Lentiviral hematopoietic stem and progenitor cell gene therapy (HSPC-GT) for metachromatic leukodystrophy (MLD): Clinical outcomes from 33 patients

Fumagalli, Francesca; Calbi, Valeria; Sessa, Maria; Zambon, Alberto A.; Baldoli, Cristina; Rancoita, Paula M.V.; Acquati, Serena; Mattia, Fabiola De; Tucci, Francesca; Gallo, Vera; Zancan, Stefano; Montini, Eugenio; Schwab, Laetitia; Downey, Gerald; Sharpe, John C.; Gabaldo, Michela; Martino, Sabata; Serio, Clelia De; Ciceri, Fabio; Filippi, Massimo; Sora, Maria Grazia Natali; Bernardo, Maria Ester; Naldini, Luigi; Biffi, Alessandra; Aiuti, Alessandro

doi:10.1016/j.ymgme.2019.11.135

Cited by 11 publications

(12 citation statements)

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“…In terms of clinical translation, the use of autologous hematopoietic stem cells genetically modified by LVs to express Hex enzymes (36) may overcome the current limitation of allogeneic BMT or HSCT, overall improving the safety and increasing the benefits of the proposed combined strategy. Of note, ex vivo HSC GT has recently received full EU marketing authorization for the treatment of early-onset metachromatic leukodystrophy patients (using autologous CD34+ cells transduced with an LV encoding the ARSA gene -Libmeldy) (90,91) and is in advanced stages of clinical testing for other neurodegenerative LSDs (92) (74). The optimization of combined LV-mediated in vivo and ex vivo GT protocols could address the unmet medical needs of patients with GM2 gangliosidoses, as well as, potentially, other LSDs for which therapeutic options are absent or insufficient.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Sala

Ornaghi

Morena

et al. 2021

Preprint

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The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.

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Section: Discussionmentioning

confidence: 99%

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Sala

Ornaghi

Morena

et al. 2021

Preprint

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“…These data provided the first formal proof that HSPC‐GT could represent a valuable and efficacious therapeutic option in MLD, and more generally in patients with lysosomal storage diseases (LSDs), where supra‐normal enzyme levels might be required for disease correction. More recently an update on the safety and efficacy of HSPC‐GT in early‐onset MLD patients have been reported and includes data on 33 patients (18 LI, 15 EJ) with a follow‐up ranging from 1 month to 7.5 years (median 2.99 years) 38 . While most of the patients were treated with the fresh formulation of the drug product, four children received the cryopreserved formulation of the same product.…”

Section: Metachromatic Leukodystrophymentioning

confidence: 99%

“…More recently an update on the safety and efficacy of HSPC-GT in early-onset MLD patients have been reported and includes data on 33 patients (18 LI, 15 EJ) with a follow-up ranging from 1 month to 7.5 years (median 2.99 years). 38 While most of the patients were treated with the fresh formulation of the drug product, four children received the cryopreserved formulation of the same product. In this large cohort of patients with MLD treated with HSPC-GT, 30 patients were alive, while two children died of disease progression and one of cerebral stroke.…”

Section: Ex Vivo Gtmentioning

confidence: 99%

Haematopoietic stem cell gene therapy in inborn errors of metabolism

Chiesa

Bernardo

2022

Br J Haematol

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Inborn errors of metabolism (IEM) constitute a heterogeneous group of single gene diseases, which cause the deficiency of critical enzymes involved in cell metabolism. The enzymatic insufficiency leads to the disruption of critical biological pathways, with accumulation of toxic metabolites in different human cells and tissues. This can lead to complex, life-threatening syndromes, affecting the skeletal structure, vision, hearing, cardiopulmonary function and neurological development. The reported cumulative incidence of IEM differs across the world, with an estimated incidence of 1:667 in Saudi Arabia and 1:2920 in Germany. 1 Current therapeutic strategies for IEM are directed towards reducing critical substrates, removing toxic metabolites or increasing the activity of the defective enzyme.Enzyme-replacement therapy (ERT) relies on the recombinant production of highly purified enzymes administered to patients affected by a number of IEM, in order to crosscorrect tissues and organs suffering from that enzymatic

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“…In MLD, the phase III clinical trial (NCT04283227) assessed the pharmacodynamic effects and the long-term safety and efficacy of OTL-200 in late juvenile patients. The main end points were focused on measuring human arylsulfatase A (ARSA) activity in cerebrospinal fluid (CSF) and neuronal metabolite N -acetyl-aspartate (NAA) to creatinine (Cr) ratio, in white matter regions of the brain [ 53 , 54 ].…”

Section: Gene Therapy In Lsdsmentioning

confidence: 99%

Therapeutic Approaches in Lysosomal Storage Diseases

et al. 2021

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Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme replacement therapy, gene therapy, or small molecules have been approved or are under clinical development to treat lysosomal storage disorders. The present article reviews the main therapeutic strategies that have been proposed so far, highlighting possible limitations and future perspectives.

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Lentiviral hematopoietic stem and progenitor cell gene therapy (HSPC-GT) for metachromatic leukodystrophy (MLD): Clinical outcomes from 33 patients

Cited by 11 publications

References 0 publications

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

Haematopoietic stem cell gene therapy in inborn errors of metabolism

Therapeutic Approaches in Lysosomal Storage Diseases

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