treatment
LSDs treatment can be approached through 5 different strategies: Gene therapy (A); Cell based therapy (B); ERT (C); SRT (D) and PC use
(E). In A, transgenic viral vectors encoding a functional enzyme are injected to the patients to infect target cells. Once in the nucleus, viral
DNA is transcribed and the functional enzyme is expressed in the endoplasmic reticulum (ER) and eventually traffics to the lysosome. In B,
HSC expressing functional enzyme are differentiated and injected to the patient. The enzyme secreted by stem cells, together with modulating factors, is taken up by patient’s cells through MP6R. In C, recombinant enzyme is directly infused in patient’s bloodstream or CSF and
taken up by cells trough the MP6R, here it traffics to the lysosome and hydrolyzes accumulated substrates. In D, an inhibitor of the enzyme
that synthesizes the substrate accumulated in patient cells is administrated to patient and carried over by the cell, where it is able to reduce
the synthesis of the storage material. In E, a PC binds the active site of a miss-folded enzyme at the ER and facilitates its transport to the
lysosome, where the chaperone is released due to low pH. Once in the lysosome, the mutated enzyme can partially perform its catalytic function.
clinical trials, nevertheless almost two decades of its use
highlighted important limitations for these drugs to actually
achieve remission of the pathology. Up to date ERT is available worldwide for 6 LSDs, including Gaucher disease (GD),
Fabry disease (FD), Pompe disease (PD) and Mucopolysaccharidosis (MPS) types I, II, and VI (Table 2).
Imiglucerase (Cerazyme, Genzyme) was the first recombinant enzyme for LSD therapy to be introduced in the market for Gaucher disease (GD) treatment [10] and was produced in Chinese Hamster Ovary cell line (CHO). This
product was followed by Velaglucerase alfa (Vpriv, Shire
Inc.), produced in a human cell line using gene activation
technology [11] and TaligluceraseAlfa, produced in a plant
cell line (Elelyso, Pfizer) [12]. In GD, the most prevalent
LSD, glucosylceramide is metabolized by -glucosidase (-
Glu), also called glucocerebrosidase, which removes the
linked glucose. All the three ERT compounds are recombinant forms of -Glu. A deficiency of this enzyme leads to
accumulation of glycosphingolipids in macrophages of liver,
bone marrow and spleen. Therefore, patients with GD exhibit hematological manifestations such as anemia thrombocytopenia, hepatosplenomegaly, skeletal deformation and
also neurological impairment [13]. While over 200 mutations
were identified for GD, 80% of the patients carries either the
N370S mutation or the L444P mutation, in at least one of the
alleles. The N370S is usually associated with Type I GD
which is related to a milder phenotype, due to prevalent accumulation of substrate in liver and spleen, while the L444P
mutation causes Type III GD, a more severe condition characterized for central nervous system (CNS) involvement [14,
15]. Treatment with ERT, is generally associated with
12 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
Table 2.
Ortolano et al.
Available ERT for LSDs.
DISEASE
KIND OF THERAPY
ACTIVE COMPOUND
PATENT
ERT
Imiglucerase
US5549892-1996
ERT
Velaglucerase alfa
US20110027254
ERT
TaligluceraseAlfa
US2008038232
SRT
Miglustat
US5525616
ERT
Agalsidase alfa
WO19989811206
ERT
Agalsidase beta
US5356804-1994
Mygalstat
US20020035072
PC
(Clinical trial phase III not approved)
US20040242539
ERT
Glucosidase alfa
WO0205841
ERT
–L-Iduronidase
US6426208
ERT
Idursulfase
US5932211
ERT
Galsulfase
WO2004043373
ERT in CSF
Rh Tripeptidyl peptidase 1
WO2007084737
Gaucher
Fabry
Pompe
MPS I
MPS II
MPS VII
Infantile NCL (CLN2)
(BMN190)
significant improvement in organ volume, anemia, thrombocytopenia and plasma levels of biomarkers. Long-term analysis
of the safety of imiglucerase therapy demonstrates a low rate
of adverse events and sero-conversion. The majority of frequently reported adverse events related to imiglucerase were
infusion-associated reactions which did not require discontinuation of treatment [16]. The success of ERT in GD is
strictly related to the fact that macrophages are the main target
for the enzyme and they can be efficiently accessed through
intravenous injection. However, the active compounds used
are not able to cross the blood brain barrier (BBB) and therefore reach the CNS, so that their efficacy in GD type III is
limited.
The first ERT treatment for Fabry Disease (FD) agalsidase beta (Fabrazyme, Genzyme) [17] was approved approximately 10 years ago and quickly followed by the development of agalsidase alfa (Replagal, Shire Inc.) [18], which
is available in Europe. Both active compound are recombinant forms of -galactosidase A (-Gal A), the enzyme
which is compromised in FD, and differs only for their glycosilation pattern, since agalsidase beta is produced in CHO
cells, while agalsidase alfa is produced in a human cell line
(clone RAG 001). FD was originally described in 1890, although the genetic cause of the disorder was detected over a
century afterwards [19]. Dysfunction of -Gal A, encoded by
GLA gene, causes globotrialosylceramide (Gb3) accumulation in the lysosomes of different cells, especially dermal
fibroblasts, cardiomyocytes vascular endothelial cells and
perineural cells Fig. (2). Due to its multisystemic involvement FD, may present a wide variety of clinical manifestations, although common symptoms are acroparesthesia, angiokeratomas, neuropathic pain, cardiomyopathy, renal failure and stroke. FD is an X- linked disease historically
thought to affect only men. Nowadays, it is understood that
females are also affected because of the random inactivation
of one of the X chromosomes so that it is possible that they
develop the disease with severe manifestations [20]. Trials
performed with either agalsidase alfa or beta showed similar
rates of safety and efficacy for both medicaments and lifethreatening side effects were absent. ERT treatment significantly reduced Gb3 concentration in heart and kidney and
also improved pain-related quality of life in patients up to six
months of treatment [21].
