Advances in the treatment of lysosomal storage disease. Annotation

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1 Advances in the treatment of lysosomal storage disease J E Wraith MB ChB FRCP FRCPCH, Director, Willink Biochemical Genetics Unit, Royal Manchester Children s Hospital, Manchester M27 4HA, UK. Annotation Correspondence to author at address above. ed@willink.demon.co.uk If a group of metabolic paediatricians had been asked 10 years ago which disorders they thought would be the most treatable at the start of the new millennium, very few would have mentioned lysosomal storage disorders (LSDs). The early onset, progressive nature, and tendency to involve the CNS have always been regarded as major hurdles to effective treatment. However, the final decade of the 20th century has seen developments in organ transplantation, enzyme replacement therapy (ERT), and gene transfer so that curative treatment for at least some of these disorders is no longer a distant goal. The lysosome is an abundant membrane-bound vacuole found in almost all cells. It encloses an acid compartment generated by proton ATPase and houses the mature forms of a number of acid hydrolases which are important in cell digestion and recycling and in forming the terminal compartment in the endocytic pathway. At least 40 different disorders are associated with pathological storage of naturally occurring compounds within lysosomes. In some instances this is the result of a deficiency of a specific hydrolase and in others it is due to a defect in transport, either of the hydrolase to the organelle or of a specific compound out of the lysosome. Table I shows a breakdown of these disorders which, by convention, are usually classed according to the storage compound. There have been few comprehensive studies of the prevalence of LSDs as a group. Recent studies from Australia and the Netherlands suggest a combined prevalence of about 1 per 7500 live births, 1, 2 which makes LSDs twice as prevalent as phenylketonuria (PKU) in these communities. The excellent text edited by Applegarth, Dimmick, and Hall 3 gives a general review of lysosomal structure and function. A feature of the majority of LSDs is the great clinical variability in diseases associated with a single enzyme defect. There may be substantial variation in the age at which the disease becomes apparent, the rate at which functional deterioration occurs, and in the range of affected tissues. As a general rule, disease presenting in infancy or early childhood is associated with a more rapid progression of symptoms and a poorer prognosis, while late-onset disease may be compatible with a normal lifespan. These clinical features crystallize many of the issues facing a systematic approach to therapy in LSD, and can be summarized as a need to identify before the onset of irreversible pathology and for therapy to restore enzyme activity successfully in a broad range of tissues, including the CNS for some LSDs. Treatment of LSDs SUPPORTIVE THERAPY Where curative therapy is not contemplated the aim is to improve quality of life of the by judicious surgeries and frequent careful assessment of their general condition. Supportive care has an important role in the management of all LSDs and until recently was all that could be offered to the majority of. A multidisciplinary approach is needed with other paediatric specialists as well as physiotherapists, dieticians, occupational therapists, and teachers being part of the therapy team. The family should receive appropriate community support, aids, adaptations, and help with financial claims. Genetic counselling is essential, as there is a risk of recurrence with all LSDs. ENZYME REPLACEMENT THERAPY There has been a resurgence of interest in ERT as a treatment for LSDs. Two factors contribute the most to this change of approach: first, the resounding success of ERT in type I Gaucher disease has revolutionized outcome in this disorder and second, the problems associated with prolonged gene expression following transfer in gene therapy experiments have proven formidable, leading to a change of direction for some therapists. ERT follows from the observation that many lysosomal enzymes can be secreted and then sequestrated by lysosomes in distant tissues and can be transferred to neighbouring cells by direct cellular contact. The circulation of lysosomal enzymes has been reviewed. 