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Title:
Combined therapies for lysosomal storage diseases
Running title: Therapies for lysosomal diseases Magdalena Gabig-Cimi?ska1,§, Joanna Jakóbkiewicz-Banecka2,§, Marcelina
Malinowska2, Anna Kloska2, Ewa Piotrowska2, Izabela Chmielarz2, Marta
Moskot1, Alicja W?grzyn1, Grzegorz W?grzyn2,* 1Laboratory of Molecular Biology (affiliated with the University of
Gda?sk), Instituite of Biochemistry and Biophysics, Polish Academy of
Sciences, Wita Stwosza 59, 80-308 Gda?sk, Poland
2Department of Molecular Biology, University of Gda?sk, Wita Stwosza 59, 80-
308 Gda?sk, Poland §These two authors contributed equally. * Corresponding author:
Prof. Grzegorz W?grzyn
Department of Molecular Biology, University of Gda?sk, Wita Stwosza 59, 80-
308 Gda?sk, Poland
Tel. +48 58 523 6024; Fax: +48 58 523 5501; e-mail:
grzegorz.wegrzyn@biol.ug.edu.pl
ABSTRACT Lysosomal storage diseases (LSDs) is a group consisting of over 50
disorders caused mostly by dysfunctions of lysosomal proteins and resultant
accumulation of particular compounds inside cells and extracellular volumes
in affected organisms. Genetic diseases are among the most difficult
targets for medical treatment. Nevertheless, understanding of molecular
bases of LSDs made it possible to develop novel procedures of treatment,
employing molecular medicine. Although various therapeutic approaches have
been proposed, and some of them were introduced into clinical practice,
none of them was found to be effective in correcting all symptoms in
treated patients. Central nervous system and skeleton appear to be the most
difficult targets to be improved. Therefore, a proposal appeared that
perhaps no single therapeutic procedure may be fully effective in treatment
of LSD patients, and only combination of two or more approaches could be a
successful therapy. In this review, we present and discuss current stage of
various combination therapies for LSDs, based on already available
published data. Keywords: combined therapies, enzyme replacement therapy, gene therapy,
hematopoietic cell transplantation, lysosomal storage diseases, small
molecular chaperones, substrate reduction therapy
Introduction: lysosomal storage diseases and therapeutic options Although currently vast majority of genetic diseases cannot be
effectively treated, several therapeutic options are available for
lysosomal storage diseases (LSDs), a group of inherited metabolic
disorders, and other treatment procedures are under development [1-5]. This
privileged position of LSDs stems from our understanding of molecular
mechanisms of these diseases and availability of various research models,
both cellular and animal, which allowed researchers to conduct extensive
studies on various potential methods of treatment [6-13]. Therefore,
despite the fact that mechanisms of LSDs appeared significantly more
complicated than initially supposed [14] specific therapies for some LSDs
are in clinical practice now [1]. Because of the nature of LSDs, most of
newly developed therapies for these diseases, or those being under
development, are based on molecular medicine.
The primary mechanisms of LSDs are based on mutations in certain genes
coding for proteins involved in lysosomal functions (note that each
particular LSD is a monogenic disorder). A lack or severe impairment of
activity of particular protein causes dysfunction of lysosomal apparatus
and accumulation of certain compound(s) in lysosomes. This is the first
step of the cascade of secondary effects leading to different perturbations
in cellular metabolism, followed by dysfunctions of tissues and organs.
LSDs are classified according to the kind of deficient protein and nature
of primarily accumulated compound(s) [15]. The mechanisms of LSDs are
presented schematically in Fig. 1.
LSDs are recognized as severe diseases, characterized by high
morbidity and mortality, with average life span below two decades. In most
diseases from this group, central nervous system (CNS) is affected, which
makes them particularly difficult to manage [16]. However, several medical
products have been approved for use in treatment of different LSDs, and
some of them were found relatively effective in treatment of somatic
symptoms [17]. On the other hand, no currently used treatment can correct
all disease symptoms. Moreover, none is effective in management of
neuronopathy in patients [1]. Therefore, a proposal appeared that perhaps
no single therapeutic procedure may be fully effective in treatment of LSD
patients, and only combination of two or more approaches could be a
successful therapy [18-21]. The most important therapies either already
used to treat LSD patients or being under development are listed in Table
1.
In this review, we present and discuss the current stage of
development of various therapeutic approaches, with special emphasis on
experiments with a combined use of more than one treatment at the time.
