Review
Emerging therapies and
therapeutic concepts for
lysosomal storage diseases
1.
Background
2.
Medical need
3.
Existing and emerging
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therapies
4.
Competitive environment
5.
Expert opinion
Thomas Kirkegaard
Orphazyme ApS, Copenhagen, Denmark
Introduction: The success of the first enzyme replacement therapy (ERT) for a
lysosomal storage disease (LSD) and the regulatory and commercial incentives
provided by authorities for orphan and rare diseases has spawned a massive
interest for developing drugs for these intriguing but devastating genetic disorders. The potential for new drugs in this arena is vast, as not only a high
number of LSDs have no available therapy, but also alternative therapeutic
approaches for diseases with existing treatment are much needed as a number of challenges facing the existing therapies have become very obvious.
A significant unmet medical need is therefore apparent for most, if not all
of the LSDs and the development of new therapies based on the increasing
knowledge of the pathophysiological mechanisms involved in these devastating diseases is therefore anticipated with great interest from all stakeholders.
Areas covered: The reader will be introduced to the intricate biological processes involved in lysosomal regulation and how these are exploited for current and emerging therapies. Therapies utilizing these processes will be
thoroughly reviewed with regard to their mechanism of action, their clinical
status and the challenges they are faced with and/or are aiming to address.
For this review, a literature research has been undertaken that covers the
years 1955 -- 2012.
Expert opinion: The interest in lysosomal biology and disease has surged over
the past decade not only in the halls of science but also of pharmaceutical
companies. As the complexity of the LSDs increasingly become revealed, so
do novel therapeutic targets continuously nurturing the development of
new candidate drugs for these devastating diseases. Among this multitude
of approaches, the ERTs still account for the vast majority of approved therapies but a number of exciting alternative approaches are emerging targeting
various components of the pathophysiological cascade. This evolution of the
field is much needed as the presently available treatments are unable to
address all clinical aspects of these multifaceted diseases. Future therapy will
most likely consist of combinations of these established and emerging
approaches as well as other yet to be discovered concepts as the complexity
of the diseases demands a certain degree of humbleness to the expectations
for a cure based on a single therapy.
Keywords: chaperone, enzyme replacement, Fabry disease, Gaucher disease, glycosphingolipids,
lysosomal storage disease, lysosomes, substrate optimization, substrate reduction, therapy
Expert Opinion on Orphan Drugs (2013) 1(5):385-404
1.
Background
Since the discovery and initial characterization of lysosomes by Francois Applemans, Robert Wattiaux and Christian de Duve in 1955 [1-3], the interest for this
still enigmatic organelle and its close relatives has seen a resurgence in the past
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T. Kirkegaard
two decades spurred by the rediscovered and increasing realization of their crucial roles in physiological homeostasis.
The interest in lysosomes from not only academia but also
biotech and pharma has been further kindled by a number
of clinical, regulatory and commercially transforming events
that have provided a new paradigm for developing therapies
for not only lysosome-related diseases but also other rare
and orphan diseases.
With the introduction of the Orphan Drugs Act in the
USA in 1983, which was followed by similar legislation in
Singapore (1991), Australia (1993), Japan (1997) and the
EU (1999), a regulatory framework has been laid down for
guiding the development of drugs for rare diseases with highly
unmet need. However, the commercial potential of developing drugs for lysosomal storage diseases (LSDs) was not realized until the development of Cerezyme (recombinant
glucosylceramidase (glucocerebrosidase) for the treatment of
type I Gaucher disease) by the Boston-based biotech
company Genzyme.
The scientific rationale for the development of lysosometargeted therapies however predates the advent of Cerezyme
by several decades and driven by the re-kindled interest in
lysosomal diseases several novel therapeutic concepts and
therapies are now emerging for these devastating disorders.
Lysosomes
As the main compartment for intracellular degradation and
subsequent recycling of cellular constituents, the lysosomes
receive both hetero- and autophagic cargo, which in the
lumen of this multifaceted organelle find their final destination. The degradation is carried out by a number of acid
hydrolases (glycosidases, proteases, sulfatases, lipases, etc.)
capable of digesting all major cellular macromolecules [4].
These acid hydrolases function optimally at the acidic pH of
the lysosomes (pH 4 -- 5) although several can still function
and have distinct roles at the neutral pH outside the lysosomes, albeit having decreased stability and/or altered
specificity [5].
Until recently, the function of many of these enzymes was
thought to be limited to intralysosomal macromolecule
turnover. However, from the complex and diverse clinical
presentation of the diseases originating from lysosomal malfunction and involvement in neoplastic events it is clear that
the lysosomes have an absolutely critical role in physiological
homeostasis [6,7]. As such, the potential impact of therapeutically addressing the lysosomes and their constituents should
not be underestimated.
Interestingly, recent data suggest that the biogenesis and
functioning of endosomal and autophagosomal pathways is
partially controlled by the transcription factor EB (TFEB),
which regulates a coordinated lysosomal expression and regulation (CLEAR) gene network [8], a finding which argues for
an evolutionary need to intimately control and efficiently
adapt the lysosomal system to rapid changes in the cells
metabolic state.
1.1
386
Dynamics of the lysosomal system
The intracellular trafficking of vesicles involved in, or related
to, the lysosomal system, serve an essential role in the mammalian cell through its delivery of membrane components,
various solute molecules and receptor-associated ligands to a
range of intra- and extracellular compartments. The main
pathways involved in this system are depicted in Figure 1,
along with highlights of the various facets of these pathways
being targeted for therapeutic intervention in the LSDs
(Figure 1).
As a testament to the importance of this system and its constituents, defects in any part of it leads to a number of severe
diseases or syndromes. Be it defects in lysosomal exocytosis
(e.g., Chediak--Higashi syndrome), reduced lysosomal catabolic efficacy (e.g., Niemann--Pick disease types A and B
and Gaucher disease), lysosomal transport machinery defects
(e.g., Griscella syndrome and Charcot--Marie--Tooth disease),
lysosomal metabolite efflux impairment (e.g., Niemann--Pick
type C and cystinosis/Fanconi syndrome) or dysfunction of
lysosomal integral membrane proteins (e.g., Danon disease),
the disease most often affect multiple organs and tissues,
involves the central nervous system (CNS) and is often fatal
at a young age in its aggressive forms [7,9-13].
In order to understand the complexity of the LSDs and
why defects in this refined machinery can lead to such detrimental clinical manifestations as well as grant the reader an
initial overview of the possibilities that might exist for therapeutic intervention, a brief description of the inter-relations
in the lysosomal system is provided below.
1.2
Endocytic route to lysosomes
The best understood endocytic pathway, which is also extensively exploited in enzyme replacement therapies (ERTs) for
the LSDs, is the receptor-mediated endocytosis of molecules
via the formation of clathrin-coated pits [14]. In the conventional receptor-mediated endocytic pathway, receptors such as
the transferrin receptor, the low-density lipoprotein receptor
and the mannose 6-phosphate receptor (M6PR) concentrate
into clathrin-coated pits on the surface of the plasma membrane and form early endosomes [15,16]. Although the majority
of lysosomal enzymes are targeted to the lysosomes from the
trans-Golgi network (TGN) through mannose-6-phosphate
(M6P)-mediated binding to M6PRs in the medial Golgi and
then released once the Golgi-derived transport vesicles fuse
with late endosomes (detailed in Section 1.2.2), some amounts
of lysosomal enzymes are destined for secretion and subsequent
reuptake from the extracellular space via plasma membrane
receptors that are either the same or similar to those involved
in intracellular sorting and the biosynthetic route to the lysosomes [15]. This concept developed from a number of metabolic
complementation studies in cells from patients with different
LSDs and is the fundamental principle for enzyme therapies
of LSDs [17].
As the endosome mature, its luminal pH steadily drops,
mainly through the action of the vacuolar-type proton
1.2.1
Expert Opinion on Orphan Drugs (2013) 1(5)
Emerging therapies and therapeutic concepts for lysosomal storage diseases
Molecular chaperone (Hsp70)
or 2nd generation ERT
Alternative receptor
system: e.g. LRP-1
ECM
Exosome
Exogenous (ERT) or secreted
enzyme (BMT/HSCT)
Mannose-6-phosphate receptor
CYTOSOL
Endocytic recycling compartment
Secretory lysosome
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Early endosome
Lysosome
Sorting endosome
Late endosome
Golgi secretory
pathway
Trans golgi network
Hybrid organelles
Cis golgi network
Chemical chaperone
technology
Autophagosome
Enzyme
Rough endoplasmic reticulum
Figure 1. Lysosomal pathways. The figure provides a general overview of the dynamics of the endolysosomal system. For a
thorough description of the events along the pathways and the therapeutic concepts illustrated in the figure, please refer to
the text.