ERT treatment for PD is performed with glucosidase alfa
(Myozime, Genzyme) [22]. PD is determined by a deficit of
acid -Glucosidase (-Glu), an hydrolase responsible for the
cleavage of the -1,4- and -1,6-glycosidic bonds of glycogen, whose accumulation causes cellular dysfunction in mul-
Lysosomal Storage Diseases Treatment
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
13
Fig. (2). Immunofluorescence of Gb3 in skin biopsy of an FD patient. Gb3 deposit is highly marked in fibroblast and the fluorescence
pattern is compatible with intralysosomal localization
tiple tissues, especially affecting skeletal and cardiac muscles. The infantile onset of PD is characterized by generalized muscle weakness, hypotonia, hepatomegaly and hypertrophic cardiomyopathy that lead to death, typically during
the first year of life due to cardio-respiratory failure. Late
onset forms of PD feature a progressive muscle weakness
without significant cardiomyopathy [23].
ERT has been shown to reduce cardiac pathology and
delay the need for ventilator support in the infantile form of
the disease; however variable effects of the drug were recorded for adult patients presenting mainly skeletal muscle
involvement [24]. The explanation for this variability is unclear and contributing factors may include the age of onset of
the treatment, the extent of pre-existing damage, immune
responses, rapid preclearance of the recombinant enzyme
and poor accessibility to motor neurons [25, 26].
ERT has been also approved for three types of mucopolysaccharidosis, LSDs caused by the alteration of enzymes
which determine the accumulation of glycosaminoglycans
(GAGs). MPS I is related to a defect in -L-iduronidase,
causing accumulation of GAGs such as heparan sulfate and
dermatan sulfate. The clinical spectra of MPS I is very
broad, including a very severe form, known as Hurler disease, characterized by pediatric onset, facial coarsening, cardio-respiratory system impairment and neurologic involvement. However, MPS I may course with a milder clinical
phenotype, known as Scheie disease, generally diagnosed
during adulthood and manifesting signs, such as delayed
growth, scoliosis and joint stiffness. The intermediate condition, which is typically treated with ERT, is defined as
Hurler-Scheie disease [27]. Treatment of MPS I with –Liduronidase (Aldurazyme, Genzyme) [28] has shown improvement in skeleton size and reduction of hepatomegaly,
although the drug is not able to cross the BBB [29, 30].
Idursulfase (Elaprase, Shire Inc.) [31] is used for the treatment of MPSII or Hunter syndrome, an X-linked inherited
disease due to the impairment of iduronate-2-sulfate. The
disease, whose patients usually die within 2-3 years, courses
with osteo-articular involvement, skeletal deformations, hepato-splenomegaly, spinal cord compression due to malformation of the occipito-cervical vertebra, respiratoryobstructive-pathology and mental delay [32]. ERT with
idursulfatase ameliorate some clinical parameters and general life quality, however the drug is more efficient if treatment starts before the manifestation of neurologic symptoms,
against which the drug does not have significant effects,
since it can not cross the BBB. MPSVI is due to a deficit of
N-acetylgalactosamine-4-sulfatase, also called arylsulfatase
B, which is responsible for the catabolism of dermatan sulfate. Neurologic impairment is absent in MPSVI patients,
due to lack of heparan sulfate accumulation and therefore
these patients usually survive until adulthood [33]. Galsulfase
(Naglazyme, Genzyme) [34] is well tolerated and determines a
significant reduction in urinary excretion of dermatan sulfate
and a significant improvement in walking test [35].
During the last decade new expression systems have been
developed in order to increase production yield and reduce
costs of ERT [36].
Calhoun et al. [37] developed a system based on Baculovirus expression systems, which allow high yield production of recombinant –Gal A in insect ovary cell line from
Spodoptera frugiperda (Sf9). Recombinant enzyme was captured by Fabry patient‘s derived fibroblast allowing 59%
increment in enzyme concentration and complete activity
restoration. Similar results were found by Berent et al. for
the -Glu expressed in Bm5, Sf21 and High Five cells [38].
Fogher and Reggi [39] expressed human -glu, -glu,
and -gal A in plant Nicotina tabacum cultures, achieving a
yield of about 1.5% of total protein content from tobacco
seeds. Similarly, Pogue et al. presented an invention in
which tobacco plants expressed -Glu or -Gal A obtaining
typically 435000 units of enzyme from 1kg of tobacco,
which could be increased up to 140-160 milions units using
14 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
young actively growing transgenic Nicotina benthamiana
[40]. Using transgenic tobacco, Radin et al. [41] described
the production of native human -Gly and -L-iduronidase
with appropriate co-translational and post-translational
modifications.
A different strategy was used by Reuser et al. [42] who
developed transgenic mice secreting -Glu in their milk to
obtain a more human-like glycosylation pattern. The produced enzyme was active in Pompe patient’s derived fibroblasts at levels similar to those obtained with the recombinant enzymes produced in CHO and other cellular systems
used in production of approved drugs. Experiments performed in PD knock out mice showed an increment in -Glu
activity in the liver, spleen, heart and skeletal muscle. Clinical trials (phase I/II) showed reduction in glycogen storages
in animals receiving biweekly injections of the enzyme [43].
In spite of the partial amelioration of patient’s quality of
life determined by the use of ERT, all of these highly expensive treatments, failed to meet the expectations in terms of
efficacy and none of them is active against neurologic manifestations. A key factor to improve the effect of these therapies is the increase of enzyme bioavailability by controlling
immune reactions against therapeutic enzymes and other
degradation processes which may occur in the bloodstream.