4, 5 In brief, the lysosomal protein is synthesized in the rough endoplasmic reticulum, transported to the Golgi following cleavage of a signal peptide, and transferred to the acidic prelysosomal compartment. At this point one of two things can happen: the protein can be segregated for immediate transfer to the lysosome or pass into a secretory pathway leading to release of the protein from the cell and then secondary reuptake via receptor mediated endocytosis into other cells. Developmental Medicine & Child Neurology 2001, 43:

2 Table I: Lysosomal storage disorders Disease Enzyme Storage Chromosome Gene Screening Diagnostic Prenatal Reference deficiency material location mutations test test diagnosis number MPS MPS I (Hurler, Iduronidase DS, HS 4p16.3 W402X, Urine WBC Enzyme CVB a 28 Scheie, Hurler/ Q70X plus GAGs Assay Scheie) many others MPS II (Hunter) Iduronate-2- DS, HS Xq27-28 No common Urine Plasma Enzyme CVB b 28 sulphatase mutations GAGs Assay MPS III (Sanfilippo) IIIA Heparan-n- HS 17q25.3 R245H, Urine WBC Enzyme CVB 29 sulphatase R74C and GAGs Assay many others IIIB N-acetyl- HS 17q21.1 No common Urine Plasma Enzyme CVB 29 glucosaminidase mutations GAGs Assay IIIC Acetyl CoA HS Uncertain Unknown Urine WBC Enzyme CVB 29 glucosamine GAGs Assay n-acetyl transferase IIID N-acetyl- HS 12q14 Very few Urine WBC Enzyme CVB 30 glucosamine- GAGs Assay 6-sulphatase MPS IV (Morquio) IVA Galactose-6- KS 16q24 I113F Urine WBC Enzyme CVB 31 sulphatase (UK and GAGs Assay Ireland) IVB β-galactosidase KS 3p21-pter No common Urine WBC CVB 28 mutations GAGs Enzyme Assay MPS VI (Maroteaux- Galactosamine-4- DS 5q13-q14 No common Urine WBC Enzyme CVB c 28 Lamy) sulphatase mutations GAGs Assay MPS VII (Sly) β-glucuronidase HS, DS 7q21.1-q22 Very few Urine WBC Enzyme CVB 28 GAGs Assay MPS IX Hyaluronidase HA 3p21.3 Very few None Cultured Unknown 32 cells Mucolipidoses ML I (Sialidosis I) Neuraminidase SA 10pter-q23 No common Urine Cultured Cultured 33 mutations sialic cells cells acid ML II (I Cell) Transferase d Many Unknown Unknown Urine Plasma Enzyme Cultured 34 oligos Assays cells or AF ML III (pseudo-hurler) IIIA As ML II Many Unknown Unknown Urine Plasma Enzyme Cultured 34 oligos Assays cells or AF IIIC Transferase - Many 16p Very few Urine Plasma Enzyme Cultured 35 δ-sub-unit oligos Assays cells or AF ML IV Unknown Unknown 19p R750W (20%) None Histology Histology 36 of CVB Sphingolipidoses GM 1 -gangliosidosis β- GM 1-3p21-3pter No common Urine WBC Enzyme CVB 37 Galactosidase gang. KS, mutations oligos Assay oligos, Glycolipids GM 2 -gangliosidosis Tay Sachs β- GM 2-15q common None WBC Enzyme CVB 38 Hexosaminidase A gang. Ashkenazi Assay Globoside, mutations oligos glycolipids MPS, mucopolysaccharidosis; DS, dermatan sulphate; HS, heparan sulphate; GAGs, glycosaminoglycans; CVB, chorion villus biopsy; WBC, white blood cell; KS, keratan sulphate; HA, hyaluronic acid; SA, sialic acid; Oligos, oligosaccharides; AF, amniotic fluid. a Low activity in CVB caution re: contamination with maternal decidua. b Always do foetal sexing as some unaffected female foetuses will have very low enzyme results. c Difficult because of cross-reactivity from other sulphatases. d UPD-N-Acetylglucosamine, lysosomal enzyme N- acetylglucosaminy-l-phoaphotoransferase. 640 Developmental Medicine & Child Neurology 2001, 43:

