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Update on safety and efficacy of lentiviral hematopoietic stem cell gene therapy (HSC-GT) for metachromatic leukodystrophy (MLD)

  • F. Fumagalli
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • V. Calbi
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • A. Zambon
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • F. Ciotti
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • L. Lorioli
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • M. Sessa
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • M. Sarzana
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • S. Canale
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • G. Antonioli
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • S. Medaglini
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • U. Del Carro
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • A. Quattrini
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • C. Baldoli
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • S. Martino
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • C. Di Serio
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • F. Ciceri
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • L. Naldini
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • M.G. Natali Sora
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • A. Biffi
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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  • A. Aiuti
    Affiliations
    Department of Neurology, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Unit of Pediatric Immunohematology and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy
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      Objective: MLD is a fatal demyelinating lysosomal disease due to Arylsulfatase A (ARSA) deficiency with no approved treatment. This is an updated ad hoc analysis of the first 21 early onset MLD patients treated with experimental HSC-GT. Methods: GT consists of autologous HSC engineered with a lentiviral vector encoding ARSA cDNA infused after Busulfan conditioning. Nine patients were Late Infantile (LI) and 12 were Early Juvenile (EJ), the latter including 1 patient classified as intermediate. Median age at treatment was 39.3 months (7.7–141.7); 8 LI and 4 EJ were treated before onset of overt disease ma manifestations. We compared the clinical outcomes to those in a cohort of 28 untreated MLD patients followed in a natural history (NH) study (16 LI and 12 EJ). Results: Nineteen patients are alive with median follow up (FU) of 29 mo (12.2–67.5); 2 EJ patients treated after onset of symptoms died due to disease progression. There was no treatment-related mortality, no evidence of abnormal clonal proliferation, and no treatment-related adverse events. We observed per persistent engraftment of gene corrected cells with a marked increase of ARSA act activity in peripheral blood and CSF. LI patients treated before symptom onset showed better motor and cognitive performance compared to the NH cohort. Prevention of progressive de demyelination on brain MRI, stabilization of nerve conduction velocities (NCV), and maturation of brainstem auditory evoked potentials (BAEP) were observed in the majority of LI subjects. Stabilization or improvement in NCV and BAEP were often preceded by a p period of deterioration in those parameters following GT. The 4 pre-symptomatic EJ patients show normal neurodevelopment to date. Conclusion: We confirm that HSC-GT continues to be well tolerated. Pre-symptomatic LI pts show a sustained clinical benefit. Prolonged FU will provide additional information on the long-term safety, clinical efficacy and factors predictive of outcome following HSC-GT.
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