Indeed a negative impact of antibody formation on therapeutic effects has been reported for GD, FD, MPS type I, and
PD, for which also autophagic build up was described [36].
Vaccaro et al. [44] used modified protozoan organisms derived from Leishmania trypanosome strains expressing Glu, -Gal, or hexosaminidase A, B, S. Modified protozoan
cultures could be used to purify the recombinant enzyme
from cell or cell supernatant, but also, and more interestingly, for direct administration of the protozoan cells and
in situ production of the enzyme (Bactofection), thus increasing local availability of the enzyme. In spite of the
therapeutic potential of this approach, preclinical trials have
to be carried out in order to check the safety of the treatment
and the possible virulence of the protozoan organism.
Recent works were also developed to improve the
amount of enzyme delivered to tissues by altering either the
ligand or the M6PR expression on target cells, in the attempt
to target organs with a key role in LSD physiopathology
[45].
Sly et al. [46] inactivated chemically the protein oligosaccharides by treating the enzyme sequentially with sodium
metaperiodate and sodium borohydrate. This treatment inactivates the two traditional recognition markers that mediate
rapid clearance from the blood by means of the mannose and
mannose6-phosphate receptors. This increased the half life in
circulation from 11 minutes to 18.5h. Efficacy of this enzyme was determined in MPS VII mouse model. After 12
weeks of treatment remarkable clearance of the storage materials in cortical neurons and visceral organs of mice was
observed.
Martini et al. Concino M [47] patented polypeptide sequences and polypeptide linkers to be potentially used in San
Filippo (MPSIII B) treatment. The polypeptide linker is
made up of sequential repeats of the following sequence
GAPGGGGGAAAAAGGGGG. This strategy is useful to
Ortolano et al.
target the recombinant enzyme in cellular types that do not
express the mannose receptor, since it is based on the insulin-like growth factor/cation-indipendent Mannose-6Phosphate Receptor M6PR (IGF-II/CI_MPR). Aerts et al.
[48] used a -Gal A substrate analogue like ceramidetrihexoside-sphingosine prior to intravenous administration of
the recombinant enzyme to bind catalytic site and prevent the
enzyme from interaction with chemical structure in the blood
stream resulting in undesired retention and reduced targeting.
The substrate also stabilizes the active site and prevent from
non physiological enzyme catalyzed reactions in the circulation. Arranz [49] chemically fused -Glu with a cell penetrating peptide which facilitates active transport through biological membranes into the lysosome. Conjugation with
DPV3 peptide did not affect enzyme activity and is taken up
into MPS VII fibroblasts, significantly improving degradation of intracellular GAGs.
Nevertheless, the most important limitation for ERT remains its poor capacity to specifically target deep layers of
many affected organs, including bone and brain, affected in
the most severe phenotypes. The development of new strategies to effectively target the brain and bone is a primary issue to improve quality of life for patients with LSDs. Experiments in tissue culture and in animal models have shown
increased efficiency of enzyme delivery for secondgeneration products and novel delivery systems are now under experimentation [50]. Neurologic symptoms represent
some of the most significant manifestation of LSDs in terms
of mortality. Indeed cerebrovascular events such as stroke
are a major risk factor for premature death in patients with
FD and CNS involvement is the worst consequence of MPSs
and GD type III among other LSDs.
To improve delivery to the CNS, intrathecal routes of
administration have been explored. Salamant-Miller et al.
[51] provided an effective method to distribute recombinant
enzymes to the CNS by intrathecal delivery, directly accessing the spinal canal through a lumbar injection of the
medicament. The injection into the cerebrospinal fluid allows the enzyme to reach different brain areas. In particular, this method is meant to be used in the treatment of
LSDs such as Krabb disease, Niemann-Pick Adisease and
MPS I, II, IIIA.
Recently, ERT have also been developed for the treatment of Late Infantile Neuronal Ceroid Lipofuscinosis
(NCL) [52, 53].
NCL is the general name for a family of at least eight
genetically separate neurodegenerative disorders that result
from excessive accumulation of lipofuscin in tissues. These
are autosomal recessive disorders of the CNS with general
fatal course which typically begin during childhood. NCLs
have been classified and named referring to the affected
genes. Up to date, linked different genes determining NCLs
have been identified: CLN1 (PPT1), CLN2 (or TPP1), CLN3,
CLN4, CLN5, CLN6, CLN7 (MFSD8), CLN8, CLN10
(CTSD) [54].
ERT for CLN2 is based on the recombinant form of
Tripeptidyl-peptidase 1, encoded by the TTP1 gene and
identified as BMN190. Biomarin started a phase1/2 clinical
trial (NCT01907087) to treat CLN2 by direct injection of
Lysosomal Storage Diseases Treatment
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
15
BMN190 in the cerebrospinal fluid using an intracranial
device.
of molecules preapproved for different medical indications
(Table 3).
All intra-cerebrospinal fluid ERT studies performed in
mice resulted in improved neurologic function and reduction
of neuropathological lesions has also been described in the
brain of dog models (MPS I, MPS IIIA) [55]. However, several questions remain regarding this approach, in particular
which route of injection (ventricular, cisternal or lumbar)
provides the most widespread distribution of the enzyme in
brain parenchyma; which type of enzyme delivery, bolus or
sustained, is preferable and, finally, what frequency of administration has to be applied. The intrathecal injection approach is currently being tested in clinical trials for MPSs.
(MPS I; NCT00638547 and NCT00852358; MPS II,
NCT00920647 and MPS IIIA; NCT01155778) [56]. Another
approach to cross the BBB was developed by Fogh et al.
