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Emptying the Stores:
Lysosomal Diseases and Therapeutic Strategies
Frances M. Platt
Department of Pharmacology,
University of Oxford,
Oxford, OX1 3QT, UK
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Abstract
Lysosomal storage disorders (LSDs), - designated as "orphan" diseases - are
inborn errors of metabolism caused by defects in genes that encode proteins
involved in various aspects of lysosomal homeostasis. For many years LSDs were
viewed as unattractive targets for the development of therapies owing to their
low prevalence. However, the development and success of the first commercial
biologic therapy for a LSD - enzyme replacement therapy (ERT) for type 1
Gaucher disease - coupled with regulatory incentives, rapidly catalyzed
commercial interest in therapeutically targeting LSDs. Despite ongoing
challenges, various therapeutic strategies for LSDs now exist, with many agents
approved, undergoing clinical trials or in preclinical development.
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Introduction
Lysosomal storage disorders are a family of over seventy rare monogenic
diseases that typically present in infancy or childhood and collectively affect
1:5000 live births [1]. However, adult onset forms also occur and are frequently
misdiagnosed, so are likely to be more prevalent than currently believed [2-4].
The vast majority of LSDs share the common cellular feature of an expanded
lysosomal system, caused by the accumulation of a variety of cellular
macromolecules (storage). The storage material(s) differs biochemically in each
disease, reflecting the nature of the primary genetic defect [5]. Most of the
causative genes encode lysosomal enzymes or proteins involved in lysosomal
enzyme modification or transport, but they can also encode lysosomal
membrane proteins [6]. When a lysosomal enzyme is deficient its substrate(s) is
stored, with membrane protein defects the pattern of storage can be more
complex, depending on the function of the protein in question. The genetics and
biochemical nature of the storage substrates for most LSDs are well defined,
however we still have an incomplete knowledge of how lysosomal dysfunction
triggers the complex cellular pathogenic cascades that occur in LSDs that cause
cell dysfunction and ultimately cell death [7]. Approximately seventy percent of
LSDs present as progressive neurodegenerative diseases, highlighting how
vulnerable the central nervous system is to lysosomal dysfunction [5]. In
addition, peripheral organs and tissues are also often affected in these diseases
and the majority are therefore chronic, multimorbidity diseases, which has
significant implications for the development of effective therapies as multiple
compartments of the body may require correction/ effective treatment. The
availability of authentic animal models of LSDs in multiple species (typically
rodents, companion animals and livestock species) has supported the study of
pathogenesis and greatly facilitated translational activity [8]. Rare and ultra rare
diseases such as LSDs, with complex pathophysiology often involving the brain,
were not historically the focus of pharmaceutical industry interest. However,
paradoxically LSDs are currently a burgeoning translational field with multiple
approved products in routine clinical use and intense academic and commercial
activity innovating new therapeutic approaches at a remarkable rate [9]. The
trigger for the translational activity in this field was the pioneering academic and
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commercial effort to develop the first biologic therapy for a LSD, enzyme
replacement therapy for type 1 Gaucher Disease [10]. The development of
biologics and more recently small molecule drugs for LSDs has made it more
important than ever that patients with these diseases are correctly diagnosed
and treated as early as possible to maximize therapeutic benefit. Newborn
screening is an expanding area that aims to identify cases at birth and instigate
treatment rapidly, should a therapy be available [11, 12]. Early diagnosis of the
first affected case in a family also provides the parents reproductive options to
prevent other cases being born in the future. The ethical dilemmas of newborn
screens are complex and how mutations of unknown significance are handled
remains a serious concern, as there is a significant risk of branding a healthy
infant with an LSD diagnosis that may never manifest clinically in the individuals
lifetime [13].
This review will provide an overview of LSDs and will assess the challenges
associated with their diagnosis, drug development and treatment. We are now in
an exciting translational era where the biologic therapies that have been the
cornerstone of treatment to date are being complemented by a diverse range of
small molecules and nucleic acid-based therapies. Therapeutic approaches either
approved, in clinical trials or where advanced pre-clinical proof of concept has
been demonstrated will be discussed.
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The Lysosome
The lysosome is an acidic organelle that serves as the major catabolic and
recycling center of nucleated cells [14]. The biogenesis of lysosomes is tightly
regulated, along with autophagic pathways, by the Coordinated Lysosomal
Expression and Regulation (CLEAR) gene network [14-16], which is under the
control of the master transcription factor EB (TFEB)[17-19] in cooperation with
transcription factor E3 (TFE3)[20]. The wider lysosomal system is now
appreciated to play a central role in general energy metabolism and the body's
response to exercise [19, 20] as well as regulating aspects of cholesterol
homeostasis [21].
The lysosome contains numerous acid hydrolases required for macromolecule
catabolism. The limiting membrane of the lysosome is populated with over 300
membrane proteins [22, 23], many of which are known to be involved in
lysosomal homeostasis. This includes the maintenance of acidic pH and
exporting metabolites generated in the lysosome to facilitate their utilization by
other organelles/compartments in various aspects of cellular metabolism [22,
23]. These membrane proteins (e.g. LAMP1) are heavily glycosylated, forming a
protective glycocalyx on the internal face of the limiting membrane. Intriguingly,
sialic acid residues on LAMP1 play a role in the process of exocytosis suggesting
that the glycocalyx does more than simply provide a carbohydrate barrier to
protect the limiting membrane from auto-catabolism [24]. However, the
functions of the majority of lysosomal membrane proteins remain unknown at
the present time [22, 23]. Lysosomes can fuse with late endosomes,
autophagosomes and phagosomes and so are important for both cellular
homeostasis and combatting infection [25]. They also form contact sites with
other organelles (e.g. mitochondria and ER) where exchange of ions, lipids and
other molecules takes place [26, 27]. This is an area that requires greater
research as it will no doubt yield major insights into lysosomal cross talk with
other organelles and provide a better understanding of how metabolites move
out of the lysosome to be utilized in other cellular compartments [27]. Over the
past twenty years, many additional functions of the lysosome have been
identified, including nutrient sensing, lysosomal cell death pathways, plasma
membrane repair and calcium signaling [28-31]. The lysosome therefore has