BMT/HSCT: Bone marrow transplantation/hematopoietic stem cell transplantation; ECM: Extracellular matrix; ERT: Enzyme replacement therapy.
ATPase (V-ATPase) [18], facilitating the dissociation of receptor and ligand while shifts in membrane lipid and protein
composition also occur as the vesicles mature to form late
endosomes and subsequently lysosomes. The late endosomes
and lysosomes differ from endosomes primarily in their
degree of acidification, higher buoyant density, higher abundance of integral lysosome-associated membrane proteins
(LAMPs) and enrichment of acidic hydrolases [19].
Biosynthetic route to lysosomes
Apart from endocytosis, late endosomes and lysosomes also
receive cargo via the M6PR pathway from the TGN (the
biosynthetic route). The cation-dependent M6PR and the
cation-independent (CI) M6PR/insulin-like growth factor1.2.2
II (IGF-II) receptor share the task of delivery of newly synthesized acid hydrolases from the TGN to the lysosomes. The
recognition of acid hydrolases by M6PRs requires the addition of carbohydrates in the endoplasmic reticulum (ER)
and the subsequent modification and phosphorylation of the
carbohydrate residues to M6P moieties in the cis-Golgi [15,20].
The M6PR-bound hydrolases are first delivered to endosomes, where they dissociate from the receptors due to the
drop in the lumenal pH, hereby allowing the receptors to
recycle back to the TGN.
Autophagic routes to lysosomes
Autophagy is the third relatively well-characterized route by
which macromolecules reach the lysosome. Autophagy is an
1.2.3
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T. Kirkegaard
evolutionary conserved pathway involved in the turnover of
long-lived proteins and organelles and is essential for maintaining cellular energy and metabolic homeostasis [21-23].
There are three main modes of autophagy: macro-, microand chaperone-mediated autophagy; macroautophagy is
characterized by a flat membrane cistern wrapping around
cytoplasmic organelles and/or a portion of cytosol thereby
forming a closed double-membrane bound vacuole, the autophagosome. The autophagosome finally fuses with lysosomes
forming autophagolysosomes/autolysosomes, where the degradation and recycling of the engulfed macromolecules occur.
Microautophagy is characterized by engulfment of cytosol by
the lysosomes through invaginations of the lysosomal membrane. Besides the macromolecules, which are present in the
engulfed cytosol, this process may also involve the uptake of
organelles such as peroxisomes and mitochondria, with these
particular autophagic processes being coined the terms pexoand mitophagy, respectively [24,25]. Finally, chaperonemediated transport of cytosolic proteins into the lysosomal
lumen presents a more direct and selective form of autophagy.
This pathway is dependent on the presence of the constitutively expressed member of the heat shock protein
70 (Hsp70) family, Hsc70 (HspA8), on both sides of the lysosomal membrane and its interaction with an isoform of the
lysosomal membrane protein, LAMP-2, the protein that is
defective in the LSD Danon disease [10,26].
Reformation of lysosomes and lysosomal
secretion/exocytosis
1.2.4
After fusion of lysosomes with late endosomes or autophagosomes, the lysosomes are reformed from the resultant hybrid
organelles through sequestration of membrane proteins and
condensation of the lumenal content [21]. The lysosomes,
however, cannot be seen as the terminal point of the endocytic
pathways as they are also able to form secretory lysosomes
through fusion with secretory granules, a process that is Ca2+dependent and was first recognized in secretory cells of
hematopoietic origin [27,28]. However, evidence also exists
for a Ca2+-regulated membrane-proximal lysosomal compartment responsible for exocytosis in non-secretory cells [29,30], a
process which is dependent on the protein Rab27a, a member
of the Rab protein family of small GTPases that have key regulatory roles in most membrane-transport steps including vesicle formation, motility, docking and fusion. At least 13 Rab
proteins are utilized in the endocytic pathways in order to
determine the fate of the various endocytosed molecules and
their vesicles and alterations in the Rab GTPases or associated
regulatory molecules give rise to a number of diseases ranging
from bleeding and pigmentation disorders (Griscelli
syndrome) through mental retardation and neuropathy
(Charcot--Marie--Tooth disease) to kidney disease (tuberous
sclerosis) and blindness (choroideremia) [11,31].
Ultimately, the reformation of lysosomes from autolysosomes (autophagosomes fused with lysosomes), endolysosomes
(late endosome--lysosome fusion) and other lysosome-hybrid
388
organelles completes each cycle of lysosomal degradation
yielding functional lysosomes that are available for another
round of macromolecular breakdown.
Importantly, the efficient processing of macromolecular
substrates in the hybrid organelles are essential for lysosomal
reformation, a process which does not occur de novo, but
is the result of a reformation/budding from the hybrid
organelles [32-34].
Defects in lysosome reformation which is thought to be
required for the exocytosis of lysosomal cargo-containing
membrane vesicles have also been shown to have pathological
consequences as evidenced by studies in Niemann--Pick type
C1 and C2 deficient cells (NPC1 and NPC2). These studies
have revealed a significant difference in the lysosomal consequences of defects in the NPC1 and NPC2 proteins which
otherwise share virtually indistinguishable clinical pathology
in patients. For NPC1, one of the primary lysosomal consequences is a compromised ability to form the initial hybrid
organelle, whereas in NPC2 deficient cells the impairment
of lysosome reformation appears to be the primary cellular
defect [7,35-38].
Interestingly, the impaired reformation of lysosomes could
also constitute a more general molecular pathological feature
of LSDs as secondary storage material in other LSDs, arising
as a consequence of the primary genetic deficiency, could
cause abnormalities in the necessary lipid dynamics involved
in not only lysosomal reformation but also vesicle docking
and fusion [39].
Lysosomal storage diseases
Individually, the LSDs are ultra-orphan diseases with
prevalences ranging from 1/60,000 live births for Gaucher
disease to 1/4.2 million live births for sialidosis. As a group
however, the combined prevalence has been estimated to be
ca. 1/7700 live births [40].
As delineated in the previous section, the interdynamics of
the lysosomal system is a complex maze of a number of crucial
events that all needs to function properly for the lysosomes to
be the effective multifunctional organelles they are. The LSDs
are excellent examples of the importance of these events
as > 50 LSDs to this day have been characterized, ranging
from primary defects in membrane proteins, transporters,
fusion machinery and of course hydrolytic enzymes with the
manifest cellular pathology associated with the diseases (lysosomal accumulation and storage) coining the name to these
devastating diseases.
More than 50 LSDs are classified according to the major
storage material accumulating, although their monogenetic
origin does not always directly predict the affected substrates
causing some discrepancies in understanding the molecular
etiology of the diseases. In sphingolipidoses for example, the
major storage materials are glycosphingolipids and immediate
derivatives thereof, whereas for the neuronal ceroid lipofuscinosis, lipofuscins are the major storage materials accumulating, but on the background of a genetically and functionally
1.3
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Emerging therapies and therapeutic concepts for lysosomal storage diseases
mixture of deficient proteases, peptidases, membrane proteins
and other proteins with as yet unknown function.
The mechanisms by which the accumulated substrates
impact cellular function and cause the pathological manifestations of the primary genetic defects are still not well
understood, although several recent advances in the understanding of these processes are now shedding light into this
dark(er) corner of human biology. These discoveries include
mechanisms related to alterations of intracellular calcium
homeostasis, impairment of autophagy, activation of signal
transduction pathways by substrates and their derivatives,
inflammation, altered intra- and limiting membrane properties
and others [7,8,39,41-44].
Earlier, clinical management of LSDs was mainly confined
to treatment of complications, although in some of the sphingolipidoses such as Gaucher and Fabry diseases attempts were
made to improve the patients’ condition by transplantation of
the major organs affected (liver and kidney, respectively), but
these interventions did not alter the course of the diseases [45].
In mucopolysaccharidosis type I (Hurler syndrome, MPSIH),
bone marrow transplantations has shown some benefit, however, provided the intervention is performed early enough [46].
The benefit of early intervention is a principle that holds not
only for bone marrow transplantations but for all therapies
applied to the LSDs, due to the irreversible nature of some
of the pathological changes during the course of the diseases.
The breakthrough in the treatment of LSDs began
modestly > 40 years ago when Neufeld and collaborators
demonstrated the principle of metabolic complementation
in cell cultures from patients with different LSDs [17,47]. Subsequent studies provided insight into the nature of the corrective factors (secreted lysosomal enzymes) and that these were
endocytosed by binding to the M6PR [48]. These early studies
showed that LSDs should be generally amenable to therapy
relying on reconstitution of the deficient enzymes by exogeneous administration of a functional version, a concept which is
known as ERT. In some cell types, exogenous lysosomal
enzymes are not recognized by the M6PR but rather by other
receptor systems which bind, for example, terminal galactose
(hepatocytes) or mannose residues (macrophages) [49]. That
several receptor systems exist, needs careful consideration during the development of effective ERTs, but also holds opportunities for changing or modifying the targeting signals of a
given enzyme in order to manipulate its pharmacodynamic
properties. A classic example is the modification of glucosylceramidase that in order to be targeted to macrophages in
Gaucher disease, has to be modified in order to expose
mannose residues [49].