[56], who produced recombinant -mannosidase fused at 5
end to the diphteria toxin translocation domain. Human fibroblasts were able to efficiently uptake the recombinant
enzyme, although in vivo evaluation was not carried out.
Sandhoff disease (SD) and Tay-Sachs disease (TSD) are
LSDs involving significant neurologic manifestations and
therefore ERT is not an adequate therapy. PC can be used to
reach the CNS and increase lysosomal translocation of mutant
-hexosaminidase (-Hex) subunits to provide an effective
therapy for both disorders [59]. -Hex is a dimeric enzyme
that is required for the removal of the terminal Nacetylgalactosamine from several glycosphingolipids (GSLs),
as well as from some glycoproteins and oligosaccharides.
-Hex can be formed by an and a subunit (-Hex A, heterodimer) or by two or subunits (-Hex S and -Hex B
homodimer, respectively). Genetic mutations in the -subunit
resulted in compromised activity of both -Hex A and -Hex
B leading to the accumulation of GSLs, GAGs, acetylgalactosamine and N-acetylglucosamine, which are responsible for
SD. On the other end, TSD results from mutations in the subunit, leading to -Hex A deficiency and the accumulation
of ganglioside GM-2 as major storage product, even though
acetylgalactosamine and N-acetylglucosamine are also accumulated [60].
On the other end, Stern et al. [57] produced chimeric
proteins comprising a polypeptide sequence selected from
leptin or granulocyte-colony-stimulating-factor (GCSf),
which can cross the BBB. They generated GCSf-hexosaminidase A and leptin -hexosidase conjugates to
intravenously infused Tay-Sachs disease mouse models with
the GCSf. Mice showed partially recovered enzyme activity
in the brain.
Finally, Boivin et al. [58] produced recombinant iduronate-2-sulfate as a fusion protein with Angiopep-2, specific
peptidic moieties (Lys-Arg-X3-X4-X5-Lys), which allow the
recombinant enzyme to cross the BBB and increase its activity in the lysosome compared to wild type enzyme. This
molecule may be potentially used for the treatment of MPS
type II.
PHARMACOLOGICAL CHAPERONES
LSDs treatment can be approached through the use of
small molecules which stabilize affected enzyme folding
(pharmacological chaperones) or reduce substrate synthesis.
A pharmacological chaperone (PC) is a specific inhibitor
that favors the correct folding of a mutated enzyme, avoiding
its degradation in the endoplasmic reticulum and enhancing
its activity. In LSDs treatment, the PC stabilizes the tertiary
structure of the lysosomal enzyme, allowing it to traffic
through the secretory pathway and reach the lysosome. Here
a catalytically competent enzyme is released upon acid hydrolysis of the PC and maintained in the active conformation
for an extended period of time [4].
Since the majority of PCs identified binds to the catalytic
site of the enzyme, substrate turnover is favored by high substrate concentration and by binders that present shorter halflife than the mutant enzyme as well as reduced binding affinity at lysosomal pH.
PCs for LSDs treatment have been designed and synthesized based on the structure of the natural substrate or alternatively identified through high throughput screening (HTS)
Mahuran et al. developed a series of carbohydrates as
possible PC agents for -Hex [61]. In particular, they identified the iminosugars acetamidodeoxynojirimycin, acetamidodideoxynojirimycin and a related acetoamido analogue of
castanospermine as potent inhibitors of -Hex. These compounds were found to increase enzymatic activity approximately 2.5 fold in TSD patient-derived fibroblasts and the
enzymatic levels were sustained for 24-48 h after drug removal [59].
HTS was performed to identify 24 initial hits among
50000 compounds; the most significant of them resulted to
be pyrimethamine, an approved antimalarial agent [62].
Pyrimethamine significantly increases enzymatic activity in
all the -subunit mutants evaluated, however it determines
an insufficient increase in enzymatic activity of the -subunit
mutants tested. In spite of this limitation, a clinical trial
Phase1/2 was initiated in patients with SD or TSD. The 8
treated patients showed significant enzymatic activity increase, however severe side effects, such as ataxia or blurred
vision, among others, appeared during the trial, causing suspension of the study [63].
PC therapy for FD was mainly developed using molecules mimicking the structure of D-galactose. Fan et al. [6466] described the use of 1-deoxygalactonojirimycin (DGJ),
as PC acting on -Gal A. Exposure to DGJ (0.2-20 μM) of
primary lymphoblast cultures from FD patients, caused a
concentration dependent increase of -Gal A activity which
was maintained for 5 days. The chaperoning action on the
mutated enzyme depends on the interaction of the NH group
of the iminosugar with the carboxylate of the aspartic acid
170 in the active site of the enzyme, as shown by crystallography [67].
In vivo studies with DGJ on FD transgenic mouse models
showed significant increase of -Gal A activity in heart, kidney, spleen and liver of the treated animals, as well as decreased levels of Gb3 in the affected tissues [68]. DJG is
16 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
Table 3.
Ortolano et al.
PCs to be used in LSD Treatment.
DISEASE
COMPOUND
PATENT
OH
Gaucher
HO
OH
WO2004037373
OH
N
8
OH
HO
OH
WO2013075227
US20130184352
OH
N
8
OH
HO
OH
US20030119874
OH
N
8
OH
HO
OH
US5844102
N
H
N
N
WO2012078855
N
NH
O
O
O
O
S
O
N
WO2009049422
N
N
N
S
Lysosomal Storage Diseases Treatment
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
17
Table (1) contd….
