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I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

5: Early Skeletal Outcome after Hematopoietic Stem Cell Gene Therapy for Mucopolysaccharidosis Type I Hurler

Type: Clinical

Presentation Details
Session Title: Clinical Trials Spotlight Symposium
Location: Concourse Hall 152 & 153
Start Time: 5/18/2023 8:15
End Time: 5/18/2023 8:30

Mucopolysaccharidosis type I Hurler (MPSIH) is a rare lysosomal storage disorder caused by defects in IDUA gene and characterized by a range of clinical manifestations including severe skeletal dysplasia. While allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents standard of care for MPSIH, skeletal abnormalities progress over time after allo-HSCT, requiring major orthopedic surgery and severely affecting patient’s quality of life.We report the early skeletal outcome in 8 MPSIH patients treated with autologous HSPC genetically modified to overexpress human IDUA and followed-up for a median of 3 years after gene therapy (GT). This is a phase I/II HSPC-GT trial (NCT03488394) which enrolled 8 patients (6 M, 2 F; mean age at treatment: 1.9±0.5 years) who lacked a non-heterozygous-HLA-matched cord blood donor and displayed IQ/DQ>70. Primary efficacy endpoint was blood IDUA activity up to supraphysiologic levels at 1-year post-GT. Secondary efficacy endpoints included growth velocity at 1- and 3-year post-treatment. Motor function and spine MRI score at 1- and 3-year post-treatment were defined as exploratory endpoints. Skeletal dysplasia was evaluated in terms of clinical (growth, measures of dorso-lumbar kyphosis and genu valgum by goniometer), functional (motor function by Peabody scale, joint range of motion [ROM]) and radiological (acetabular index [AI] and migration percentage [MP] at hip X-Rays and MRIs, spine MRI score) parameters at baseline and at multiple timepoints, up to 3-year after treatment. All patients are alive at 3-year follow-up and show sustained engraftment of gene-corrected cells with supraphysiologic blood IDUA activity. Urinary GAG excretion reduced to normal or near-normal values by 1-year post GT and remains stable at 3-year follow-up. All patients have progressed along expected growth percentiles of healthy children and exhibit longitudinal growth within the normal range adjusted for age and gender at last follow-up. They also show progressive increase in sitting height and adequate height velocity. Clinical measures of sitting and standing kyphosis showed a trend toward reduction in evaluable patients. Genu valgum is clinically stable with degrees within the physiological range (≤ 10°) in all evaluable patients from year 2 after GT up to the latest follow-up. Motor function showed progressive acquisition of motor skills, while ROM measurement demonstrated improved stiffness at the level of shoulder, elbow, hip and knee joints. Mean AI and MP measured at hip X-Rays and MRIs showed progressive decrease after GT, indicating a reduction in hip dysplasia. Typical spine alterations measured at MRI through a specific score (Pontesilli et al.) showed an overall stabilization after GT up to 3-year follow-up (mean score: 3.5 at baseline, 3.3 at 3-year follow-up). HSPC-GT has shown extensive metabolic correction with a favorable safety profile. Early skeletal outcome after HSPC-GT indicates stabilization of skeletal dysplasia at multiple sites up to 3 years post-treatment. A longer follow-up is needed to draw definitive conclusions on the impact of HSPC-GT on MPSIH skeletal manifestations, as compared with standard of care. Pontesilli S, et al. J Pediatr. 2022 Jan;240:297-301.e5.

Maurizio De Pellegrin1, Giulia Consiglieri1, Francesca Tucci1, Barbara Guerrini1, Silvia Pontesilli2, Chiara Filisetti1, Stefano Scarparo1, Marina Sarzana1, Paolo Silvani2, Giulia Forni3, Simona Miglietta1, Serena Gasperini4, Alessandro Cattoni4, Cristina Baldoli2, Fabio Ciceri2, Giancarlo La Marca3, Rossella Parini1, Luigi M. Naldini5, Alessandro Aiuti6, Bernhard Rudolf Gentner7, Maria Ester Bernardo1

1San Raffaele Telethon Institute for Gene Therapy, Milano, Italy,2San Raffaele Scientific Institute, Milano, Italy,3Meyer's Children Hospital, Milano, Italy,4A.O. “San Gerardo”, Monza, Milano, Italy,5SR-TIGET, Milan, Italy,6San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy,7SR-TIGET, Via Varese 16b, Roma, Italy
 M. Bernardo: None.

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