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Acta Myol. 2007 July; 26(1): 87–92.
PMCID: PMC2949325

Update on treatment of lysosomal storage diseases


Lysosomal storage diseases (LSDs) are a large group of disorders caused by a deficiency of specific enzymes responsible for the degradation of substances present in lysosomes.

In the past few years, treatments for LSDs were non specific and could only cope with signs and symptoms of the diseases. A successful therapeutic approach to LSDs should instead address to the underlying causes of the diseases, thus helping the degradation of the accumulated metabolites in the various organs, and at the same time preventing their further deposition. One way is to see to an available source of the deficient enzyme: bone marrow transplantation, enzyme replacement therapy and gene therapy are based on this rationale. The purpose of substrate reduction therapy is to down regulate the formation of the lysosomal substance to a rate at which the residual enzyme activity can catabolize the stored and de novo produced lysosomal substrate. Chemical chaperone therapy is based on small molecules able to bind and stabilize the misfolded enzymes.

This paper offers a historical overview on the therapeutic strategies for LSDs.


Lysosomal storage diseases (LSDs) are a large group of disorders caused by a deficiency of specific enzymes responsible for the degradation of substances present in lysosomes (1).

Except for red blood cells, lysosomes are contained in all cells of the organism, thus the metabolic disorder may affect different organs and systems at the same time.

The clinical signs characterizing the different diseases depend on the quantity and type of accumulated substance; in general, the disease is named after the type of undegraded substrate. Most LSDs have an autosomal recessive inheritance pattern. Mucopolysaccharidosis type II, Fabry disease and Danon disease are X-linked.

From a clinical point of view, the biochemical alteration turns into a gradually deteriorating clinical picture: coarse facial features, hepatosplenomegaly, skeletal anomalies; various degrees of mental retardation prevail in Mucopolysaccharidoses, Mucolipidoses and Glycoproteinoses, while the remaining LSDs are mainly characterized by an involvement of the central nervous system, associated, in some forms, with hepatosplenomegaly.

The prognosis is very serious in most LSDs and great effort has always been made to find treatment options fit to face the underlying causes. A successful therapeutic approach to LSDs should ensure an available source of the deficient enzyme, thus helping the degradation of the accumulated metabolites in the various organs, and at the same time preventing their further deposition. This paper offers a historical overview on the therapeutic strategies for LSDs.

Therapeutic strategies to ameliorate LSDs

Different therapeutic approaches were used in the past to face the underlying causes of the diseases: infusion of plasma or plasma fractions, intravenous injection of exogenous enzymes extracted from human tissues, infusion of leukocytes and implantation of skin fibroblasts or amniotic cells. Though theoretically correct, all these first therapeutic attempts resulted in a poor efficacy from a clinical point of view, and their use in patients was impractical. However, they led to the innovative therapies, such as bone marrow transplantation (BMT) and infusion of recombinant enzymes, laying the foundation for gene therapy as well. Table Table11 lists the therapeutic approaches that have showed efficacy and an acceptable level of practicability in treating LSDs.

Table 1
Therapeutic Strategies for LSDs.

Bone marrow transplantation (BMT)

In the early 1980s Hobbs et al. (2) published the first results concerning the use of BMT in two patients affected by Hurler syndrome. The rationale of such approach was the possibility of providing a patient with a permanent source of the defective enzyme. Through BMT, hematopoietic stem cells of the donor colonize the bone marrow of the recipient, where they differentiate into the various hematopoietic lines. The monocyte-macrophage system is the basic mechanism of the therapeutic action, as it is based on the capability of the circulating monocytes to escape from the vessels and migrate inside the organs where they turn into macrophages. When reaching the different sites, the macrophages secrete the defective enzyme, which is internalized by the surrounding affected cells; then the enzyme reaches the lysosomes and degrades the stored, undigested material.

A second less important mechanism lies in the capability of a patient’s affected cells of the patient to pick up the enzyme secreted by the cells of the donor in the plasma through an endocytosis mechanism.

