A Phase 1/2 Clinical Trial of Enzyme Replacement in Fabry Disease: Pharmacokinetic, Substrate Clearance, and Safety Studies

Eng, Christine M.; Banikazemi, Maryam; Gordon, Ronald E.; Goldman, Martin; Phelps, Robert; Kim, Leona; Gass, Alan; Winston, Jonathan; Dikman, Steven; Fallon, John T.; Brodie, Scott E.; Stacy, Charles B.; Mehta, Davendra; Parsons, Rosaleen B.; Norton, Karen I.; O'callaghan, M. W.; Desnick, Robert J.

doi:10.1086/318809

Cited by 351 publications

(257 citation statements)

References 14 publications

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“…Patients lacking expression of LAMAN1, 3, 6 may develop antibodies against the recombinant enzyme affecting ERT efficacy. However, in this first clinical study for alpha‐mannosidosis the frequency of infusion‐related reactions as well as the production of antibodies against the recombinant enzyme was low19 in comparison with other ERT studies 50, 51, 52, 53, 54. Furthermore, these rhLAMAN‐specific antibodies were shown not to be neutralizing, suggesting only mild immunological complications with regard to future ERT.…”

Section: Discussioncontrasting

confidence: 55%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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ObjectiveThe lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.MethodsHere, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.ResultsChronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.InterpretationOur data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.

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Section: Discussioncontrasting

confidence: 55%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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“…patients with non-specific neuropathic pain, AK or CV but without heart or kidney involvement), a skin biopsy with characteristic storage on electron microscopy (EM) could confirm the diagnosis of FD. The presence of characteristic storage in the skin has been well documented in most classical male FD patients (Eng et al 2001;Thurberg et al 2004), while reports on skin biopsies in nonclassical FD patients, i.e. who have confirmed storage in a kidney or heart biopsy but not fulfilling the criteria for a definite classical diagnosis of FD (Table 1), are lacking.…”

Section: Pathologymentioning

confidence: 99%

Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

et al. 2014

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Introduction: Individuals with neuropathic pain, angiokeratoma (AK) and/or cornea verticillata (CV) may be tested for Fabry disease (FD). Classical FD is characterised by a specific pattern of these features. When a patient presents with a non-specific pattern, the pathogenicity of a variant in the a-galactosidase A (GLA) gene may be unclear. This uncertainty often leads to considerable distress and inappropriate counselling and treatment. We developed a clinical approach for these individuals with an uncertain diagnosis of FD.Materials and Methods: A document was presented to an FD expert panel with background information based on

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“…With advancing age, vascular disease of the heart, kidneys, and brain leads to early demise, typically in the fourth and fifth decades of life. Currently, there is no specific treatment for Fabry disease, but recent animal and human clinical trials have indicated the feasibility of recombinant enzyme replacement therapy (Ioannou et al 2001;Eng et al 2000Eng et al , 2001.…”

Section: Introductionmentioning

confidence: 99%

Fabry disease: twenty novel α-galactosidase A mutations causing the classical phenotype

et al. 2001

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Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase, α-galactosidase A (EC 3.2.1.22; α-Gal A). The nature of the molecular lesions in the α-Gal A gene in 40 unrelated families with the classical phenotype (absent α-Gal A activity) was determined in order to provide precise heterozygote detection and prenatal diagnosis, and to explore possible genotype/ phenotype correlations. Genomic DNA was isolated from unrelated affected males, and the entire α-Gal A coding region and flanking intronic sequences were analyzed by polymerase chain reaction (PCR) amplification and automated sequencing. Twenty new mutations were identified: M51K, D92N, D136H, F169S, C172F, L191Q, S247P, Q250X, P259R, G261D, T282N, R301P, W349X, T410K, 124delAT, 842delTAA, 1033delTC, 82insG, 893insG, and 903insG. In the remaining 20 unrelated Fabry families, 17 previously reported mutations were detected. These studies further define the heterogeneity of mutations in the α-Gal A gene causing the classic Fabry disease phenotype, and permit precise heterozygote detection and prenatal diagnosis.

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A Phase 1/2 Clinical Trial of Enzyme Replacement in Fabry Disease: Pharmacokinetic, Substrate Clearance, and Safety Studies

Cited by 351 publications

References 14 publications

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

Fabry disease: twenty novel α-galactosidase A mutations causing the classical phenotype

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