DISEASE
COMPOUND
PATENT
OH
H
N
Tay Sachs
OH
WO2004103368
Shandon
O
OH
X
N
H
OH
HO
OH
WO2006125141
Pompe
WO2007150064
OH
N
H
OH
HO
OH
OH
HO
OH
US20020035072
Fabry
US20040242539
OH
OH
N
H
N
H
R1
O
R3
P
O
N
R2
WO2005051331
Newmann-Pick
O
Rn
(CH2)m
HO
O
OH
Krabbe
WO2009061906
N
OH
HO
OH
OH
N
WO2008034575
Gangliosidosis
H
N
O
O
currently the active component of mygalstat hydrochloride, a
new potential drug that is currently being evaluated for
treatment of FD in phase 3 clinical trials [69].
Patent by Elfrida and Do [70] describes a method to predict the response to a PC-based treatment of FD. In particular, the invention provides an in vitro assay for determining
-Gal A responsiveness to a PC such as 1-deoxygalactonojirimycin in a cell line expressing a mutant form -Gal A, the
same method is potentially applicable as diagnosis method
for FD patients.
Sawkar [71, 72] and co-workers found that N-(nnonyl)deoxynojirimycin can increase -Glu activity in cell
based assays acting as a PC in GD therapy. This molecule
allows a 1.65 fold increase of enzyme activity in homozygous cells carrying the N370S mutation, persisting during 6
days. Nevertheless, the same compound did not affect -Glu
activity in cells derived from subject carrying the homozygous mutation L444P, associated with GD’s most severe
phenotype. Following N-(n-nonyl)deoxynojirimycin many
other iminosugars analogues were developed and tested on
18 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
patient’s derived cells: among them 1-adamantylcarboxamide
was able to increase enzyme activity in N370S and G202R
mutants, but not in L444P.
N,N-Disubstituted carboxamide chaperones were patented by Mahuran et al. and resulted in 1.6 fold increased
activity for -glucosidase in N370S affected patient’s derived fibroblast [73-75].
Yu et al. [76, 77] designed -1-C-alkyl iminosugars to
act as PCs in GD and found about 2 fold increased -Glu
activity, following treatment of N370S mutant cells with one
of the synthesized analogues. The same compound also determined a modest increase (1.3 fold) in enzyme activity in
cell derived from patients carrying the in L444P mutation.
Fan et al. [78, 79] identified isofagamin as a promising
lead structure for the treatment of GD and were able to show
increased -Glu activity in cells derived from N370S and
L444P affected patients. The tested azasugar causes a conformational change in the enzyme revealing a hydrophobic
groove postulated to interact with the ceramide moiety of the
natural substrate [80]. The obtained results were confirmed
following treatment of mutant L444P mice and put the basis
for Phase 1 and 2 clinical trials, which unfortunately were
afterwards discontinued, failing to show a clinically meaning
full end point in most of the involved patients.
It is worth noting that the biological activity of the described compounds in GD treatment is due not only to the
carbohydrate mimetic portion of the molecule interacting
with the active site, but also to the contribution of the long
alkyl chains mimicking the ceramide portion of the substrate
and helping to cross cell membranes.
Maegawa et al. [81] performed a HTS of FDA approved
compounds to find good PC candidates for GD therapy.
Among the analyzed molecules, ambroxole was able to stabilize N370S mutated -Glu. Activity was increased in patient’s derived cells homozygous for the N370S mutation. In
an extensive HST study designed with the goal to find molecule increasing traslocation to the lysosome, Marugan et al.
[82] found quinazoline compounds able to stabilize -Glu.
At the same time they identified pyrazolopyrimidine as a
class of non-inhibitory compounds which can stabilize the
mutated enzyme and improve its trafficking. These molecules are of particular interest for their ability to cross the
BBB [83, 84].
Finally, an inhibition-based primary screen identified
5[(4-methyl-phenyl)thio]quinazoline-2,4-diamine [85] which
demonstrated a 2.5 fold increased -glu activity when used at
12.5μM on cells derived from patient carrying the N370S
mutation [86]. This compound is also active to stabilize galactosidase (-Gal) and can be potentially used also in PC
therapy of Gangliosidosis and Morquio B disease (MPS IV
B), which are caused by a deficit of this enzyme. Compromised -Gal activity in gangliosoidosis leads to lysosomal
accumulation of glycolipids associated to severe neurodegeneration. On the other end, Morquio B disease mostly affects skeletal system and has little if any neurological involvement. The different phenotypes in the two diseases
seems to be mutation related. Iminosuguras derivates of galactose were also considered for the PC treatment of these
Ortolano et al.
pathologies. Suetz et al. [87, 88] synthesized a series of
DGJ-analogs, which were tested in Gangliosidosis patient
derived fibroblasts, however these compound were little effective against the most severe forms of the disease [89].
A possible PC therapy for Krabbe disease was developed
by Lee et al. [90]. Krabbe disease or globoid cell leukodystrophy is caused by low galactocerebrosidase activity resulting in the accumulation of the highly toxic GSL Galactosylsphingosine. The disease is characterized by severe demyelization with apoptosis of oligodendrocytes, since Galactosylsphingosine is a major component of white matter,
which is also metabolized by galactocerebrosidase. The consequence of this is a profound neurodegeneration and premature death. Following HTS, Loboline was identified as a
weak inhibitor of galactocerebrosidase in D528N mutant cell
lines, showing a 50% increase in enzyme activity. However,
this compound presented significant BBB penetration and
can be considered as an optimal leading molecule for chaperoning therapy [91].
Okumiya et al. [92-94] tested 1-deoxynojirimycin and
several N-alkylated analogues in cultured fibroblast cell lines
from PD patients. These iminosugars are 10x to 250x more
selective for -Glu compared to -Glu form. In details, 1deoxynojirimycin showed increased activity in 2 out of 5
tested cell lines. Cell lines derived from patients carrying
many different mutations (ej.L552P, S529V, A445P, R432C)
were tested and give satisfactory results in chaperoning activity for -Glu [95-97]. Preliminary studied of 1deoxynojirimycin administration to PD mouse model
showed daily important reduction of substrate in heart, diaphragm, gastrocnemius, soleus and brain [98]. Compound
AT2220 is being evaluated in a phase 2 clinical trials and at
lower doses to avoid toxicity.