The success of ERT in Gaucher disease has made this
approach the standard for treating lysosomal storage disorders
(Table 1), although the first clinical trial of an ERT in
1973 (GM2-gangliosidosis) was not a clinical success although
it did confirm the biochemical principle. In this trial, an infant
was injected with hexosaminidase A that had been purified
from human urine, resulting in a remarkable reduction of
the storage substance in the circulation. However, the patient’s
clinical condition remained unchanged [50]. The success of
treating Gaucher and the apparent failure in treating
GM2-gangliosidosis stresses the crucial point, that therapies
should be developed that affect the primary sites of pathology.
Unfortunately for the LSDs, the major organ involved in most
of these diseases is the CNS which by no means is an easy
organ to reach and even less so to rescue.
This realization has prompted the development of a number of therapies aimed not only at addressing the peripheral
symptoms of the LSDs but importantly these novel concepts
often aim at providing a clinical benefit in terms of manifestation of CNS-related symptoms, the holy grail of
LSD therapy.
2.
Medical need
The LSDs number over 50 diseases with a combined incidence of approx. 1/7700 and with only a very limited number
having approved therapies available.
The clinical manifestations of these diseases are extremely
variable ranging from severe debilitating, lethal diseases in
early infancy, to attenuated presentations in late adulthood,
often with no clear genotype/phenotype correlation as exemplified by Niemann--Pick disease type C in which the disease
can vary from severe, lethal infantile disease to a more psychiatric symptom-driven disease that gradually manifest itself
during the later decades [51].
The current standard of treatment has evolved from mainly
supportive care and symptomatic treatment to the standard of
today, ERT, that became available to patients with Gaucher
disease two decades ago and now has also been developed
and approved for other LSDs such as Fabry disease, MPS
types I, II and VI and Pompe disease (Table 1). The efficacy
of many of these therapies is limited however, due to the
fact that the exogenously provided enzymes do not have effect
on all aspects of the diseases. This is caused in part by the irreversibility of some aspects of these diseases but is also due to
the enzyme formulations’ inherent inability to reach all major
target organs in therapeutically efficacious amounts. Particularly the CNS, but also bone, cartilage, cardiovascular and
renal systems are not necessarily efficiently targeted by enzyme
replacement strategies due to the extremely selective permeability of the blood--brain barrier (BBB) and restricted
receptor expression and lack of sufficient blood flow to support the needed doses for efficacy in other peripheral tissues
and organs.
Furthermore, the formation of antibodies against the exogenously delivered enzyme may have a negative impact on efficacy as well as elicit unwanted infusion-related adverse
events [52,53].
It comes as little surprise therefore, that there exists a
substantial unmet need for the development of therapies
addressing the limitations described above as well as providing
alternative treatment regimens that eventually might even
Expert Opinion on Orphan Drugs (2013) 1(5)
389
T. Kirkegaard
Table 1. Overview of marketed therapies available for LSDs.
LSD
Drug
Company
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Status
Mechanism
Gaucher disease Cerezyme (imiglucerase)
Gaucher disease VPRIV (velaglucerase alfa)
Gaucher disease Elelyso (taliglucerase)
Genzyme
Shire HGT
Protalix
On market ERT
On market ERT
On market ERT
Gaucher disease Zavesca (miglustat)
Actelion
On market SRT
Fabry disease
Fabry disease
Fabrazyme (agalsidase beta)
Replagal (agalsidase alfa)
Genzyme
Shire HGT
On market ERT
On market ERT
Niemann--Pick
type C disease
Zavesca (miglustat)
Actelion
On market SRT
MPS type I
MPS type II
MPS type VI
Pompe disease
Cystinosis
Cystinosis
Genzyme
Aldurazyme (laronidase)
Shire HGT
Elaprase (idursulfase)
Biomarin
Naglazyme (galsulfase)
Myozyme (alglucosidase alfa) Genzyme
Various
Cystagon (cysteamine)
Sigma-Tau
Cystaran (cysteamine)
Pharmaceuticals
On market
On market
On market
On market
On market
Approved
Comments
Plant cell manufacture,
only approved in the USA
Only for Gaucher type I patients
for whom ERT is unsuitable
Not approved in the USA,
approved in the EU, Asia
and Canada
Not approved in the USA,
approved in the EU, Canada,
Switzerland, Brazil, Australia,
Turkey and Israel
ERT
ERT
ERT
ERT
Cysteamine suppl. On market 1994
Cysteamine suppl. Cysteamine ophthalmic solution
ERT: Enzyme replacement therapy; LSD: Lysosomal storage disease; MPS: Mucopolysaccharidosis; SRT: Substrate reduction therapy.
supplement each other based on a rational understanding of
their distinguishing mechanisms of action.
3.
Existing and emerging therapies
The currently approved pharmacological therapies for LSDs
are summarized in Table 1, while emerging therapies and therapeutic concepts are extensively covered in Tables 2 and 3. As
can be readily seen, both established and emerging therapies
are dominated by ERT or second-generation variants thereof.
The following sections provide a comprehensive overview
of current and emerging therapies for the LSDs and will focus
on the scientific and medical rationale for these therapeutic
concepts.
Bone marrow transplantation/hematopoietic
stem cell transplantation
3.1
Bone marrow and hematopoietic stem cell transplantations
(BMT/HSCT) can trace the origin of their scientific rationale
back to the same fundamental principle of metabolic crosscorrection as the ERTs, that is, the ability of lysosomal enzymes
to enter into a secretion-reuptake cycle. The first uses of transplantation approaches emerged in the 1980s and have seen its
use in many of the LSDs including MPS types I, VI and VII,
metachromatic leukodystrophy (MLD), alpha-mannosidosis,
fucosidosis, Krabbe disease and type III Gaucher disease [54].
Despite a rather extensive use of BMT/HSCT in MPS type
I and 1H (Hurler variant) and with some promising results,
particularly in terms of reducing visceromegaly, cardiac function and airway obstruction [55], it is unfortunately still hard
to conclude decisively on the status of this potentially effective
390
therapy as most reports on BMT and HSCT are both
anecdotal and/or only encompass a small number of patients.
However, with the advancement of methods for HSCT and
with a more systematic approach in evaluating the therapy
there is no scientific reason as to why BMT/HSCT should
not be a both viable and a promising therapy for many of
the LSDs, although several challenges such as the occurrence
of variable musculoskeletal disease progression even after successful stem cell transplantation (SCT) in MPSIH patients
have to be overcome [56,57].
Enzyme replacement therapies
As for bone marrow and hematopoietic SCTs the fundamental principle of ERT is the same: the substitution of the deficient enzyme by a functional version hereof.
Provided the enzyme can be manufactured and safely
administered, the administration of the enzyme usually takes
place through either weekly or biweekly infusions although
more frequent administrations are also seen for some ERTs
such as asfotase alfa in development for hypophosphatasia
(Clinicaltrials identifier: NCT01176266).
The promise of most ERTs lies in their potential capacity
to correct the pathology of non-neural tissue as the enzymes
are incapable of traversing the BBB, although many peripheral
tissues such as bone, cartilage, cardiovascular and renal systems are not easily reached due to the biology of the receptor
systems needed for the endocytosis of the exogenously
delivered enzymes.
Tables 1 and 2 summarize the ERTs that have been
approved for marketing authorization and those that are in
current development, respectively.