3 Table I continued Disease Enzyme Storage Chromosome Gene Screening Diagnostic Prenatal Reference deficiency material location mutations test test diagnosis number Sandhoff β- GM 2-5q13 Common None WBC Enzyme CVB 39 Hexosaminidase gang. Maronite Assay A & B oligos mutation GM 2 -gangliosidosis Gm 2 activator GM 2-5q32-33 Very few None Cultured cells Unknown 40 gang. and natural glycolipids substrate Globoid cell Galacto- Galactosyl- 14q31 502T/del None WBC Enzyme CVB 41 leucodystrophy cerebrosidase ceramides (40%) Assay Krabbe MLD Arylsulphatase Sulpha- 22q13-3 IVS2+1G None WBC Enzyme CVB 42 A tides A and Assay P426L (50%) MLD Saposin B activator Sulphi- 10q21 Very few None Sulphatide In theory 43 (sap B) tides, loading of sulphatide GM 1 -gang, cultured cells loading of glycolipids cultured cells +/or DNA Fabry disease α-galactosidase A Galacyosyl- Xq22 No common None WBC Enzyme CVB 44 sphingo- mutations Assay lipids oligos Gaucher disease β-glucosidase Gluco- 1q21 N370S, 84gg, None WBC Enzyme CVB 45 ceramide L444P IVS2+1, Assay D409H, R463C Gaucher disease Saposin As above 10q21 Very few None Unknown Unknown 46 C activator Farber disease Ceramidase Ceramide 8p Very few None WBC Enzyme CVB 47 Assay Niemann - Sphingomyelinase Sphingo- 11p L302P, R496L, None WBC Enzyme CVB 48 Pick A and B myelin fs330, R608 Assay Glyco-proteinoses α-mannosidosis α-mannosidase α-manno- 19p13.2-q12 R750W (20%) Urine WBC Enzyme CVB 49 sides oligos Assay β-mannosidosis β-mannosidase β-manno- 4p Very few Urine WBC Enzyme CVB 49 sides oligos Assay Fucosidosis Fucosidase Fucosides 1p24 No common Urine WBC Enzyme CVB 49 glycolipids mutations oligos Assay Aspartylglucos- Aspartylglucos- Aspartyl- 4q32-33 C163S Urine WBC Enzyme CVB 50 aminuria aminidase glu- (90% of oligos Assay cosamine Finnish ) Schindler disease α-galactosidase N-acetyl- 22q Very few Urine WBC Enzyme CVB 49 B Galacto- oligos Assay samid glycolipids Glycogen Pompe disease α-glucosidase Glycogen 17q23 No common ECG Lymphocyte CVB 51 mutations character- Enzyme Assay istic Lipid Niemann Pick C Unknown Cholesterol 2 genes: I1061T Filipin Cholesterol Cultured 53 sphin- NPC 1-18q staining of esterification cells (not golipids NPC 2 - cultured cells studies always unknown possible) Wolman disease Acid lipase Cholesterol 10q c. 894 G>A None WBC Enzyme CVB 52 and cholesterol esters Assay ester storage disease WBC, white blood cell; CVB, chorion villus biopsy; MLD, metachromatic leucodystrophy; Oligos, oligosaccharides. Annotation 641

4 Table I continued Disease Enzyme Storage Chromosome Gene Screening Diagnostic Prenatal Reference deficiency material location mutations test test diagnosis number Monosaccharide aminoacids and monomers ISSD (infantile sialic Sialic acid Sialic acid 6q14-q15 R39C/other Urine Cultured cells AF 54 acid storage disease) transporter glucuronic mutation oligo Salla disease As ISSD As ISSSD As ISSD R39C homo As ISSD As ISSD As ISSD 54 Cystine Cystine Cystine 17p13 Common Renal WBC cystine Cultured 55 Transporter deletion tubular cells disease Cobalamin F Cobalamin Cobalamin Unknown MMA, Hcy Cultured cells Cultured 56 disease Transporter cells Danon disease Lamp-2 Cyto- Xq24 Very few None Unknown Unknown 57 plasmic debris and glycogen Peptides Pycnodysostosis Cathepsin k Bone 1q21 Very few X-ray Poss. DNA Poss. DNA 58 proteins S-acylated proteins Ceroid lipofuscinosis (CLN, Batten disease) CLN 1 (infantile) Palmitoyl Saposins 1p32 R122W Histology Cultured cells DNA 59 Protein (Finland) and DNA thioesterase CLN 2 (late Pepstatin Subunit C 11p common Histology Cutured cells DNA 59 infantile) insensitive mitochon- mutations and DNA carboxypeptidase drial ATP in exon 6 synthase = 60% CLN 3 (juvenile) Membrane As CLN 2 16p21 Common Histology DNA DNA 59 protein deletion (c del) CLN 4 (adult, Unknown As CLN 2 Unknown Unknown Histology Histology Unknown 59 Kuf disease) CLN 5 (late Membrane As CLN 2 13q22 Common Histology DNA DNA 59 infantile, protein deletion Finnish variant) (c1175delat) CLN 6 (late Unknown As CLN 2 15q-q23 Very few Histology Histology Unknown 59 infantile variant) CLN 7 (late Unknown Unknown Unknown Very few Histology Histology Unknown 60 infantile variant) CLN 8 (progressive Membrane As CLN 2 8p23 Very few Histology Histology Unknown 59 epilepsy with protein mental retardation, EPMR) Multiple enzyme deficiencies Multiple sulphatase Multiple Sulpha- Unknown Unknown Urine WBC and Plasma CVB 42 deficiency sulphatase tides, GAGs Enzyme Assays enzymes glycolipids, GAGs Galactosialidosis Neuraminidase Oligos, 20q13.3 Very few Urine Cultured cells Cultured 61 and β- sialic oligos cells galactosidase acid protective protein AF, amniotic fluid; WBC, white blood cell; GAGs, glycosaminoglycans; CVB, chorion villus biopsy; Oligos, oligosaccharides. 642 Developmental Medicine & Child Neurology 2001, 43:

5 Uptake is primarily mediated via the mannose-6-phosphate receptor, although other receptors are implicated depending on cell and tissue. This internal enzyme circulation has been exploited successfully in the treatment of Gaucher disease (see Table I). In this condition a deficiency of β-glucocerebrosidase leads to an accumulation of glucosylceramide within the deficient cell. Gaucher disease has all the typical clinical features of a LSD with early and late forms and a wide variety of phenotypic expression. The most prevalent form of the disease (type I, chronic non-neuronopathic) primarily affects the reticuloendothelial system and spares the CNS. Affected have a combination of bone marrow infiltration and failure, hepatosplenomegaly, and bone disease often leading to painful crises. Untreated, the disorder can be fatal and is a cause of long-term disability, especially due to the skeletal involvement in survivors. Early attempts at ERT in the 1970s were unsuccessful due to hepatic sequestration of the infused enzyme. 6 Increasing knowledge of normal lysosomal enzyme circulation led to modifications in the enzyme, which was initially purified from placentae (Ceredase, Genzyme Corporation, Boston, USA). Sequential deglycosylation of purified recombinant enzyme results in an enzyme with an exposed terminal mannose residue that targets the mannose lectin on macrophage plasma membranes (Cerezyme, Genzyme Corporation, Boston, USA). Studies have confirmed the efficacy and therapeutic similarity of intravenous Ceredase and Cerezyme. Cerezyme has the potential of being theoretically unlimited in supply and free of potential pathogenic contaminants. 7 Studies continue to try to find the optimum dosage regimen, 8 but there is no longer any doubt about efficacy and improvement in quality of life for treated. 9 Success in treating Gaucher disease has stimulated the development of ERT protocols for other LSDs and many of these are now at an advanced stage. The next enzyme likely to be available for clinical use is recombinant α-galactosidase. Phase III studies of the use of this preparation in Fabry disease have been recently reported 10 and these confirm the early clinical promise demonstrated in phase I and II studies. 11 At least one open-label phase III study has also been carried out into acid maltase deficiency. Early results suggest improvement and prolonged survival due to reversal of the cardiomyopathy in the infantile Pompe variant. 12 However, this is a generalized disorder and more prolonged follow-up is necessary before a firm statement can be made on longterm therapeutic benefits to other organs such as the CNS. Mucopolysaccharidosis type I (MPS) was one of the first LSDs for which experimental therapy was considered and tried. Bone marrow transplantation (BMT) has been shown to alter the natural history of the severe variants of this disease, (MPS type IH Hurler syndrome, see later). Most parents who have children with more attenuated forms of this condition (MPS type IH/S, Hurler/Scheie or IS, Scheie syndrome) are unwilling to consider BMT because of the associated risks and for these steady deterioration often leads to death or severe disability by early adulthood. ERT (given weekly by intravenous infusion) in a canine model of the disease suggested efficacy 13 and this has been confirmed in early human studies. 