Schuchman and Desnick [99] patented a molecular chaperon of potential use in Niemann-Pick disease type A and B
to improve activity of sphingomyelinase. The lysosomal
storage disorders Niemann-Pick disease, SMPD1-associated
(Type A and B) are characterized by deficiency in acid
sphingomyelinase, caused by a mutation in the SMPD1 gene.
Mutations to this gene are more commonly found in those of
Ashkenazi Jewish descent (1:80-1:100) or of North African
descent. Niemann-Pick Type C (NPC) is also a lysosomal
storage disorder, but instead is caused by mutations in either
NPC1 or NPC2 gene. These PCs are based on the structure
of sphingomielin, ceramide or phosphonucleotide analogues
[100].
SUBSTRATE REDUCTION THERAPY
Substrate reduction therapy (SRT) consists in the use of
an inhibitor for an enzyme which is involved in the synthesis
of the substrate for the affected enzyme. At present the only
SRT approved for GD is based on N-butyldeoxynojirimycin
(Miglustat) administration Fig. (3) [101]. This active principle inhibits glucosylceramide synthase avoiding glycosphingolipids accumulation. Miglustat may only be used in the
treatment of GD type 1 patients for whom enzyme replacement therapy is unsuitable and it has been approved in the
European Union for the treatment of progressive neurological manifestations in adult or pediatric patients with Niemann-Pick type C disease (NPC) [102].
Lysosomal Storage Diseases Treatment
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
OH
also in clinical trials, such as the one for metachromatic leukodystrophy (MLD) (NCT00633139).
HO
OH
MLD is autosomal recessive LSD caused by mutations in
the ARSA gene and leading to the deficiency of the arylsulfatase A, which causes widespread demyelinization and neurodegeneration. In 2010 clinical trials have been started testing lentiviral vectors to transfer ARSA gene in bone marrow
derived hematopoietic stem cell. Biffi et al. found that the
treatment halted disease manifestations in presymptomatic
children with late-infantile MLD, who were followed during
24 months [105, 106].
OH
N
N-butyldeoxynojirimycin (Miglustat)
US5525616 (1996)
Mucopolysaccharidosis VII (MPS VII, Sly disease) is the
inherited metabolic disorder with the highest number of trials
performed, exploring different alternatives to reach the CNS
[107]. Davidson et al. [108] expressed the -glucoronidase
gene to intravenously infuse a feline immunodeficiency virus
(FIV)-derived retrovirus, which was capable to treat and
prevent visual and neurologic alterations of the disease.
Fig. (3). Compound used for SRT of GD. Structure of Nbutyldeoxynojirimycin (Miglustat), the active compound of an approved therapy for GD based on SRT.
STR is also used for the treatment of infantile nephropathic cystinosis, a rare genetic disease due to dysfunction
of cystinosine transporter expressed in lysosomal membrane.
Cysteamine is used in these patients to convert accumulated
cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can pass through the lysosomal membrane of patients with cystinosis [103].
AAV-based constructs were also designed for the treatment of MPSVII. AAV vectors are gene transfer tools that
largely contributed to the advances of biologic therapies in
recent years, owing to their low immunogenicity, no pathogenicity, and stability [109].
The same active compound has also been used to treat
NCL related to PPT1 which is involved in lysosomal degradation of S-fatty acylated proteins [104].
Patent by Podsakoff [110] describes AAV vectors expressing -glucuronidase for potential therapy of MPS VII.
Intravenously injected animals presented long term expression of the gene and significant reduction of GAGs storage
in tissues. Moreover intrathecal injection of the same vector
into the cerebrospinal fluid, to both neonatal and adult
animals, results in therapeutic levels of -glucuronidase into
the brain and the complete elimination of GAGs storage in
the tissue. Promising preclinical tests were also undertaken
in dog models of MPSI and MPS III B to access efficiency
of AAV-based gene therapies in short to medium terms
[111-114].
GENE THERAPY
An array of different viral vectors and viral serotypes,
including lentivirus, adenovirus, and adeno-associated virus
(AAV) has been tested in the last decades to achieve gene
therapy of LSDs and in particular to achieve remission of
neurological manifestations (Table 4).
These innovative methods for delivering recombinant
enzymes into the CNS increased in interest, following the
successful results obtained not only in animal models, but
Table 4.
Gene and Cell Therapy Based Clinical Trials for LSDs.
Disease
Vector
Delivery Method
Patent
Clinical Trial
MLD
Lentivirus
Intravenus infusion
WO2010125471
Phase I/II IT0019
NCT00633139
MPSVII
(FIV)-Derived retrovirus
Intravenus infusion
WO2000073482
Phase I US07-58
MPSI
Retrovirus
Intraperitoneal
US20040023218
FR0005
POMPE
AAV1
Intramuscular
US20080069803
(Sly disease)
Phase I/II
NCT00976352
Late Infantile NCL
AAV2 /AAVrh10
Intracraneal
WO2008154198
(CLN2)
Phase I
NCT00151216
NCT01161576
Infantile and Late infantile NCL
Neural stem cell transplantation
Neurosurgical transplantation
US20026497872
NCT00337636
HSCT
Bone marrow transplant
US2007009500
NCT00668564
(CLN1 and CLN2)
Niemann-Pick
19
20 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
Moreover, Podsakoff et al. registered patents [115,116]
for AAV1-mediated gene transfer into muscle tissue of GAA
gene, encoding acid -glucosidase, to treat PD. PD is a good
candidate disease to test the intramuscular injection route of
administration, since the affected isoform of the enzyme is
mainly expressed in the muscle. Muscle delivery can be considered for treatment of metabolic diseases only when low
levels of expression are required and when there is no need
for secretion of the transgene. Efficiency of these constructs
is being tested in an ongoing clinical trial (NCT00976352)
through a series of intra-diaphragmatic injections. Initial
safety and ventilatory outcomes of these trials were published this year [117].