3.2
Expert Opinion on Orphan Drugs (2013) 1(5)
BMN-701 (IGF2-GAA)
Duvoglustat + ERT
OXY 2098-85 (modified GAA)
Sebelipase alfa (lysosomal acid lipase)
p97 (melanotransferrin)/ERT conjugate
Angiopep-ERT conjugate
MPS type VII
Niemann--Pick type B
Pompe disease
Pompe disease
Pompe disease
Pompe disease
Wolman disease
Undisclosed LSDs
Undisclosed LSDs
Expert Opinion on Orphan Drugs (2013) 1(5)
GSK/Angiochem
Synageva
Shire HGT/biOasis
Amicus
Oxyrane
Biomarin
Ultragenyx
Genzyme
Genzyme
Shire HGT
Synageva
Biomarin
JCR Pharmaceuticals/GSK
Shire HGT
Armagen
Shire HGT
Discovery
Phase II
Discovery
Phase II
Preclinical
Phase I
Preclinical
Phase I
Preclinical
Preclinical
Preclinical
Phase III
Preclinical
Phase I/II
Preclinical
Phase I/II
Preclinical
Phase I/II
Preclinical
Phase II
Phase II
Phase I/II
Preclinical
Preclinical
Preclinical
Preclinical
Preclinical
Status
ERT
Second-generation
ERT
Second-generation
ERT
ERT
ERT
Second-generation
ERT
Second-generation
ERT
CCT/ERT
Second-generation
ERT
ERT
ERT
ERT
Second-generation
ERT
ERT
ERT
ERT
Second-generation
ERT
Second-generation
ERT
ERT
ERT
CCT/ERT
ERT
ERT
ERT
ERT
ERT
ERT
Mechanism
p97 to facilitate transport
of ERT across BBB
Angiopep targets LRP-1
to facilitate transport
across BBB
Carbohydrate remodeling
to target CI-M6PR
Fusion protein of IGF2
peptide and GAA
Combination approach
Engineered 95 kDa
precursor to target
CI-M6PR
Intrathecal delivery
Intrathecal delivery
Insulin receptor antibody
fused to iduronate-2-sulfatase
Intrathecal delivery
Insulin receptor antibody
fused to arylsulfatase A
Insulin receptor antibody
fused to iduronidase
Intrathecal delivery
Oral ERT
Combination approach
Plant cell manufacture
Comments
+
+
-
+
-
+
-
+
+
+
+
+
+
-
-
CNS targeting
ASM: Acid sphingomyelinase; BBB: Blood--brain barrier; CCT: Chemical chaperone technology; CI-M6PR: Cation-independent mannose-6-phosphate receptor; CNS: Central nervous system; ERT: Enzyme replacement
therapy; GAA: Acid alpha-glucosidase; HIRmAb: Monoclonal antibody to the human insulin receptor; IGF2: Insulin-like growth factor 2; LRP-1: Low-density lipoprotein receptor-related protein 1; LSD: Lysosomal storage
disease; MLD: Metachromatic leukodystrophy; TPP1: Tripeptidyl peptidase-1.
MPS type IIIB
MPS type IIIB
MPS type IVA
JR-032 (iduronate-2-sulfatase)
Intrathecal HGT 1410
(heparan N-sulfatase)
Intrathecal HGT 3010
SBC-103 (a-N-acetyl-glucosaminidase)
BMN-110 GALNS
(N-acetylgalactosamine-6 sulfatase)
UX003 (b-glucuronidase)
ASM
Neo-rhGAA
MPS type II
MPS type IIIA
MPS type II
Intrathecal Elaprase
(iduronate-2-sulfatase)
AGT-182 (HIRmAb-iduronate-2-sulfatase
AGT-181 (HIRmAb-iduronidase)
MPS type I
MPS type II
Shire HGT
Armagen
Intrathecal HGT 1110 (arylsulfatase A)
AGT-183 (HIRmAb-arylsulfatase A)
Armagen
Zymenex
Amicus/GSK
Protalix
JCR Pharmaceuticals/GSK
JCR Pharmaceuticals/GSK
Protalix
Zymenex
Biomarin
Company
Lamazym (alpha-D-mannosidase)
Migalastat + ERT
PRX-102 (a-galactosidase-A)
JR-051 (a-galactosidase A)
JR-101 (glucocerebrosidase)
Oral glucocerebrosidase
Galaczym (galactocerebrosidase)
BMN-190 (TPP1)
Drug candidate
Alpha-mannosidosis
Fabry disease
Fabry disease
Fabry disease
Gaucher disease
Gaucher disease
Krabbe disease
Late infantile NCL
(Batten)
MLD
MLD
LSD
Table 2. Overview of ERTs and second-generation variants in commercial development for LSDs.
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391
T. Kirkegaard
Table 3. Overview of non-ERT emerging therapies in commercial development for LSDs.
LSD
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Multiple LSDs
(sphingolipidoses
amongst others (ao))
Multiple LSDs
Drug candidate
Company
Status
Mechanism
Comments
CNS
targeting
Orph-001 (Hsp70)
Orphazyme
Preclinical
MCT
Main receptor LRP-1,
targets BBB
+
Orph-002
(orally available
small molecules)
Not disclosed
Orphazyme
Preclinical
MCT
Non-toxic, small molecule
molecular chaperone
inducers, BBB penetrating
Ganglioside synthesis
inhibition
Inhibition of 2-O sulfation
of heparan sulfate
Combination approach
+
Multiple LSDs
(gangliosidoses)
Multiple LSDs
Not disclosed
(MPS types I, II and III)
Gaucher disease
AT2101 + ERT,
AT3375 + ERT
Fabry disease
Migalastat
Zacharon
Discovery
Pharmaceuticals
Zacharon
Preclinical
Pharmaceuticals
Amicus
Preclinical
SRT
CCT/ERT
Amicus/GSK
Phase III
CCT
Fabry disease
MPS type IIIA
Migalastat + ERT
SAF-301
(AAVrh.10SGSH- SUMF1)
Amicus/GSK
Lysogene
Phase II
Phase I/II
CCT/ERT
GT
MPS type IIIB
Phase I/II
GT
Niemann--Pick type C
Viral vector carrying a-N- UniQure
acetylglucosaminidase
HPB-cyclodextrin
NICHD
Pompe disease
Cystinosis
Duvoglustat + ERT
RP103
SOT
Study did not meet
primary end points
Combination approach
rh.10 serotyped adenoassociated virus carrying
the deficient SGSH and
SUMF1 gene
+
+
+
+
Phase I
Cholesterol sequestering +
agent, ICV administration
Amicus
Phase II
CCT/ERT
Combination approach
Raptor
Registration Slow release Reformulation approach
Pharmaceuticals
cysteamine
Combination approaches with ERT have been included.
BBB: Blood--brain barrier; CCT: Chemical chaperone technology; CNS: Central nervous system; ERT: Enzyme replacement therapy; GT: Gene therapy; Hsp70: Heat
shock protein 70; ICV: Intracerebroventricular; LRP-1: Low-density lipoprotein receptor-related protein 1; LSD: Lysosomal storage disease; MCT: Molecular
chaperone therapy; MPS: Mucopolysaccharidosis; NICHD: National Institute of Child Health and Human Development; SOT: Substrate optimization therapy;
SRT: Substrate reduction therapy.
The first marketed ERT was developed for type I Gaucher
disease, a sphingolipid storage disorder, characterized by
splenomegaly, thrombocytopenia and anemia. The first clinical trial was performed by Brady and collaborators with an
enzyme preparation purified from human placenta, treated
with specific glycosidases to facilitate uptake by mannose
receptors on the macrophages which is the main cell type
involved in the disease [49]. Based on the positive data from
this trial, the enzyme preparation (Ceredase, Genzyme)
was approved for patients with Gaucher disease and was
some years later replaced by a recombinant form, imiglucerase
(Cerezyme, Genzyme). A number of reports and publications
have confirmed the long-lasting positive effect as well as the
safety and tolerability of imiglucerase in patients suffering
from type I Gaucher disease which has led to ERT becoming
the standard of care for these patients [58,59] but does not have
any influence on the CNS symptoms of the disease as seen in
the neuropathic forms of the disease, not even at high
doses [60].
The initial success of imiglucerase, has led to the development of ERT for other LSDs such as Fabry disease, Pompe
disease and several of the MPS. In Fabry disease for example,
392
two different a-galactosidase enzymes have been developed,
but although Fabry disease is a glycosphingolipidosis just as
Gaucher disease, its pathology is significantly different from
that of Gaucher, giving rise to a number of challenges mainly
associated with the proper engagement of the ERT with the
target organs. In Fabry disease, kidney failure, cardiomyopathy and cerebrovascular events are the main complications
which give rise to the morbidity and mortality associated
with this disease while most clinical efficacy measurements
have been based on plasma Gb3 levels (the main accumulating lipid) [61,62]. While plasma Gb3 levels are quite easily
quantifiable and respond readily to intravenous injections of
ERT, the main organs giving rise to disease symptomatology
are neither as readily accessible to therapy nor as well investigated [61]. This inconsistency in addressing clinically relevant
end points has made a clear conclusion on the benefits of
ERT for Fabry disease difficult and the experience with
ERT for Fabry disease has not been as satisfying as that in
Gaucher disease, in which the pathological storage mainly
involves a more easily targetable cell population. Also,
recently the central role of Gb3 in Fabry disease and its relevance as a surrogate marker has been questioned as the lyso
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derivative of Gb3 (globotriaosylsphingosine) may be a more
pathologically relevant metabolite [63,64].
The findings in Fabry disease highlights the importance for
a given therapy to reach the clinically relevant target organs in
therapeutically efficacious doses, and the need to monitor this
rigorously to aid conclusions on the effectiveness of a given
therapy. It also points to the challenge that not only for Fabry
disease, but for many of the LSDs, the current understanding
of their molecular pathology is still far from complete.
