Acta Pædiatrica ISSN 0803–5253

REVIEW ARTICLE

Gaucher disease: unmet treatment needsAtul Mehta (atul.mehta@royalfree.nhs.uk)Lysosomal Storage Disorders Unit, Department of Haematology, Royal Free Hospital and University College Medical School, London, UK

KeywordsEnzyme replacement therapy, Gaucher disease,Substrate reduction therapy, Treatment

CorrespondenceA Mehta, Department of Haematology, Royal FreeHospital and University College Medical School,Pond Street, London, NW3 2QG, UK.Tel: +44 207 830 2814 |Fax: +44 207 830 2313 |E-mail: atul.mehta@royalfree.nhs.uk

DOI:10.1111/j.1651-2227.2008.00653.x

AbstractGaucher disease is a multisystemic metabolic disorder arising from a deficiency of lysosomal

glucocerebrosidase. The predominant clinical manifestations of the disease are hepatosplenomegaly,

peripheral blood cytopenias and skeletal disease. Treatment with enzyme replacement therapy (ERT)

and substrate reduction therapy (SRT) has been shown to be effective in improving organ volume,

anaemia, thrombocytopenia, bone markers and biomarkers in patients with Gaucher disease.

However, some patient needs remain unmet because of the limited availability of treatment, the

inaccessibility of certain disease sites and emerging disease manifestations. An increase in

haematological, lymphoreticular and immune system malignancies has been observed in patients

with Gaucher disease, but mechanisms underlying the development of these are not fully

understood. Mild neurological manifestations may also affect patients with type 1 Gaucher disease,

but treatment with ERT or SRT does not improve neurological function. Potential new treatments for

Gaucher disease include small molecules, which may penetrate tissues that are not accessible by ERT.

Conclusion: ERT currently remains the most effective treatment for Gaucher disease. New treatments are

emerging, but deficiencies in understanding basic pathophysiological mechanisms hinder progress.

INTRODUCTIONGaucher disease is a multisystemic metabolic disorder aris-ing from a deficiency of lysosomal glucocerebrosidase. It isconventional to categorize the disease into types 1, 2 and3; type 1 being the adult non-neuronopathic form, type 2being an infantile neuronopathic form and type 3 being anintermediate form with significant systemic manifestationsand usually some degree of mild neurological manifestation(1). Adult (type 1) Gaucher disease is the most commonform with an incidence of approximately 1:40 000 amongstthe general population, but a much higher incidence (ap-proximately 1:1000) amongst individuals of Ashkenazi Jew-ish origin. It is conventional to regard the predominantsystemic clinical manifestations (e.g. hepatosplenomegaly,peripheral blood cytopenias and skeletal disease) as pri-marily resulting from deficiency of lysosomal glucocere-brosidase in macrophages, thereby leading to substrateaccumulation within the lysosomes of macrophages withinreticuloendothelial cells. Macrophages, however, are verywidely distributed throughout the body and have widespreadroles, not only as scavengers of effete blood cells, butalso as key mediators of immune regulation and cytokinemetabolism, all of which may be perturbed in Gaucherdisease.

The advent of enzyme replacement therapy (ERT) hasrevolutionized the outlook for patients with Gaucher dis-ease. The long-term international safety experience ofimiglucerase (Cerezyme®; Genzyme Corp., Cambridge, MA,USA) has recently been published, and it demonstrates a lowrate of adverse events amongst more than 4000 treatmentrecipients (2). Selected patients with Gaucher disease arealso suitable for treatment with substrate reduction therapy

(SRT) using the oral glucosylceramide synthase inhibitor,miglustat (Zavesca®; Actelion, Allschwil, Switzerland) (3,4).Against the background of the success of imiglucerase asERT for Gaucher disease and the availability of SRT, it is ap-propriate to consider the extent to which current treatmentapproaches meet the needs of patients. The major areas ofunmet patient need relate to the following:

• limitations of currently available treatment,• inaccessibility of certain disease sites; for example central

nervous system (CNS) and, to a lesser extent, bone andlungs,

• emerging disease manifestations; for example, malignancyand neurological changes.