Intraparenchymal injection was also attempted to reach
global delivery of viral vectors in the brain in LSDs severely
affecting CNS such as NCL [118-120] and Niemann-Pick A
disease [121].
AAV serotype 2 vector expressing the human CLN2
cDNA (AAV2 CU h-CLN2) was administered to 12 locations in the CNS of 10 children with late infantile NCL.
However, the treatment resulted in death in one of the patients due to serious adverse effects, the etiology of which
could not be determined and was not apparently related to
the vector AAV2 CU hCLN2. Assessment of the neurologic
rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared
with control subjects. In a second study the vector was injected in rats and monkeys to establish a safe dose to be used
in clinical trials on human patients [54].
Dodge and Cheng also [120] provided methods to deliver
a gene to the CNS and affected visceral organs by intraventricular administration of a recombinant neurotrophic AAV
based viral vector, expressing other defective enzyme related
to LSDs. These constructs encode genes linked to alterations
in the CNS, such as Niemann-Pick A or B, Hurler disease,
Hunter disease, Sly disease and GD. As an example, Nacetyl glucosamine-1-phosphotransferase is targeted to the
central nervous system in subjects having Mucopolysaccharidoses (MPS) by the administration of recombinant AAV4
encoding this transgene.
Patent by Passini [121] describes a suitable method for
therapeutic approach of LSDs affecting the CNS, such as
Niemann-Pick Type A and Type B. The method consists in
contacting an axonal ending of a neuron with a high titer of
AAV carrying a therapeutic transgene (e.g. acid sphingomyelinase), so that the vector is axonally transported in a
retrograde fashion and the product can be expressed distally
to the administration site. The invention is based in part on
the discovery and demonstration that the injection of acid
sphingomyelinase into the diseased brain of an animal model
resulted in protein expression within multiple distal sites
consistent with the topographical organization of the projection neurons that innervate the injection site. In particular,
AAV-9 has shown high transduction efficiency when delivered intracranially as a result of axonal transport. Additional
studies will be required to identify the disease specific molecular signature of the brain endothelium in humans, which
may differ from those of experimental animals.
Ortolano et al.
Sena-Estevez et al. [122] produced constructs that can
efficiently reach the brain of patients and are potentially useful for gene therapy of TSD, SD and GM1-gangliosidosis.
The two constructs are based on AAVrh8 and respectively
express the -subunit and -subunit of -N-acetylhexosaminidase. The active compounds are administred in didderent brain areas (i.e., thalamus, striatum, deep cerebellar nuclei, ventral tegmental area, and lateral ventricles) through an
injection in the CSF.
For FD Yew et al. [123] developed recombinant viral and
non viral vectors comprising a gene encoding the human
lysosomal enzyme -Gal A capable of transducing the target
cells and producing a sustained expression of the gene.
Similar approaches, based on AAV vectors, were proposed by Desmaris et al. for Hurler disease and MLD [124],
as well as by Mahuran et al. for the treatment of GD [125].
CELL BASED THERAPY
Cell-based therapy has also been explored to deliver
genes of interest in the brain and potentially treat LSD patients. The introduction of gene-modified or un-modified
cells into LSD patient may be undertaken in two ways: direct
CNS implantation or engraftment outside the brain, most
commonly involving hematopoietic stem cell transplantation
(HSCT).
Direct engraftment of human CNS stem cells into the CNS
has been used in a completed clinical trial in infantile and late
infantile neuronal ceroid lipofuscinosis (NCT00337636). Trials demonstrated the feasibility of this approach and the absence of transplantation-related serious adverse events,
which supports further exploration of human CNS stem cells
transplantation as a potential treatment for select subtypes of
NCL. [126, 127]. It was also reported that immunosupression by mycophenolate, may be useful in slowing down the
progress of CLN3 related NCL [128].
Shihabuddin et al. [129] disclosed methods for treating
lysosomal storage diseases that affect the CNS. The method
involves administering non-immortalized neural stem cells
secreting lysosomal hydrolases into the brain. In particular,
this invention claims a possible treatment for Niemann-Pick
A disease.
Greater research focus has been spent examining the engraftment outside the brain [130]. This therapeutic approach
consists in HSCT of autologous cells that have been genetically modified to express the missing protein. Three clinical
trials are currently underway to acces the efficacy of modified hematopoietic stem cells in MPSII, MPSVII and MLD
[131]. Related to this, a recent report indicates an excellent
survival rate, resolution of hepatosplenomegaly and stabilization of cardiovascular problems in children with MPSII
treated with bone marrow transplantation; however neuropsychological outcomes were variables and did not show a
convincing evidence of neurological benefit [132].
Autologous HSCT has also been successfully carried out
in patients with Niemann Pick C type 2, at early age (16
months). Follow up of patients during 5 years highlighted the
Lysosomal Storage Diseases Treatment
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
absence of respiratory compromising and gross motor developmental progresses [133].