If one turns to another group of LSDs, the MPS, the pattern observed for Fabry disease repeats itself. In MPS, there
are 11 known genetic deficiencies all involving enzymes that
are part of the catabolism of glycosaminoglycans (GAGs), giving rise to seven distinct MPS types. As with Fabry disease, the
MPS are multisystemic diseases, affecting a multitude of cell
types in a variety of tissues [65]. For MPSI, II and VI, ERT
is now available [66-69], while first- or second-generation
ERTs are also in development for several of the diseases
(Table 2). For all of the approved ERTs, hepatosplenomegaly
responds rapidly to the administration of intravenous enzyme
with a concomitant reduction in urinary excretion of GAGs
but as for Fabry disease, the main disease burden lies not
within the easiest accessible organs, as the functional problems
the MPS patients suffer are rather due to skeletal dystosis and
involvement of the soft tissues, heart and lungs. The clinical
efficacy of ERT when measured in terms of joint mobility,
vital capacity and walk tests, has not been nearly as clear as
the effects observed on surrogate markers, and while the
ERTs have evidently not been able to influence the CNS
manifestations of the diseases, they have to some extent been
able to alter the natural history of the disease and can in
some cases improve the patient’s quality of life. As for the
other LSDs, the earlier the intervention, the better.
The latest ERT marketed for a new LSD indication is
alglucosidase alfa for the treatment of Pompe disease (glycogen storage disease type II, acid maltase deficiency), which is
primarily affecting the muscle tissue, enabling a better ERT
targeting of the clinically relevant tissue. For this disease, as
for many of the LSDs, there is a broad spectrum of disease
presentation with the most severe, infantile onset cases presenting in the first weeks after birth with both cardiovascular
and skeletal myopathy while later onset cases usually sees a
sparing of the cardiovascular tissue but manifesting itself
with a progressive proximal myopathy which can lead to
respiratory failure, if involving the musculature of the diaphragm. The clinical efficacy of this ERT has been very
encouraging with early intervention in the infantile cases
being lifesaving, even in cases of advanced disease [70,71]. The
efficacy of the ERT has furthermore been confirmed by several clinical trials in patients with different age of onset and
disease severity and alglucosidase alfa has received approval
for treatment of Pompe disease for all age groups [72].
It is evident that several factors define the clinical success of
a given ERT: the primary challenge for any ERT lies in its
clinical efficacy on the organ systems involved. As described,
these systems vary from disease to disease but are often organs
which are not readily accessible to ERT.
Although there are reports of enzymes successfully crossing
the BBB in animal models of MLD and alpha-mannosidosis [73,74], clinical data for all commercially available ERTs
have not shown any evidence of ERTs being able to penetrate
the BBB and provide a therapeutic benefit to the patients. It is
therefore of little surprise that all the second-generation ERTs
(as well as many of the other emerging therapies) are aiming at
either crossing the BBB and/or increasing the uptake of
enzyme into the relevant peripheral tissue.
Of the latter there are currently several biologically similar
approaches in development for the treatment of Pompe disease in which the primary tissue to target is the muscle tissue.
Whether through carbohydrate remodeling of the enzyme
itself, its conjugation to a IGF2-derived peptide tag or the
engineering of a precursor form of the enzyme, all of these
second-generation approaches aim at changing the biodistribution toward increased uptake in muscle tissue of the active
enzyme by increasing its affinity to the CI-M6PR [75-77].
When it comes to targeting second-generation ERTs for
transport across the BBB several approaches are in development. One approach is intrathecal delivery of standard ERT
which is in clinical development for MPSII, MPSIIIA and
MLD. Another and well-characterized alternative approach
is the more physiological approach of utilizing endogeneous
receptor systems for enzyme transcytosis across the BBB, an
approach that is considered to have several advantages compared with the rather invasive surgical procedure of intrathecal
infusion of enzymes [78]. Although several receptor systems
have been characterized that facilitate transport across the
BBB, for the LSDs two main receptor systems are currently
being targeted by various companies in the hope that these
will provide access for the engineered enzymes to the neurons
of the CNS in therapeutically relevant doses. These emerging
approaches are targeting enzymes for the treatment of MPSI,
MPSII, MLD and other LSDs to the CNS via either the
insulin receptor or the probably best characterized blood-brain transcytosis receptor, LRP-1 (low-density lipoprotein
receptor-related protein 1) (CD91) [79-84].
For the targeting of the insulin receptor, engineered versions
of the enzyme are fused to the carboxyl terminus of the heavy
chain of a chimeric monoclonal antibody (mAb) to the human
insulin receptor (HIR). These HIRmAb--enzyme fusion proteins then cross the BBB via the endogenous insulin receptor
and acts as a so-called molecular Trojan horse to ferry the
enzyme into brain with approximately 2 -- 3% of injected
dose reaching the brain [80,85].
The LRP-1 and -2 have been exploited to target a large
variety of drugs to the brain and LRP is the best characterized
system for BBB penetration to date [78]. LRP-1 has a number
of physiological ligands and this has formed the basis for two
alternate fusion protein approaches, one relying on the conjugation of p97/melanotransferrin to the enzyme of interest, the
other on an optimized peptide, a so-called angiopep, with
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T. Kirkegaard
increased affinity for the LRP-1 receptor [82,84]. Interestingly,
the human molecular chaperone Hsp70 which is being developed for the treatment of a panel of LSDs and covered later in
this review also utilize LRP-1 as one of its primary
receptors [86].
Besides the above, a number of different targeting systems
are being explored academically, such as intercellular adhesion
molecule (ICAM) and apolipoprotein B (ApoB)-mediated
carriers [87,88] but it is considered beyond this review to cover
all early discovery pharmacology not in a company or
company-related pipeline.
Based on the preclinical activity surrounding the secondgeneration ERTs, one can only hope that any of these
approaches will prove successful, but a number of challenges
are facing the development of these more extensively engineered enzymes: Although promising data have been generated in murine models of the disease for many of these
compounds, only a marginal ratio of the total injected enzyme
becomes available to the CNS and it remains to be seen if this
amount of enzyme can confer the same therapeutic benefit in
human subjects. This challenge unfortunately only becomes
harder when one considers that chronic administration of
these modified enzymes will be necessary for sustained effect
in patients as this will almost certainly give rise to significant
antibody responses, as has been seen for all ERTs, albeit to
various degrees.
Also, the use of any receptor system begs the question as to
what effect will be caused by the extra-physiological use of
such a system to deliver drugs, that is, could any adverse signaling cascades be activated or will the natural receptor halflife, distribution and activity be compromised by this extra
utilization. Also, does the receptor actively transport the
drug across the BBB or is the drug just binding to the receptor
and sequestered in the BBB endothelium? For LRP-1 for
example, these considerations are not necessarily a major
problem as the receptor is rather promiscuous with many
ligands already using the receptor and as it also has one of
the fastest transcytosis rates (transfer coefficient/Kin) of any
BBB receptor system [89], adverse receptor signaling, saturation and re-distribution as well as drug sequestration in the
endothelium should not pose a significant risk for this system
although this of course remains to be tested clinically.
Given all the challenges that remain to be faced by the
second-generation ERTs, one should bear in mind however,
that significant clinical benefit has been achieved for other diseases in which receptor systems have been exploited, for example, in the case for dopamine/L-Dopa for Parkinson’s disease
patients, in which the large neutral amino acid carrier has
been used to deliver L-Dopa, the metabolic precursor of dopamine, to the brain resulting in a clear clinical benefit as
dopamine in itself is not able to cross the BBB.
Substrate reduction therapies
Whereas ERTs focus on increasing the catabolism of buildup substrate, the principle in substrate reduction therapy
3.3
394
(SRT) is to limit the production of substrate to the catabolically compromised lysosomes. The first demonstration of
this principle was done by Platt et al. in 1994 with the
imino sugar N-butyldeoxynojirimycin (NB-DNJ, miglustat,
Zavesca) which has the ability to inhibit the enzymatic activity of ceramide glucosyltransferase (glucosylceramide synthase) which synthesizes glucosylceramide, the precursor of
several glycosphingolids such as the globo- and gangliosides,
and which is the main accumulating lipid in Gaucher disease [90]. Miglustat was subsequently tested in a clinical trial
with 28 Gaucher disease patients, who for several reasons
did not receive ERT and on basis of this trial miglustat gained
marketing approval in Europe and the USA for the treatment
of adult patients with mild to moderate type 1 Gaucher
disease for whom ERT is not a therapeutic option [91].
An SRT based on the inhibition of ceramide glucosyltransferase holds the potential of being a therapy for all LSDs with
glycosphingolipid storage and since miglustat crosses the
BBB, this therapy has been evaluated for a number of sphingolipidoses with prominent neurodegeneration such as
Tay--Sachs disease, type 3 Gaucher disease, MPSIII, juvenile
GM2-gangliosidosis and Niemann--Pick type C disease [92-96].