14 A phase III study started in January 2001 in the UK and other centres in Europe, Canada, and the USA. ERT is also planned for Niemann-Pick B disease (sphingomyelinase deficiency), mucopolysaccharidosis type II (iduronate sulphatase deficiency, Hunter syndrome) and mucopolysaccharidosis type VI (galactosamine-4-sulphatase deficiency, Maroteux-Lamy syndrome), but these programmes are at an earlier stage of development. What problems are anticipated with ERT? There will certainly be some who will develop antibodies to what, for them, are foreign proteins. Fortunately this does not seem to have attenuated response to therapy in Gaucher disease 15 and strategies have been developed in this disorder for who have difficult antibody problems. 16 The other main issue with regard to therapy is cost. ERT will be impossible in some countries that have other major public health issues to deal with and a limited health budget. The development costs of ERT are high and, as a result, it is anticipated that the cost of therapy will be expensive. As more biotechnology companies become interested in this therapeutic approach, competition may drive prices downwards, but not enough to allow ERT to be regarded as a cheap solution to the problems of LSDs. It is important that therapies are initiated and monitored by clinicians who are knowledgeable about the disease and the therapy to avoid a costly resource being abused. BONE MARROW TRANSPLANTATION The first BMT for a LSD took place 20 years ago 17 and it is surprising that the therapy still remains contentious to a number of clinicians. There can be no doubt that this therapy, while far from ideal, can favourably alter the natural history of a number of different LSDs including some that affect the CNS. In fact, 1981, almost every LSD has been treated by BMT somewhere in the world, with very variable results. The greatest experience is in mucopolysaccharidosis type IH (Hurler syndrome), with over 200 treated; most of the following discussion is specifically about this disorder. For other conditions and for a general discussion of the background to BMT there is an excellent review by Steward. 18 One of the biggest problems in interpreting the results of BMT was the uncontrolled way in which it was performed in the earliest days of therapy. Too many children were transplanted at a late age with less-than-perfect donors and so early results were dominated by the very negative experience of high mortality and many survivors developing severe learning difficulties. In MPS IH, early treatment by BMT (open to some debate but probably less than 18 months of age 19, 20 ), can certainly protect the CNS from the neurodegenerative element of this disease. In addition, soft tissue correction occurs quickly with reduction in hepatosplenomegaly, improvement in cardiac function, and resolution of upper airways obstruction A big disappointment with treatment has been the very poor skeletal correction. The majority of require extensive orthopaedic and neurosurgical procedures to correct spinal deformity, hip dysplasia, and progressive genu valgum deformity. In the early days of treatment, these skeletal complications were not anticipated and the greatest deformity is probably seen in the older survivors. We are now much more proactive with regard to the bone disease and involve our specialist orthopaedic colleagues in management from a very early stage. There are still a number of unresolved issues and despite the relatively long history as a therapy, BMT should continue to be considered as a treatment that is likely to be subject to technical improvement in years to come. In addition to solving the problem of poor skeletal response, challenges include Annotation 643

