Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy

Abstract AIMS: Evaluation of safety and clinical activity of Gene-Activated ® human glucocerebrosidase (GA-GCB) as a new intravenous enzyme replacement therapy (ERT) for patients with type I Gaucher disease participating in a 9 month, open-label Phase I/II clinical study. BACKGROUND: GA-GCB is human glucocerebrosidase (GCB) produced in a well-characterized, continuous human cell line using proprietary gene activation technology. GA-GCB has an identical amino acid sequence to the naturally occurring human enzyme and contains terminal mannose residues that target the enzyme to macrophages, the primary target cells in Gaucher disease. Nine month study results of GA-GCB treatment will be presented. METHODS: Twelve adult patients (7 females /5 males) with type I Gaucher disease with clinically significant anemia, thrombocytopenia, hepatomegaly and/or splenomegaly, were enrolled in a 9 month Phase I/II clinical trial. Patients received GA-GCB every other week for a total of 40 weeks (20 infusions). A staggered dose escalation of GA-GCB was performed in the first 3 patients: these patients received 15 U/kg at the first infusion, 30 U/kg at the second infusion, and then 60 U/kg IV every other week for a total of 20 IV infusions. The remaining 9 patients received 60 U/kg beginning with their first dose. Anti-GA-GCB antibodies were tested in all patients during the 9 months of treatment. All patients were routinely evaluated for hemoglobin, platelets, liver and spleen volumes, infusion reactions and adverse events. In addition, serum samples were analyzed for disease biomarkers: chitotriosidase and CCL18. RESULTS: Eleven of the 12 patients who were enrolled in the trial have been treated for nine months. One patient withdrew consent after three injections for reasons not related to treatment. Dose escalation from 15 U/kg to 60 U/kg was well tolerated in the first three patients. The remaining patients received 60 U/kg every other week throughout the course of the study. Anti-GA-GCB antibody test results were negative for all patients. Mean hemoglobin and platelet values, below the normal range at baseline, improved after 9 months of GA-GCB treatment to levels consistent with the therapeutic goals for ERT in Gaucher disease (Seminars in Hematology 2004). Analysis of the liver and spleen volumes decreased following 9 months of treatment. In addition, serum chitotriosidase and CCL18 levels decreased over the 9 months of GA-GCB treatment. CONCLUSION: ERT with GA-GCB was well tolerated and demonstrated clinical activity in well-established clinical markers in patients with type 1 Gaucher disease when administered IV every other week at 60 U/kg over 9 months. Results suggest that GA-GCB holds promise as a new therapeutic option for ERT in Gaucher disease.

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Rational use of substrate reduction therapy and enzyme replacement therapy in patients with type I Gaucher disease (Uso racional de los tratamientos por inhibición de sustrato y enzimático sustitutivo en pacientes con enfermedad de Gaucher tipo I)

http://isrctn.org/> ◽

10.1186/isrctn05147495 ◽

2012 ◽

Author(s):

Pilar Giraldo Castellano

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Substrate Reduction Therapy ◽

Type I ◽

Rational Use ◽

Enzyme Replacement ◽

Substrate Reduction

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Ghrelin, leptin and adiponectin levels in Gaucher disease type I patients on enzyme replacement therapy

Clinical Nutrition ◽

10.1016/j.clnu.2014.08.010 ◽

2015 ◽

Vol 34 (4) ◽

pp. 727-731 ◽

Cited By ~ 6

Author(s):

Divair Doneda ◽

André L. Lopes ◽

Bruno C. Teixeira ◽

Suzana D. Mittelstadt ◽

Cileide C. Moulin ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Disease Type ◽

Type I ◽

Enzyme Replacement

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MDS/Secondary AML Associated with Type I Gaucher Disease

Blood ◽

10.1182/blood-2018-99-116058 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5193-5193 ◽

Cited By ~ 1

Author(s):

Atsushi Okamoto ◽

Kenta Yamamoto ◽

Go Eguchi ◽

Yoshitaka Kanai ◽

Terufumi Yamaguchi ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Peripheral Blood ◽