Except for Niemann--Pick type C disease, none of these trials
have shown improvement in the miglustat-treated patients
although some of these data should be handled with care as
the studies were done on very limited numbers of patients.
For Niemann--Pick type C, miglustat received marketing
approval in Europe in 2009 based on a clinical trial in patients
aged 12 or older, which demonstrated that treatment with
miglustat improved eye movement velocity and swallowing
capacity [95].
Being a small molecule sugar analog, the side-effect profile
of miglustat is significantly different from the side-effect
profiles associated with ERTs with miglustat having a broader
array of side effects including gastrointestinal symptoms,
particularly diarrhea.
A conceptually similar, but chemically different, approach
for SRT centered on ceramide-based inhibitors of ceramide
glucosyltransferase provides a novel alternative to the imino
sugar-based SRT. Based on this approach, a new inhibitor
of ceramide glucosyltransferase, eliglustat tartrate (Genz112638) is currently in development for Gaucher disease
type I, and has shown promising results in an open-label
Phase II trial, combining a higher specificity for ceramide
glucosyltransferase with a more beneficial side-effect profile
compared with miglustat and having a clear effect on several
disease parameters [97].
For the MPS, the accumulation of GAGs can be inhibited
by genistein, an isoflavone extract from soybeans being
explored academically. The effect of genistein on urinary
GAG excretion, hair morphology and behavior has been
tested in an open-label study of 10 patients suffering from
either MPSIIIA or IIIB and a 2-year follow-up including eight
patients assessing the cognitive function and general status
was recently published. Albeit consisting of a small number
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Emerging therapies and therapeutic concepts for lysosomal storage diseases
of patients, after 1 year of oral administration of a genisteinrich soy isoflavone extract (5 mg/kg/day), a statistically significant improvement was observed with a larger variance in
efficacy being apparent after 2 years [98].
Chaperone technologies
As most LSDs are characterized by significantly reduced
enzyme activity due to missense mutations rather than a
complete loss of function, the LSDs have long been thought
amenable to chaperoning by chemical substrate mimics
targeting the active site of the relevant enzyme for increased
stability/folding.
A more recent approach relies on utilizing the already existing molecular chaperone machinery available in the cells in
order to avoid the inherently counterproductive mechanism
of enzyme inhibition associated with chemical chaperone
therapies.
The advantages to both approaches compared with ERT
include better distribution profiles including CNS availability
as well as easier drug administration as the small molecule
approaches for both concepts offer the potential of oral
administration rather than the more patient-demanding
infusions of ERT.
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3.4
Molecular chaperone technologies
There are currently two approaches in development for utilizing the naturally occurring molecular chaperone machinery,
both exploiting the recently discovered mechanism for how
the archetypical molecular chaperone Hsp70 aside from its
well-characterized cytoprotective effects also enhances cell survival and functionality through a direct lysosomal action [43].
One approach relies on the receptor-mediated endocytic
uptake of a recombinant version of Hsp70 whereas the second
approach relies on utilizing small molecules capable of
enhancing the endogenous production of heat shock proteins,
here amongst Hsp70. Hsp70 is an evolutionarily highly conserved molecular chaperone which has been shown to promote the survival of stressed cells by inhibiting lysosomal
membrane permeabilization [99-101], a hallmark of stressinduced cell death [6,102]. Recently, Kirkegaard et al. described
how Hsp70 stabilizes lysosomes by binding to the endolysosomal anionic phospholipid bis(monoacylglycero)phosphate
(BMP), an essential co-factor for lysosomal sphingolipid
metabolism hereby facilitating the BMP binding and
increased activity of acid sphingomyelinase (ASM), the
enzyme compromised in Niemann--Pick diseases. Notably,
the reduced ASM activity in cells from patients with
Niemann--Pick disease A and B was shown to associate with
a marked decrease in lysosomal stability, and this phenotype
as well as the pathological accumulation of unstable lysosomes
could be effectively corrected by treatment with recombinant
Hsp70. The mechanism of action of Hsp70 entails the prospect of using the protein for the treatment of several LSDs,
most notably the sphingolipidoses involving enzymes that
are dependent on interaction with BMP [103] and it is
3.4.1
currently in preclinical development for a number of
these diseases.
The approach to utilize small molecules to increase the
expression of heat shock proteins during pathological stress
conditions and harness this response for therapeutic use, stems
from the ability of these molecules to stabilize the transcription factor for the heat shock proteins, heat shock factor1 (HSF-1) [104]. Interestingly, this emerging approach for
LSDs is also in development for a number of neurodegenerative conditions, including amyotrophic lateral sclerosis and
has a well-described safety record with very limited side
effects, which could possibly accelerate the development of
this therapeutic concept for LSDs [105].
Chemical chaperone technologies
Contrary to the molecular chaperone approach which utilizes
the potentiating effects of endogenous cellular chaperones,
chemical chaperone technologies rely on using competitive
inhibitors of lysosomal enzymes at subinhibitory concentrations in order to facilitate the transition of poorly folded
lysosomal enzymes otherwise caught in the ER/proteasomal
degradation machinery to the lysosomes as first described
by Fan et al in 1999 [106]. On maturation and entry in the
lysosomes, the concept demands that the kinetics of the
enzyme/inhibitor interaction are shifted due to for example,
the reduced pH of the lysosomes, facilitating the dissociation
of the inhibitor and the enzyme, thus finally leaving a larger
fraction of the functionally compromised enzyme available
for increased substrate degradation in the lysosome [106,107].
A number of molecules are in development for LSDs based
on this approach, including combination efforts with ERTs.
The most advanced program for a LSD utilizing a chemical
chaperone as stand-alone therapy is deoxygalactonojirimycin
(DGJ; migalastat hydrochloride) which is currently in
Phase III for Fabry disease. Despite a considerable power
in this study as 67 patients diagnosed with Fabry disease
with genetic mutations amenable to chaperone monotherapy
were enrolled, the study recently reported an initial negative
outcome, as it did not meet any of its primary end points
during its first phase [108].
Although not in formal development programs for LSDs, the
Food and Drug Administration (FDA)-approved drugs pyrimethamine and ambroxol have been identified as possible
chemical chaperones for hexosaminidase A and ceramide glucosyltransferase and both have been tested in cells from patients
suffering from late-onset forms of GM2-gangliosidosis
(Tay--Sachs and Sandhoff disease) and Gaucher disease [109,110].
Recently, data from a small-scale open-label Phase I/II clinical
study of the tolerability and efficacy of pyrimethamine in
Sandhoff disease patients have been reported [111]. A significant
side-effect profile was observed at doses of 75 mg pyrimethamine daily, while variable enzyme activity enhancement was
seen at 50 mg/day. Although the design of the study does not
allow for proper conclusions, the significant side-effect profile
characterized by neurological side effects such as ataxia and
3.4.2
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incoordination experienced in all subjects of the study, and the
very narrow window to the dose conferring a seemingly
increased enzymatic activity presents significant challenges for
the further development of this compound.
Combination therapies of chemical chaperones and ERTs
are being pursued for Gaucher, Fabry and Pompe diseases
and are currently in preclinical (Gaucher) and Phase II (Fabry
and Pompe) stages of development. Given the recent development challenges of the chemical chaperones (duvoglustat and
migalastat) for Pompe and Fabry disease, respectively, the
evaluation of these inhibitors in ERT combination studies
for Pompe and Fabry diseases will be interesting.
Substrate optimization
The mechanism of action of current therapies targeting the
substrates accumulating in LSDs such as miglustat and eliglustat tartrate is focused on the inhibition of enzymes necessary for substrate biosynthesis and as such this approach
entails the risk of reducing the substrate to a level where its
normal functions are compromised. As an alternative to
this, a concept has been described in which small molecules
are used, not to prevent synthesis of substrates, but rather to
modify their biosynthesis in order to change the structure of
the substrate, which then no longer is dependent on the deficient enzyme for degradation but can be degraded by alternative enzymes with normal function [112]. This strategy
has been termed substrate optimization therapy and is currently in development for MPS types I, II and III in which
the targets for the substrate optimization are glucosaminoglycans (GAGs). By compound library screening, 15 inhibitors of GAG synthesis were identified that can be categorized
into N-, 2-O-, or 6-O sulfation inhibitors. A 2-O sulfation
inhibitor, ZP2345, could reduce the levels of 2-O sulfation
with a compensatory increase in 6-O sulfation of heparan
sulfate with the modified heparan sulfate being more amenable to degradation in vitro in fibroblasts from MPS type II
patients (iduronate sulfatase deficiency) [113]. Albeit still
early stage, the technology has the potential of being able
to target more than one MPS with the same compound as
well as being able to cross the BBB and other organs that
have proven hard to reach for ERTs.