6 the high incidence of graft rejection in MPS IH and other LSDs treated by BMT. Assessment needs to be made of the use of bone-marrow stromal cells as stem cells for nonhaematopoietic tissues (mesenchymal stem cells 22 ). Other possible future directions for this form of therapy are discussed in some detail in Steward s review. 18 GENE THERAPY Gene therapy is defined as the introduction of nucleic acids into cells to cure or treat a disease process (for a general review see the work of Fairbairn and Testa 23 ). In human studies more than 2000 have been enrolled in over 300 trials, but it is debatable whether any has shown any persistent therapeutic benefit. The majority of studies are phase I or phase II studies aimed at establishing efficacy in the treatment of malignant disease. The safety of such approaches in single gene disorders has recently been called into question with the death of a patient with ornithine carbamyl transferase deficiency treated with an adenoviral vector. 24 Of the various approaches that have been investigated with LSDs, haematopoietic stem cellmediated gene transfer has been the most. This would appear to be the best approach because of the existing experience with BMT. Such an approach has been accomplished in a number of mouse model systems leading to partial or complete correction of the disease phenotype. 25 A number of formidable challenges remain in humans. Persistence of expression and the need for efficient neurotropic vectors will be needed for most LSDs. Of some concern is the early indication of potential antibody problems after transfer of a gene identified as foreign by a previously mutant patient. This may be more of a problem in with null mutations although this could not be predicted with any certainty. 26 SUBSTRATE DEPRIVATION The curative attempts at treatment described so far are aimed at correcting the genetic defect either directly by gene transfer, or indirectly by BMT, or by augmenting the missing enzyme with exogenous recombinant protein. Substrate deprivation therapy tackles the same problem by attempting to prevent the accumulation of the harmful substrate within the cell and thus restoring physiological balance between substrate and product. To be effective there must be some residual enzyme activity present in the patient s cells or no reversal of pathology could be anticipated. This is certainly found in many affected and indeed residual enzyme levels that are only a fraction of normal levels can protect an individual from developing a severe variant of a disorder. One type of substrate deprivation therapy currently under trial aims at impairing the synthesis of glycosphingolipids (GSLs) to match the impaired rate of catabolism. Not only does it assume that there is some residual enzyme activity, but also that a partial deficiency of GSLs is compatible with normal health and development. Oral, daily, N-butyldeoxynojirimycin (OGT 918, Oxford Glycosciences, Abingdon, Oxfordshire) inhibits glucosyltransferase, a key enzyme in the synthesis of GSLs and has been used in both animal and human studies. In a study of 28 with non-neuronopathic Gaucher disease, clear evidence of efficacy was seen on a number of key clinical features. 27 Although side effects were seen in the study, in particular diarrhoea, the results justify further studies of this approach to treatment, especially as this form of small molecule therapy is potentially effective in diseases with a CNS component. A number of further studies are under development. Conclusion Although LSDs present formidable therapeutic challenges significant progress has been made in this area. Curative treatment seems a more realistic goal with LSDs than with other inborn errors of metabolism e.g. disorders of intermediary metabolism or mitochondrial disease to give just two examples. One can envisage combination therapies being used with one treatment modality supplemented or replaced by another as the circumstances of the patient or the disease change. Clinicians who manage with LSDs will have more tools in their therapeutic toolbox, but these will still have to be used carefully and correctly. Early diagnosis will become more essential, strengthening the case for neonatal screening for this group of conditions that are twice as prevalent as PKU. Accepted for publication 4th January References 1. Miekle PJ, Hopwood JJ, Clague AE, Carey WF. (1999) Prevalence of lysosomal storage disorders. 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