HOW EFFECTIVE IS CURRENTLY AVAILABLE TREATMENT?In the United Kingdom, treatment is organized such thatpatients with lysosomal storage disorders attend specialistcentres for regular assessment and supervision of treatment.The Royal Free Hospital in London is one of six designatedcentres in the United Kingdom and we have over 70 pa-tients attending (Table 1). We have recently evaluated ourcohort (5) to assess their response to treatment and to gradeit using the goals of therapy recently identified by an Inter-national Working Group (6,7). All nine patients who hadever received SRT, had also previously received ERT. SRTwas prescribed in accordance with the European Guidelines(8). The identified goals were broadly useful and we wereable to score our patients in terms of changes in bone dis-ease, levels of anaemia and tiredness, bleeding and bruising,organ size, lung function and quality of life. A number ofbiomarkers (serum angiotensin-converting enzyme, serum

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Figure 1 Magnetic resonance image (MRI) of the knees in a female patient with Gaucher disease before (A) and after (B) enzyme replacement therapy (ERT). Thepatient was 27 years of age at the time of the first scan. There is substantial improvement in the texture of the bone and bone marrow in (B), which is taken after3.5 years of ERT. Scoring systems based on MRI allow these improvements to be quantified.

chitotriosidase, acid phosphatase and serum ferritin) wereuseful in assessing the progress of patients with Gaucherdisease, and we also used these laboratory variables to re-fine the identified goals and improve assessment of diseaseprogress. All patients had had serial magnetic resonanceimaging (MRI) examinations of the skeleton. Although itis difficult to quantify changes seen on MRI, the recent ad-vent of scoring systems (e.g. Spanish MRI [S-MRI] (9)) willmake this an increasingly important tool for future studies.In the present study, clear improvements in the appearanceof skeletal MRIs were seen in many patients (Fig. 1). Thepreliminary results of our survey suggest that ERT and SRTare extremely useful for achievement of certain goals, for ex-ample improvement in organ volumes, anaemia, thrombo-cytopenia, bone markers and biomarkers. While improve-ments in bone pain and skeletal MRI were frequently ob-served, patients nevertheless remain susceptible to furtherbone disease with a continuing requirement for orthopaedicintervention and joint replacement surgery.

PATIENT CONVENIENCEERT has to be administered intravenously and is usuallygiven every 2 weeks. Nearly all patients attending units in theUnited Kingdom and the Netherlands (10,11) receive theirERT in the home, and this has been found to be a convenientand appropriate way of delivering the treatment. A survey ofpatients attending our own unit has recently confirmed thatmost patients have no difficulty in complying with the treat-

Table 1 The Royal Free Hospital cohort of patients with Gaucher disease

Males Females Total(n = 39) (n = 34) (n = 73)

Age, years (median [range]) 43 (8–94) 50 (18–84) 45 (18–94)Age at diagnosis, years 26 (2–90) 30 (3–79) 29 (2–90)

(median [range])Patients on treatment (n) 33 30 63Ever had SRT (n) 6 3 9Ever had ERT (n) 33 30 63Time on ERT, months 10 (9–192) 9 (6–180) 10 (6–192)

(median [range])Ever had a splenectomy (n) 9 9 18

ERT, enzyme replacement therapy; SRT, substrate reduction therapy.

ment (10). Although patients express a desire for oral treat-ment, they have a greater preference for a treatment with anestablished efficacy and safety record.

HOW WELL CAN ERT ACCESS TISSUES?Although ERT is well tolerated, up to 15% of patients willdevelop antibodies (2). Newer enzymes are under develop-ment, such as gene-activated glucocerebrosidase, whichhas shown significant activity in phase I clinical studies(12). The uptake of mannose-terminated imiglucerase bymacrophages has been optimized. However, some recentreports have indicated that splenic macrophages may lack

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mannose receptors (13), raising the question that mannosetermination may not be the optimum way of targeting theenzyme to the appropriate cells. Other ways of targeting theenzyme, for example by linking it to intercellular adhesionmolecule-1 (14) or by injecting it directly into osteoblasts(15), have been suggested. ERT is unable to cross the blood–brain barrier and therefore cannot access the CNS. Recentapproaches have examined the feasibility of directly injectingthe enzyme into the CNS, for example using the techniqueof convection-enhanced delivery under MRI visualization(16). Although this approach is clearly feasible and poten-tially effective, it is hugely intensive in terms of its use ofresources.

SANCTUARY SITES: LYMPHORETICULAR AND IMMUNE SYSTEMSA number of studies have examined the prevalence of malig-nant disease amongst patients with Gaucher disease (17,18).Overall, no significant increases have been found. How-ever, it is clear that certain neoplasms, for example mul-tiple myeloma and non-Hodgkin’s lymphoma, appear tobe more common among subjects with Gaucher disease(19,20). A survey from the International Gaucher Registry(20) confirmed a significant increase in the incidence ofmyeloma amongst Gaucher disease sufferers. There is alsoan increased incidence of polyclonal and monoclonal gam-mopathies among patients with Gaucher disease. The pre-cise mechanisms are unclear, but this may reflect ongoingimmune stimulation by accumulated substrate withinmacrophages. An increased incidence of lymphoma andlymphadenopathy has also been observed in patients withGaucher disease (21). Some subjects have been described ashaving persistent lymphadenopathy in the absence of overtmalignancy, and biopsies have shown collections of acti-vated macrophages, storage cells, lymphocytes and plasmacells (so called Gaucheroma) (22). The mechanisms un-derlying the development of malignant transformation areunknown. Myelodysplasia is characterized by disorderedgrowth of myeloid cells within the marrow with evidenceof abnormal control mechanisms. Myelodysplasia and acutemyeloid leukaemia have also been observed amongst pa-tients with Gaucher disease (23) and it is clear, both from theliterature and from personal experience, that when patientswith Gaucher disease develop such malignancies, they areresistant to chemotherapy. It is plausible that these longer-term manifestations may become more prominent as pa-tients live longer. The use of small molecules, such as SRT,may offer a means of accessing these sites more easily thanERT.