3.5
Gene therapy
A number of gene therapeutic approaches using retro-, lenti- or
adeno-associated viral vectors have been evaluated pharmacologically in a comprehensive array of animal models of LSDs and
the general conclusion is that this therapeutic approach has
shown clear disease-modifying capacity in vivo [114]. The main
challenges that remain to be overcome are the transfer of these
findings to larger brains (the human brain volume is ca. 2000
times that of the mice, making efficient pan-cerebral delivery a
challenge even with intracranial injections), the possible immunogenic responses to the viral vectors carrying the gene of interest as well as the potential need for immune suppression for the
patients who are complete null for the enzyme.
3.6
396
Despite these challenges, a number of clinical trials have
been initiated for the LSDs, but as is the case for many trials
within the LSD field the trials are featuring small number of
patients and solid conclusions are hard to make as only a
small number of studies have been completed. Reports on
completed studies of gene therapy in Gaucher disease and
MPS type II using retroviral vectors showed only low expression of the gene product and no improvement in disease
pathology [115,116]. However, these were the first two clinical
trials of gene therapy in LSDs and since their initiation more
than a decade ago there has been a marked development
and improvement of vector design and delivery which will
hopefully lead to improved results. Although a recently completed study in Batten disease involving direct injection of a
recombinant adeno-associated viral (rAAV) serotype 2-based
vector into the CNS of affected children indicated that progression of disease might have been slowed, a clear therapeutic benefit was not established and significant serious adverse
events were also encountered, the causes of which could
not be identified [117]. However, as for the retroviruses,
rAAV-based gene therapy has also evolved substantially since
the initiation of this study and several studies are underway
utilizing other rAAV serotype vectors in for example, Pompe
disease [118] and MPS types IIIA and IIIB, the latter two
being researched and developed in commercial settings.
The ongoing Pompe disease study uses a rAAV
serotype 1 (rAAV1) vector encoding acid-a-glucosidase,
and recently reported preliminary findings [118]. No adverse
events or systemic toxicities related to vector administration
were reported and significant elevation in respiratory
parameters was noted for the first cohort of patients on the
lower dose of treatment. These findings are encouraging
for the development of gene therapies for LSDs, but the
hope that all pathological components of a given LSD can
be corrected by a systemic delivery of a single vector is probably too optimistic as the complex nature of these devastating diseases makes even this approach extremely difficult.
A number of factors such as the timing of gene transfer in
relation to diagnosis and symptom onset/aggravation,
the variable levels of gene product needed to efficaciously
treat various organ pathologies and the possible immune
consequences related to administration procedures, choice
of vector and naivety to gene therapy product will all
have to be addressed in order to bring about the full
potential of this therapeutic approach.
On top of these scientific and development challenges,
challenges regarding regulatory considerations and commercial feasibility of developing gene therapies are also considerable. Very encouragingly however, for gene therapy as a
future therapy for a number of genetic diseases, not only the
LSDs, the first European regulatory approval of a gene therapy was recently announced, with this therapy also being
based on an rAAV1 vector, AAV1-LPLS447X (alipogene
tiparvovec, Glybera) targeting lipoprotein lipase deficiency,
an ultra-rare genetic disease [119].
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Other therapies and emerging approaches
The LSD cystinosis involves lysosomal storage of the amino
acid cystine in all organs and tissues due to a defect in the
lysosomal membrane transport protein, cystinosin, and was
the first LSD recognized to be due to defective lysosomal
membrane transport, and thus serves as a prototype for a small
group of lysosomal transport disorders. In 1994, a novel therapy was approved based on depleting cysteine in the form of
orally administered cysteamine bitartrate (Cystagon), which
has revolutionized the management and prognosis of nephropathic cystinosis [120]. On administration, cysteamine enters
the lysosomes and reacts with cystine, forming the mixed
disulfide of half cystine (cysteine) and cysteamine. This complex can then exit the lysosomes via the transport system for
cationic amino acids [121]. The efficacy of cysteamine has
been validated in a number of studies and cysteamine therapy
should be considered for all affected individuals, regardless of
age and transplantation status [122].
The side-effect profile of cysteamine includes unpleasant
taste, nausea and other digestive issues with the most common
side effect being nausea that can be alleviated with antiemetics
in the early stages of therapy initiation [122]. A different route
of administration targets photophobia associated with the disease as topical cysteamine eye drops, administered every
1 -- 2 h, dissolve corneal crystals and ameliorate this part of
the pathology within a few weeks [123].
As nonsense mutations have been identified in a number of
LSDs, leading to premature translation termination and the
synthesis of truncated protein as in the case of the Arg220X
mutation in Fabry disease, and as there exist evidence that
small molecule drugs such as gentamicin can induce the readthough of such premature stop codons, bringing about
increases in otherwise null enzymatic activity, the concept of
stop-codon readthrough has been explored in the severe
form of MPS type I (Hurler disease). In cell cultures of patient
fibroblasts carrying different nonsense mutations, gentamicin
treatment increased the a-L-iduronidase activity in all cell
lines tested except one providing an initial in vitro proof-ofconcept for this approach [124]. Further development of aminoglycoside analogs exhibiting reduced cell toxicity and superior readthrough efficiency compared with gentamicin might
hold hopes for an even better therapeutic future for this
emerging concept [125]. In addition to the aminoglycosides, a
novel chemical compound was recently identified, which
selectively induces ribosomal readthrough of premature, but
not normal termination codons [126]. This compound,
PCT124 (ataluren), has entered clinical trials and might
hold great potential for genetic disorders such as cystic fibrosis, for which no other therapeutic options are available [127].
As exemplified with the use of cysteamine for cystinosis, the
reduction of storage material might not only be achieved by
enhancement of enzymatic activity or inhibition of substrate
synthesis as covered in the previous sections. Accumulating
substrates might also be eliminated by substances such as
2-hydroxy-propyl-b-cyclodextrin, which is capable of binding
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3.7
unesterified cholesterol and other hydrophobic molecules. As
unesterified cholesterol is one of the major storage compounds in Niemann--Pick type C disease, the compound has
been tested in both the murine and feline model of the disease. Encouraging data from the most commonly used mouse
model of the disease (the NPCnih model) led to the FDA
approval of a compassionate use trial of cyclodextrin in a small
number of patients suffering from advanced Niemann--Pick
type C disease [128-130]. As cyclodextrins have been widely
used as formulation vehicles to increase the amount of drug,
including hormones and vitamins, which can be solubilized
in aqueous vehicles [131], its use and toxicological profile has
been extensively studied in rodents, dogs and monkeys where
it is well tolerated at low doses [131,132]. However, daily i.v.
administration of greater than 200 mg/kg caused reduced
body weight, foamy macrophage infiltration of the lungs, elevations in hepatic enzymes, increased Kuppfer cells in the liver
and renal cortical tubular vacuolization in rodents [131,133,134].
Doses used to reach therapeutic effect in the murine model
of Niemann--Pick type C are several-fold higher than the
doses at which no adverse events are seen (4000 mg/kg used
in the NPC mouse models) and apart from the available
toxicological data in healthy animals increasing data from
animal models of LSDs strongly suggest that the use of
this compound for any LSD should be carefully evaluated as
a number of side effects have been seen on treatment
including hearing loss and increased cholesterol burden and
macrophage infiltration of the lungs [128,135-137]. Furthermore,
as cyclodextrin does not cross the BBB [138] and as its use in
other murine models of cholesterol-storing LSDs such as
GM1-gangliosidosis and MPSIIIA had no effect on storage [130], it is clear that the mechanism of action is not fully
understood. Addressing these challenges will hopefully aid
the development and future therapeutic approaches relying
on this class of compounds.
Based on the complex pathology of the LSDs and the various
cellular and biological organelles and processes involved, a
number of experimental strategies, some including commercially available compounds, are being researched for their use
as disease modifiers. These approaches include calcium modulation, enhancing exocytosis, regulation of proteostasis, modulation of autophagy and the use of non-steroidal antiinflammatory drugs [42,139-145]. While most of these approaches
are at an early stage and still have a long way ahead to the clinic,
it is clear that a multifaceted approach is most likely needed to
address the complex pathology of LSDs. No doubt, as the
understanding of disease pathology advance, additional creative
approaches to treatment will emerge and undergo similar early
development with the hope that any of these approaches
ultimately lead to clinical benefit for the patients.
4.
Competitive environment
Table 1 summarizes the current status of the competitive
environment for LSD therapies with market approval,
Expert Opinion on Orphan Drugs (2013) 1(5)
397
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T. Kirkegaard
while Tables 2 and 3 summarize the various emerging therapies and concepts and provide a thorough overview of the status of the programs in primarily commercial development
pipelines for the LSDs.