The results described by Hobbs and coworkers were strikingly encouraging; straight afterwards, BMT became a choice therapy for many patients affected by different lysosomal storage disorders and various severity of symptoms. Since most patients were affected by different types of Mucopolysaccharidosis, the wide range of severity of symptoms, the utilization of different typologies of donors and various ablative regimens were the main causes of the presence of wide-ranging results difficult to compare and unify. Therefore, it became necessary to find a consensus on the eligibility criteria of the patients undergoing BMT. In 1991 the International Society for the Correction of Genetic Diseases by Transplantation (COGENT) developed a guideline and suggested that only children under three years with intelligence quotient above 70 should undergo BMT; in addition the availability of a HLA-matching donor is mandatory (3).

More than 500 patients affected by lysosomal storage disorders have been treated with allogenic stem cell transplantation with variable success (4, 5) and references therein.

Enzyme Replacement Therapy (ERT)

In 1964 De Duve first suggested that LSDs could be treated by replacing the defective enzyme (6), but only with the advent of molecular genetic techniques, therapeutic amounts of the defective enzymes could be synthesized and ERT is now available for several LSDs (Table (Table2)2) (7, 8) and references therein. Gaucher disease was the first LSD treated with recombinant human α-glucocerebrosidase; recombinant mannose-terminated human glucocerebrosidase, imiglucerase, has become the ‘gold-standard’ for non-neuronopathic type 1 Gaucher which all other therapeutic approaches are compared to. Non-neuronopathic type 1 Gaucher patients experience significant improvements from baseline in haematological measures (haemoglobin level and platelet count), organomegaly measures and bone manifestations in response to ERT. At the moment there are specific drugs for the treatment of Fabry disease, Hurler-Scheie (Mucopolysaccharidosis I H-S, MPS IH-S) and Scheie (MPS IS) syndromes, Hunter syndrome (MPS II), Maroteaux-Lamy (MPS VI) syndrome, and Pompe disease. Treatments for Niemann-Pick B disease, Metachromatic leukodystrophy and α-mannosidosis are at the preclinical stage (Table (Table22).

Table 2
Lysosomal Storage Diseases treated with ERT.

Studies carried out so far have proved a consistent positive effect of ERT on Fabry patients substantially modifying their natural history; in particular reduction of neuropathic pain, improvement of renal, myocardial and nerve fiber functions have been shown.

Intravenous administration of α-L-iduronidase resulted in clinical and biochemical improvement of patients with MPS IH-S and MPI IS, ameliorating their range of shoulder motion and elbow extension. Patients showed an increase of growth rate and a reduction of glycosaminoglycans in the urine. Hepatosplenomegaly decreased significantly, the number of incidents of apnea and hypopnea during sleep decreased, New York Heart Association functional class improved by one or two classes. It is convenient to point out that the use of ERT is advisable only in the types of LSD without mental retardation, since the exogenous enzyme does not cross the hematoencephalic barrier and so would be uneffective in patients with mental retardation (Hurler syndrome, Sanfilippo syndrome, Tay-Sachs syndrome, etc.).

The treatment efficacy of MPS II with α-L-iduronate sulphatase has been tested in a phase I/II clinical trial on twelve patients, and afterwards in an open label extension study. There was a decrease of the excretion of glycosaminoglycans in the urine, the volume of liver and spleen decreased, the six-minute walk test improved, and the range of joint motion increased.

Recombinant human N-acetylgalactosamine-4-sulphatase (arylsulphatase B) available for the treatment of Maroteaux-Lamy Syndrome (MPS VI) proved to be efficient in reducing the urinary glycosaminoglycans, improving the ability of the patients to walk, increasing the range of shoulder motion, and reducing the joint pain.

Finally, ERT was successful in the treatment of Pompe disease, with the extension of life span for Pompe patients with the infantile-onset form to more than four years, and significant improvement of general conditions and walking ability in Pompe patients with the late-onset form.

Other Therapeutic Approaches

ERT proved to be effective and highly beneficial in treating lysosomal storage diseases; in addition, great effort has been made to develop novel strategies to be used either alone or in combination with ERT.