UNDERLYING MECHANISMS PREDISPOSING TOHAEMATOLOGICAL MALIGNANCYThe mechanisms whereby patients with Gaucher disease arepredisposed to haematological malignancy are unknown.There is an increasing interest in the role of ceramideand ceramide analogues as signalling molecules, which maypromote malignant transformation and modulate apoptotic

pathways (24). There is good evidence that ceramide ac-cumulation leads to an increased activity of P-glycoprotein(25), which is a membrane-bound efflux pump responsiblefor reducing the intracellular concentration of chemothera-peutic agents in cancer cells. Ceramide accumulation is apotential factor in reducing apoptosis of cells that have in-creased substrate, and glucosyl synthetase inhibitors suchas miglustat may have a role in modulating the underlyingmechanisms (26,27).

SANCTUARY SITES: THE NERVOUS SYSTEMIt is increasingly recognized that Gaucher disease has aspectrum of clinical manifestations and that mild neuro-logical manifestations are frequently seen in adults withtype 1 Gaucher disease (28). There is an increased inci-dence of Parkinson’s disease amongst these individuals (29),which tends to be extremely labile and difficult to control(30). There appears to be an increased incidence of periph-eral neuropathy amongst patients with Gaucher disease anda possible association with vitamin B12 deficiency andgammopathies (31). ERT will have no impact on these mani-festations. SRT will have no beneficial effect and indeedmay be a contributory factor to neuropathy in Gaucherdisease (3).

NEW TREATMENT APPROACHESBy using small molecules one could promote greater tis-sue distribution with the potential for better penetra-tion into tissues that are not well accessed by ERT.There is evidence that bone disease improves in pa-tients receiving SRT with miglustat (32,33). A com-bination therapy of miglustat with imiglucerase mayprovide benefit in patients with severe Gaucher dis-ease who have severe skeletal involvement. Theoret-ically, the two treatment approaches should synergize ratherthan antagonize. Newer forms of SRT are under develop-ment, including ceramide analogues which are currently inphase I trials (34,35).

Chemical chaperones are small molecules that stabilizeproteins against misfolding, thus enabling them to trafficfrom the endoplasmic reticulum to their final intracellularlocation. They combine the benefits of the small moleculeapproach – oral bioavailability, cell permeability and thepotential to cross the blood–brain barrier – with the speci-ficity of selectively targeting glucocerebrosidase. A poten-tial disadvantage is that each individual mutation wouldrequire a different drug; though it is noteworthy that miglus-tat has been reported to have activity as a chaperone in bothGaucher disease (36) and Pompe disease (37).

Gene therapy approaches have previously been shown tobe applicable to patients with Gaucher disease, and newerapproaches are being developed and tested in animal mod-els (38). There is an increasing interest in the value ofstem cell transplantation in lysosomal storage disorders gen-erally, and new approaches that combine early stem celltransplantation with ERT may be particularly effective inchildren (39).

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CONCLUSIONGaucher disease is an excellent example of a molecular dis-ease for which management has come of age. Although ERTremains the cornerstone and the gold standard, a range of ef-fective treatments are emerging for lysosomal storage disor-ders (40). However, deficiencies in understanding the basicpathophysiological mechanisms hinder progress. It is clearthat disturbed sphingolipid metabolism will affect intra- andintercellular communication, and this could underlie clini-cal manifestations as diverse as myelodysplasia and Parkin-son’s disease. It is highly unlikely that ERT (or indeed anyother treatment modality) will be effective once these com-plications have arisen. Unmet treatment needs are thereforelikely to remain for the foreseeable future. Moreover, thechallenges are not simply for patients, physicians and phar-macologists; society as a whole must meet the challenge ofcaring for sufferers and for making effective treatments avail-able and affordable for all.

CONFLICT OF INTERESTS STATEMENTAM has received support for research, consultancy andtravel and honoraria for speaking at educational meetingsfrom various pharmaceutical companies, including ShireHGT, Genzyme Corp., Actelion and Amicus Therapeutics.

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