Ramaswamy [134] developed a method for transgene
expression in cells by homologous recombination. This invention involves the use of dominant-negative and loss of
function mutations in components of the intracellular Golgi
to lysosome sorting pathway as a mean to enhance the secretion of one or more lysosomal proenzyme in somatic cells
providing a treatment for LSDs, particularly in neuronal
cells. In particular, homologous recombination may be used
to engineer therapeutically useful cells, such as glial progenitor cells, mesenchymal stem cells and astrocyte precursor
cells, to enhance secretion of one or more lysosomal enzymes. Gain-of-function or loss-of-function mutations in
components of the intracellular Golgi to lysosome sorting
pathway are used to enhance secretion of one or more
lysosomal enzymes.
Garbuzova-Davis et al. [135] patented a method for treating a fetus or embryo suspected of having congenital conditions including San Filippo's syndrome, Hunter's syndrome,
Hurler's syndrome, TSD, GD, von Gierke's disease, PD,
among others. The method involves intravenous injection of
human umbilical cord blood cells expressing lysosomal enzyme to a mother carrying a fetus of embryo affected by a
specific inborn metabolic error.
Finally, Van der Loo et al. [136] patented optimization
methods for a successful genetic correction of diseases, mediated by hematopoietic stem cells. This invention accesses
minimum HCS chimerism and gene dosage for correction of
a hematopoietic disease, such as sickle cell anemia. The invention further relates to a method of improving and/or correcting one or more CNS abnormalities caused by one or
more lysosomal storage disease. The invention also relates to
methods of improving titer in transfection-based bioreactor
culture production or transfection-based production systems
using eukaryotic cells.
CURRENT & FUTURE DEVELOPMENTS
In spite of the great efforts and the achieved advances in
the field of LSDs treatment, these diseases are still lifethreatening and limiting, with respect to quality of life, for
many patients. ERT represented an enormous improvement
for some LSDs affected individuals, but also revealed to
have numerous limitations to reach the target of pathology
remission. As an example, some studies reported that ERT
provides only minimal improvement on cardiovascular parameters in FD patients [137]. The main limitation associated to ERT such as high cost, immunologic response and
lack of efficacy to CNS represents significant challenges for
future development of new drugs.
PC are low-cost promising tools to cross the BBB and
improve the drug action on the CNS, however they also present challenges to face for their improvement, especially
regarding the fact that in the majority of the cases they are
active only for specific mutations. In addition, the effects of
PC on the glycosylation pattern of the protein, which influence translocation process to Golgi, endosome and
lysosome, have not been clarified.
21
On the other hand, gene therapy vectors seem to be a
good option for complete remission of the pathology, but
they presents enormous difficulties to establish safe administration regime and it is difficult to foresee long term undesired effects. Moreover some of these treatments are often
associated to invasive route of administration, which does
not meet patient compliance.
At the same time, all the proposed strategic therapies are
probably really effective only if associated with early onset
of the treatment and presymptomatic diagnosis, as all the
described therapeutic tools will have little efficacy to revert
preexisting tissue damage.
A feasible and possibly effective strategy to improve
LSDs therapies can be the combination between ERT and
PC. Single PC administration previous to ERT can stabilize
the recombinant enzyme while in the neutral pH environment of the blood and therefore ameliorate immune response
and ERT half-life facilitating cellular uptake. Successful
combination therapies have already been described for GD,
PD and FD in preclinical studies [138-140] and are under
study in clinical trials for FD and PD (NCT01196871,
NCT01380743).
Another promising approach for a new treatment could
be the correction of the genetic defects through the implant
of modified HSC, which may help to overcome toxicity
problems related to viral vector based gene therapy. However, cell based therapy has to be still considerably implemented and also issues related to ethical debate on the source
of donor cells have to be taken into account.
Even though LSDs treatment is still an unmet clinical
need, the great efforts of the scientific community testified
by the wide number of clinical studies and patents registered
in the last decade allow being optimist on the evolution of
therapeutic strategies for the near future.
CONFLICT OF INTEREST
Shire Pharmaceuticals Iberica granted a research project
to CN, SO and IV collaborated in the development of this
project and CS declare no conflict of interest.
ACKNOWLEDGEMENTS
The authors wish to thank Tania Vazquez-Santos for
proof revision.
Research activity of the authors is supported by grants
from the “Instituto de Salud Carlos III” (PI11/00842 to S.O.,
PI10/02628 to CN) and European Union funded projects:
Spain-RDR (IRDiRC), BIOCAPS (FP7/REGPOT-20122013.1, agreement no. 316265).
ABBREVIATIONS
AAV
=
Adeno Associated Virus
BBB
=
Blood Brain Barrier
CHO
=
Chinese Hamster Ovary
CNS
=
Central Nervous System
22 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014, Vol. 8, No. 1
CSF
=
Cerebral spinal fluid
[10]
DGJ
=
1-Deoxygalactonojirimycin
[11]
ERT
=
Enzyme Replacement Therapy
[12]
FD
=
Fabry Disease
GM
=
Ganglioside
[13]
GD
=
Gaucher Disease
[14]
GAG
=
Glycosaminoglycans
GSL
=
Glycosphingolipid
[15]
HSCT
=
Hematopoietic Stem Cell Transplantation
[16]
HTS
=
High Throughput Screening
LSD
=
Lysosomal Storage Disease
M6PR
=
Mannose-6-Phosphate Receptor
MLD
=
Metachromatic Leukodystrophy
MPS
=
Mucopolysaccharidosis
NCL
=
Neuronal Ceroid Lipofuscinosis
PC
=
Pharmacological Chaperone
PD
=
Pompe Disease
SD
=
Sandhoff Disease
SRT
=
Substrate Reduction Therapy
TSD
=
Tay-Sachs Diseases
-Gal A
=
-Galactosidase A
-Glu
=
-Glucosidase
-Gal
=
-Galactosidase
-Glu
=
-Glucosidase
-Hex
=
-Hexosaminidase
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
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