An approach to the treatment of some LSDs is the use of substances able to inhibit the storage of specific metabolites, by depriving the lysosomes of the undegraded substance. In particular, this therapeutic strategy, called substrate reduction therapy (SRT), was first used in Gaucher disease, and recently it has been tested in Fabry disease and GM1 and GM2 Gangliosidoses, as well. The main idea is that patients who have significant residual enzyme activity can gradually clear the lysosomal storage material. The drugs used in this approach aim at retarding the formation of the lysosomal substance to a rate at which the residual enzyme activity can catabolize stored and incoming lysosomal substance. Two main classes of inhibitors of glycosphingolipid biosynthesis have at present been described. Both inhibit the ceramide-specific glucosyltransferase: the first class of inhibitors is made of analogues of ceramide; the second one of N-alkylated iminosugars (9). N-butyldeoxynojirimycin (Miglustat) was approved for patients with mild to moderate type 1 Gaucher disease unwilling or unable to receive ERT (10). The use of hydrophobic iminosugars seemed to be promising in mouse models of Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis and Niemann-Pick disease type C (11, 12). At present many more trails with miglustat are being carried out in patients with Niemann-Pick disease type C, late-onset Tay-Sachs disease and juvenile Sandhoff disease (GM2 gangliosidosis).

A new therapeutic strategy has been recently undertaken for some LSDs; it is based on the use of “chaperone” substances, that have the function of binding and stabilizing misfolding-prone proteins, thus increasing the residual enzyme activity (7). In particular, it has been proved that the infusion of galactose or certain reversible competitive inhibitors of α-galactosidase A (such as 1-deoxy-galactonojirimycin) can increase the residual enzyme activity in cultures of fibroblasts from patients with the cardiac variant of Fabry disease (13). An active site-directed chemical chaperone for α-galactosidase A to treat Fabry disease is currently in phase I clinical trial. Matsuda and coworkers have synthesized a galactose derivative for the chaperone chemical therapy of GM1-gangliosidosis (14). At present, chemical chaperoning has shown to be effective in increasing the activity of the highly prevalent N370S and the less common G202R glucocerebrosidase variants, by culturing Gaucher patient’s fibroblasts with a variety of iminosugar compounds (15).

Finally, in the last few years, many studies have been carried out in vitro as well as on animal models to evaluate the effectiveness of gene therapy in LSDs. This therapeutic strategy is based on the idea of directly transfering the normal gene into the defective cells in order to supply the active enzyme and, consequently, reduce the intralysosomal undegraded substances. This can be achieved by either ex vivo or direct in vivo gene therapy strategies. Table Table33 lists the viral vectors tested so far for in vivo gene transfer (16, 17) and references therein.

Table 3
Gene therapy strategies ((16, 17) and references therein).

Experiments on animal models have been carried out in Mucopolysaccharidosis I, II, III, VI, VII, in many Lipidoses, such as Gaucher disease, Fabry disease, Metachromatic leukodystrophy, GM1 and GM2 Gangliosidosis, Niemann-Pick disease, Farber disease and Pompe disease. The results of such studies have been univocal and have shown the effectiveness of gene therapy in vitro as well as on animal models. As far as we know, the only data about gene therapy on man concern one case of Mucopolysaccharidosis II (18), three patients affected by Mucopolysaccharidosis I (19) and some patients suffering from Gaucher disease (20). Considering the researches carried out so far, we think that many problems have still to be solved before proving unequivocally effectiveness and safety of this treatment in man: a patient’s optimal age for undergoing gene therapy, the possible development of immunologic reactions, the capability to modulate both levels and duration of enzyme activity, the need of finding a specific ablative regimen for BMT approach.


As above reported, therapeutic approaches toward finding treatment options fit to face the underlying causes are many: so far positive results, unanimously accepted by the international scientific community, have been obtained only for few lysosomal disorders. However, LSDs, though quite rare diseases, are getting more and more investments from private enterprises interested in orphan drug production. The above mentioned fact lets us hope that, in a near future, the natural development of more and more diseases will be influenced and thus modified.


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