Gaucher Disease ◽

Conflicts Of Interest ◽

Refractory Anemia ◽

Type I ◽

Secondary Aml ◽

Enzyme Replacement ◽

Pathologic Fractures

Abstract [Introduction] Gaucher disease is one of lysosomal diseases, and it is an extremely rare disease characterized by anemia, thrombocytopenia, splenomegaly, multiple pathologic fractures and so on. It has been reported that Gaucher disease often merges with blood malignant diseases. However, there are no reports of myelodysplastic syndrome/secondary AML (MDS/s-AML) concomitant with type I Gaucher disease. Furthermore, we carried out parallel treatment of enzyme replacement therapy for type I Gaucher disease and azacitidine therapy for MDS/s-AML. [Case] A 69-year-old woman admitted to our hospital because of multiple abnormal fractures. She was diagnosed of MDS (refractory anemia) in 2011 by a previous doctor. As anemia and thrombocytopenia gradually worsened on May 2017, she was transferred to our department on August 8, 2017. At the time of visit, typical pneumonia determined with chest X-P and CT has been observed and high value of CRP (11.0mg/dl) was existed. Pneumonia improved promptly with antibiotic therapy, however, high value of CRP continued, and bilateral chest and right back pain got worse. We carried out plain CT and MRI (DWIBS). In results, splenomegaly, bilateral rib fracture and osteolytic changes in the right iliac bone were observed. Although bone marrow biopsy was performed twice without significant findings, Gaucher disease has been suspected and glucocerebrosidase activity was measured. As expected, a significant decrease of the enzyme activity was observed. Finally, a diagnosis of type I Gaucher disease was made. We started enzyme replacement therapy for glucocerebrosidase. Therefore, reduction of splenomegaly and independency of transfusion were induced by several replacement therapy. Further, multiple bone fracture lesions have improved. Further, juvenile leukocyte including myeloblasts in peripheral blood (PB) also decreased. Therefore, we suspected that the replacement therapy improved not only several symptoms of Gaucher disease, but several hematological findings of MDS. However, WT1-mRNA in the peripheral blood has gradually increased. Moreover, progression of MDS/s-AML was observed after two months. We selected azacitidine therapy in considering of performance state of the patient. In addition to enzyme supplementation therapy, azacitidine therapy was performed in parallel. After several treatment of azacitidine, blasts in PB were decreased significantly with independency of transfusion. [Conclusion] We deeply indicate that the combination of enzyme replacement therapy and azacitidine therapy is useful for cases of MDS/s-AML associated with Gaucher disease. There is a possibility that the reduction of the enzyme is involved not only in Gaucher disease but in the ontogeny of blood diseases such as MDS. The effects of enzyme replacement therapy of Gaucher's disease for MDS/s-AML should be discussed. Disclosures No relevant conflicts of interest to declare.

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REDUCED DOSING REGIMEN OF ENZYME REPLACEMENT THERAPY IN ADULT PATIENTS WITH TYPE I GAUCHER DISEASE: PRELIMINARY RESULTS

Hematology and Transfusiology ◽

10.35754/0234-5730-2019-64-3-331-341 ◽

2019 ◽

Vol 64 (3) ◽

pp. 331-341 ◽

Cited By ~ 1

Author(s):

R. V. Ponomarev ◽

K. A. Lukina ◽

E. P. Sysoeva ◽

R. B. Chavynchak ◽

A. A. Solovyeva ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Lysosomal Storage Diseases ◽

Adult Patients ◽

Type I ◽

Treatment Goals ◽

Lysosomal Storage ◽

Current Standard ◽

Enzyme Replacement

Introduction. Gaucher disease (GD) belongs to the group of lysosomal storage diseases. Enzyme replacement therapy (ERT) is considered to be the current standard in GD treatment. No reduced ERT regimen has thus far been developed. Aim. To develop an optimal reduced ERT regimen for adult patients with type I GD, which is scientifically and economically viable.Materials and methods. The study included 100 adult patients with type I GD who achieved treatment goals following at least two years of the standard ERT regimen. Patients were prescribed a reduced ERT regimen, which consisted in increasing the interval between the infusions of the recombinant enzyme up to 4 weeks, at a dose of 15–20 units/kg of body weight. The efficacy of the reduced ERT regimen was assessed once every 12 months according to main GD parameters. The follow-up period in the study ranged from 12 to 36 months.Results. The patients with type I GD who achieved treatment goals following the standard ERT regimen and were then prescribed a reduced ERT regimen retained a stable therapeutic effect of the initial treatment according to all parameters: no clinically significant differences found in haemoglobin and platelet levels, spleen size and specific infiltration of femur bone marrow.Conclusion. An increase in the intervals between infusions of the recombinant glucocerebrosidase up to 4 weeks for 12, 24 and 36 months did not lead to worsening of the laboratory and instrumental parameters associated with GD.