The emerging concepts being explored for LSDs with high
unmet clinical needs or unaddressed pathology such as CNS
deterioration is an exciting field which holds a number of
promises for complimentary mechanisms of action offering a
potentially larger arsenal of drugs for future therapy but in
addition hereto, a number of primarily ERT projects are
also being developed for LSDs with established and effective
therapy as for example, type 1 Gaucher disease.
For type 1 Gaucher disease, three therapies are already
commercially available (two ERTs (imiglucerase and velaglucerase alfa) and one SRT (miglustat)), with two ERT programs, a CCT/ERT combination program and an SRT also
currently in development. The two ERT programs are based
on alternative manufacturing systems and whether the products of these programs have significant differentiating factors
with therapeutic relevance to the established therapies will
be interesting to follow. Interestingly, one of these products,
taliglucerase (Elelyso, Protalix/Pfizer), was recently approved
by the FDA (1 May 2012), but was rejected marketing
approval by the EU commission as velaglucerase alfa
(VPRIV) has 10 years marketing exclusivity under the
orphan drug framework.
5.
Expert opinion
The current state of the LSD field is both complex and
encouraging. Complex as the understanding of the underlying
molecular pathology of the vast heterogeneity in clinical presentation is still limited and constantly evolves. Encouraging
as novel therapeutic approaches evolve from these discoveries,
carrying with them the hope that they may eventually impact
the course of these devastating diseases.
Among this multitude of approaches, the ERTs still reign
supreme in number of products commercially available, as
well as number of programs in the development pipelines of
pharmaceutical companies, although a number of alternative
approaches are emerging.
Gaucher disease was the first LSD for which ERT became
available and the impact made by this approach not only clinically but also commercially subsequently prompted the
development of ERTs for a number of other LSDs. Recently,
a 10-year follow-up study of Gaucher disease patients treated
with ERT reported the lasting impact on patients health by
treatment with imiglucerase but the same degree of success
has unfortunately not been achieved with all ERTs although
early intervention in for example, infantile Pompe disease
has also been a marked success as this has proved life-saving [59,70]. Importantly, lessons learned from the use of
ERTs in the clinic have clarified the challenges still facing
ERTs and these are by no means trivial; adverse immunological reactions to infusion of enzyme are common and many
398
sites of pathology are not effectively treated by intravenous
administration of enzyme as these sites are not easily reached
by the infused enzyme. In addition, some manifestations of
disease has proven very hard to alleviate such as bone disease
in Gaucher disease and the MPS, renal complications in Fabry
disease and the degeneration of the CNS observed in many
LSDs. All of these sites provide therapeutic targets which
have yet to be efficiently reached by an ERT or therapeutic
variant hereof.
A major therapeutic advancement will therefore be molecules which can reach these sites of pathology and a number
of the emerging therapies are indeed aiming at exactly this,
with therapies being able to cross the BBB being a particular
focus for many of these development efforts. Until now only
one drug approved for an LSD has shown indications that it
might affect CNS complications. The orally administered
SRT, miglustat, was first approved for the treatment of adult
patients with mild to moderate type 1 Gaucher disease for
whom ERT is not a therapeutic option [91] and has since
been approved in the EU and other countries for the treatment of Niemann--Pick type C based on a clinical trial, which
demonstrated that treatment with miglustat improved eye
movement velocity and swallowing capacity indicating an
effect on CNS pathology [95]. The challenges facing SRTs
are based on their inherently unspecific mechanism of action
as the inhibition of ceramide glucosyltransferase (an early
core component in the glycosphingolipid synthesis pathway)
by virtue of the sequential synthesis steps in this pathway
unavoidably affects the synthesis and equilibrium of all downstream derivatives. Furthermore, miglustat is known to inhibit
several glycosidases, including a-glucosidase I and II as well as
sucrase and maltase, which might also explain parts of its sideeffect profile [146]. This inherent non-specificity raises concerns about long-term toxicities or adverse events for any
SRT but to date the side effects such as diarrhea have been
controllable, although there are still concerns regarding the
tremors and paresthesias that develop in some treated
patients [91]. A novel SRT in development, eliglustat tartrate,
has shown promising data including a more benign sideeffect profile, probably owing to its higher selectivity, but
unfortunately this agent is a target for P-glycoprotein meaning that it is efficiently pumped out of the brain and hence
will most likely not have an impact on CNS disease in
patients [97,147,148]. Nevertheless, the higher specificity and
milder adverse events indicate that this compound hold great
potential for being an efficacious SRT for the treatment of
peripheral disease in Gaucher disease and other sphingolipidoses, and the promise of SRT still spurs design of new agents
combining increased specificity and brain penetrating properties, providing a continued flow of potentially beneficial drugs
for a large subset of the LSDs [148].
Gene therapy strategies are a possibly very important intervention which has seen a breakthrough with the EU approval
of the first gene therapy (Glybera). This approach might offer
an alternative to existing therapies as might oral approaches
Expert Opinion on Orphan Drugs (2013) 1(5)
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Emerging therapies and therapeutic concepts for lysosomal storage diseases
and approaches with mechanisms of action across diseases
such as the SRT and molecular chaperone therapies.
In case of chaperone approaches to treating LSDs, two
intriguing concepts with the potential of addressing several
LSDs including diseases with CNS involvement are in development. These are approaches that employ either endogenous
molecular or chemical chaperones, respectively. The
approaches are inherently dissimilar as the molecular chaperone therapy approach utilizes the endogenous chaperone
machinery to not only enhance the activity of compromised
enzymes but also provide the dysfunctional lysosomes and
cells with the survival promoting benefits of the heat shock
proteins [43,103].
Almost counterintuitively, chemical chaperone technologies use competitive inhibitors to enhance residual enzyme
activity, with the technology having a plausible theoretical
basis in the conformational memory of proteins. CCT uses
competitive inhibitors of lysosomal enzymes at subinhibitory concentrations in order to facilitate the transition of
poorly folded lysosomal enzymes otherwise caught in the
ER/proteasomal degradation machinery to the lysosomes [106]. The technology has seen widespread development with a number of programs in current clinical trials,
but recent clinical data have highlighted the difficulties in
using inhibitors in already severely compromised enzymatic
systems. The most recent setback being reported only
recently as initial data from a Phase III randomized,
placebo-controlled study of migalastat in Fabry disease
including 67 patients showed that the study did not meet
its primary end points [108].
A major aid to any clinical trial and a significant advancement to the understanding of LSDs will be the development
of tests/biomarkers that accurately predict the disease outcomes and aggressiveness. Tools for better and early diagnosis
are also needed as the often irreversible degeneration and
pathology observed for many of these diseases prompt an early
and efficient intervention in order to have the highest likelihood of significantly improving the clinical outcome. The
development of these tools will be important not just for the
understanding of the diseases and their progression but will
hopefully allow for better clinical trial designs and a better
definition of subpopulations of patients that will have better
or poorer responses to therapies.
As early intervention is generally considered a prerequisite
for the prevention of irreversible complications in any LSD,
the development of suitable biomarkers is of significant importance as their absence makes it difficult to support presymptomatic pharmacological therapy without the capacity to monitor
consequences of the intervention. Of course, early lifesaving interventions are completely unethical to withhold in
for example, infantile Pompe, Krabbe and Niemann--Pick
type A disease, but when should one intervene in more gradually developing diseases? As the current therapies are not benign
and have not only medical but also social and economical implications for the patient in terms of insurability and employability, the initiation of therapy needs very careful consideration
which will also be the case for the therapies in development.
However, progress in biomarker characterization is being
made for a number of diseases such as Gaucher disease, Fabry
disease, the MPS and Niemann--Pick type C disease [149-151].
No doubt the number of emerging therapies for LSDs is
encouraging, with a lot of exciting biological mechanisms
being explored as potential drug targets. This is however,
also necessary as the complex nature of the diseases almost certainly demands a combined effort targeting not only general
or specific pathology but rather aims at a shot-gun approach
for treatment utilizing a battery of therapeutic modalities to
deal with the intricate molecular pathology underlying these
devastating diseases.
Importantly, the significant cost of therapy for these very
rare diseases has to be considered not only at an individual
level, but also by physicians and society at large as we seek
to improve the life of patients with LSDs. This consideration
becomes of particular relevance in the case of combination
therapies, which will most likely be the future way to improve
the life of patients who by odd chance have developed such
devastating diseases.
Declaration of interest
The author is employed by and holds shares in Orphazyme
ApS, which develops therapies for lysosomal storage diseases.
Expert Opinion on Orphan Drugs (2013) 1(5)
399
T. Kirkegaard
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Affiliation
Thomas Kirkegaard PhD
Chief Scientific Officer,
Orphazyme ApS, Ole Maaløes Vej 3,
2200 Copenhagen, Denmark
Tel: +45 40532454;
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