Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34 + Cells for Correction of Fabry Disease

Huang, Ju; Khan, Aneal; Au, Bryan; Barber, Dwayne L.; López-Vásquez, Lucía; Prokopishyn, Nicole L.; Boutin, Michel; Rothe, Michael; Rip, Jack W.; Abaoui, Mona; Nagree, Murtaza S.; Dworski, Shaalee; Schambach, Axel; Keating, Armand; West, Michael; Klassen, John S.; Turner, Patricia V.; Sirrs, Sandra; Rupar, C. Anthony; Auray‐Blais, Christiane; Foley, Ronan; Medin, Jeffrey A.

doi:10.1016/j.omtm.2017.05.003

Cited by 39 publications

(40 citation statements)

References 48 publications

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“…The ASAH1 (experimental lentivirus) and α-galactosidase A (AGA, control lentivirus) vectors were provided by J.A.M. Generation of the transfer plasmid, pDY-AGA, was described previously (26). pDY-ASAH1 was constructed using similar methods.…”

Section: Resultsmentioning

confidence: 99%

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Benitez

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing “psychosine hypothesis.” We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.

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Section: Resultsmentioning

confidence: 99%

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Benitez

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…84 Research is also under way for a gene therapy approach to achieve tissue-specific overexpression of GLA, resulting in a clinical trial (https://clinicaltrials.gov/ ct2/show/NCT02800070?term5gene1therapy&cond5fabry& rank53). 85…”

Section: Oral Therapymentioning

confidence: 99%

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

Lenders

Brand

2018

JASN

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FOS, Fabry outcome survey; 95% CI, 95% confidence interval; LRI, low renal impairment; HRI, high renal impairment; mGFR, measured glomerular filtration rate; OR, odds ratio. 62 95% CI, 95% confidence interval; FOS, Fabry outcome survey; LRI, low renal impairment; HRI, high renal impairment; LVMI, left ventricular mass index; LVM, left ventricular mass; MWT, mean wall thickness; LVH, left ventricular hypertrophy; IVST, interventricular septum thickness; RWT, relative wall thickness; LVWT, left ventricular wall thickness.

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“…ACDase deficiency is an attractive target for gene therapy because it is caused by a single gene defect. In fact, several gene therapies for monogenic lysosomal storage disorders are currently being investigated in clinical trials [ 170 – 172 ]. In the context of ACDase deficiency, one early study demonstrated that FD patient cells recovered ACDase activity when the cells were infected with an onco-retroviral vector that engineered expression of human ACDase [ 173 ].…”

Section: Research Treatment and Future Therapymentioning

confidence: 99%

Acid ceramidase deficiency: Farber disease and SMA-PME

Yu¹,

Amintas²,

Levade

et al. 2018

Orphanet J Rare Dis

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104

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Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0845-z) contains supplementary material, which is available to authorized users.

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Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34 + Cells for Correction of Fabry Disease

Cited by 39 publications

References 48 publications

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

Acid ceramidase deficiency: Farber disease and SMA-PME

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