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Enzyme replacement therapy in adult patients with type I Gaucher disease

Terapevticheskii arkhiv ◽

10.26442/00403660.2019.07.000327 ◽

2019 ◽

Vol 91 (7) ◽

pp. 127-131

Author(s):

R V Ponomarev ◽

E A Lukina

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Progressive Disease ◽

Clinical Phenotype ◽

Type I ◽

Therapeutic Goals ◽

Enzyme Replacement ◽

The Status ◽

Functional Deficiency

Enzyme replacement therapy (ERT) is the standard for the treatment of Gaucher disease (GD). A lifelong intravenous administration of a recombinant analogue of human glucocerebrosidase compensates for the functional deficiency of its own enzyme. The use of ERT has changed the clinical phenotype of GD, a severe progressive disease has been turned into the status of an asymptomatic metabolic defect. At the same time, a reduced dosing ERT regimen applied in Gaucher patients who had achieved therapeutic goals has not yet been developed.

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Variation of Serum Lipid Profile during Enzyme Replacement Therapy, in Patients with Type 1 Gauchers Disease.

Blood ◽

10.1182/blood.v108.11.3849.3849 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3849-3849

Author(s):

Argiris Symeonidis ◽

Derralynn Hughes ◽

Linda Richfield ◽

Atul Mehta

Keyword(s):

Platelet Count ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Success Rate ◽

Gaucher Disease ◽

Type I ◽

Success Rates ◽

Enzyme Replacement ◽

Pulmonary Manifestations ◽

N370s Mutation

Abstract Enzyme Replacement Therapy (ERT) has dramatically changed the clinical course and prognosis of patients with Gaucher disease. We have assessed the extent to which the recently defined Goals of Therapy (Pastores et al, Semin Hematol 41(suppl 5):4–14) in 9 major fields (anemia, thrombocytopenia, hepatomegaly, splenomegaly, skeletal pathology,biomarkers, pulmonary manifestations, growth and functional health and well being) were achieved in our cohort of patients with type I Gaucher disease. Fifty-seven patients (27 females, 30 males, median age at diagnosis 30 years (range 2–77 years) and at start of ERT 39 years (range 5–79 years) were assessed. The median period of ERT was 94 months (range 24–155 months). Patients on ERT for less than 2 years were excluded. Twenty five specific goals are defined within the 9 fields. The median overall success rate was 20 of 25 goals or 80% per patient (range 12–25 goals or 60–100%). The success rate for 9 goals was 100% ( normalization of hemoglobin 1 year post-splenectomy, no major bleeding 1 year after ERT start, doubling of baseline platelet count in severely thrombocytopenic patients 2 years after ERT start, maintenance of platelet count in non-thrombocytopenic patients, prevention of bone crises, reversion of hepatopulmonary syndrome and dependence on oxygen, amelioration of pulmonary hypertension and prevention of rapid deterioration of pulmonary disease and sudden death). Higher success rates were achieved for the goals related to thrombocytopenia (97.9%) and pulmonary manifestations (97%) although in the latter case the applicability was low. Lower success rates were achieved for the goals related to bone manifestations (78.7%). There was no significant difference in the success rate between males and females, splenectomised and non-splenectomised patients, and between patients treated less or more than 6 years. However patients started on ERT before the 40th year of age exhibited significantly higher success rate as compared to patients started after the 40th year (p=0.047) and there was a significant inverse correlation between overall success rate and patient’s age at treatment start (r = − 0.437). Finally, the success rate was higher among double heterozygotes, carrying the N370S mutation, as compared to patients homozygous for the N370S mutation (89.2±9.6% vs. 80.2±12.9%, p=0.016).

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