Particular LSDs or subgroups of them will be discussed sequentially to
underline specificity of each disease or a subgroup of disorders.
Gaucher disease
Gaucher disease (GD) is caused by mutations in the GBA gene, coding
for lysosomal glucocerebrosidase, and resultant accumulation of
glucosylceramide and glucosylsphingosine. Currently there are two different
therapeutic approaches approved for GD, one based on enzyme replacement
therapy (ERT) and the other on substrate reduction therapy (SRT). ERT with
imiglucerase (Cerezyme; Genzyme Corporation), velaglucerase alpha (VPRIV;
Shire HGT) or taliglucerase alpha (Elelyso; Pfizer and Protalix
BioTherapeutics) corrects disease manifestations in visceral organs and
haematological parameters, but fails to manage neurological symptoms in
neuronopathic types of GD (type 2 and 3). An approved SRT for Gaucher
disease is based on oral administration of N-butyldeoxynojirimycin (NB-DNJ,
miglustat, Zavesca; Actelion Pharmaceuticals), an iminosugar acting as an
inhibitor of glucosylceramide biosynthesis by reversible inhibition of
glucosylceramide synthase activity. Miglustat has been shown to improve
clinical features in patients with GD type 1 (non-neuronopathic) with mild
to moderated symptoms who are unable to be treated with ERT (reviewed in
[22]). Some other therapeutic strategies for Gaucher disease are tested in
vitro or are a subject of clinical trials, e.g. SRT with eliglustat
tartrate, that is another glucosylceramide synthase inhibitor [23], or
therapies with drugs acting as pharmacological chaperones (PC) for
glucocerebrosidase such as isofagomine (IFG) [24, 25] and ambroxol (to
date, commonly used as a mucolytic drug) [26, 27].
Several studies described also effects of different combination
therapies for GD using cell cultures, animal models as well as studies on
humans. A case of an adult white male Gaucher disease type 3 patient was
described, who received ERT alone for several years, and next SRT with
miglustat was included in the treatment together with imiglucerase [28].
During the ERT treatment, started at the age of 18, first with alglucerase,
then continued with imiglucerase combined with anticonvulsant drugs,
visceral and hematological parameters markedly improved, but the
neurological deterioration and epileptic manifestation progressed. Next,
during twoyears of combination therapy with miglustat and imiglucerase, an
improvement of the neurological outcome of the disease has been reported,
especially regarding the epilepsy events and speech as symptoms of the
neuropathology [28]. On the contrary, 24-month, phase II, open-label
clinical trial conducted on type 3 Gaucher disease patients revealed no
effect of miglustat treatment combined with ERT on neurological
manifestations of the disease [29]. Nevertheless, some positive effects on
systemic disease were observed during the trial, including improvement in
pulmonary function and decrease in chitotriosidase activity [29]. On the
other hand, the case of three siblings with type 3 Gaucher disease treated
with ERT combined with SRT was reported [30]. Treatment with high-dose
imiglucerase (120 U/kg) together with miglustat, started at the age of 5
months in the youngest sibling, resulted in complete neurological
stabilization and age-appropriated psychomotor development in that patient
after two years of combination therapy. Although including miglustat to
high-dose ERT treatment of two elder siblings (at the age of 14 and 10
years), who were already severely developmentally delayed, did not improve
the neurological status, it remained stable and no further deterioration
was observed after two years of combination treatment. Additionally,
chitotriosidase activity in cerebrospinal fluid was not elevated after 1.5
year of combination treatment comparing to the baseline. These results
suggested that this kind of therapeutic approach, based on combination of
ERT and SRT with miglustat, might prevent neurodegeneration in GD type 3
[30].
In another clinical trial, the safety and efficacy of miglustat
treatment was tested in Gaucher disease type 1 patients, first stabilized
with imiglucerase and next switched to miglustat monotherapy or to
combination therapy with miglustat and intravenous enzyme replacement [31].
After 6 months of treatment, clinical parameters of Gaucher disease type 1
were stable in most patients switched to miglustat, comparing to the group
continuing imiglucerase monotherapy. However, combination therapy
(miglustat with imiglucerase) did not show any additional benefit comparing
to both monotherapies. Miglustat was shown to be well tolerated either
alone or in combination with imiglucerase [31]. Similar results (i.e. no
change in liver volume) of miglustat monotherapy during 24 months after
switch from previous ERT, were obtained, suggesting that miglustat could
maintain clinical stability (ClinicalTrials.gov identifier: NCT0031