Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome.

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Preserving Ambulation in a Gene Therapy-Treated Girl Affected by Metachromatic Leukodystrophy: A Case Report.

(1) Background: Atidarsagene autotemcel is a hematopoietic stem and progenitor cell gene therapy (HSPC-GT) approved to treat early-onset metachromatic leukodystrophy (MLD). The purpose of this case report is to describe the long-term management of residual gait impairment of a child with late infantile MLD treated with HSPC-GT. (2) Methods: Assessment included Gross Motor Function Measure-88, nerve conduction study, body mass index (BMI), Modified Tardieu Scale, passive range of motion, modified Medical Research Council scale, and gait analysis. Interventions included orthoses, a walker, orthopedic surgery, physiotherapy, and botulinum. (3) Results: Orthoses and a walker were fundamental to maintaining ambulation. Orthopedic surgery positively influenced gait by reducing equinovarus. Nonetheless, unilateral recurrence of varo-supination was observed, attributable to spasticity and muscle imbalance. Botulinum improved foot alignment but induced transient overall weakness. A significant increase in BMI occurred. Finally, a shift to bilateral valgopronation was observed, more easily managed with orthoses. (4) Conclusions: HSPC-GT preserved survival and locomotor abilities. Rehabilitation was then considered fundamental as a complementary treatment. Muscle imbalance and increased BMI contributed to gait deterioration in the growing phase. Caution is recommended when considering botulinum in similar subjects, as the risk of inducing overall weakness can outweigh the benefits of spasticity reduction.

Spontaneous fractures in custom-made porous hydroxyapatite cranioplasty implants: is fragility the only culprit?

BACKGROUND: Although the porous hydroxyapatite (PHA) used in custom-made cranioplasty implants is a material appreciated for its biomimetic properties, before osteointegration it is initially very fragile. Nevertheless, we wondered whether this primary fragility is entirely due to brittleness or whether the surgeon's actions may influence the behavior of the material. METHODS: To study the influence of the surgeon's behavior, we made a virtual model of a custom-made PHA cranioplasty implant and submitted it to three implant procedural variables using finite element methods. In the first test, a scenario in which the surgeon's design, validation, and positioning techniques are impeccable, the edges of the implant adhered well to the craniectomy margins. In the second test, a discrepancy between a portion of the perimeter of the craniectomy and the profile of the prosthesis was modeled, and in the third test, several gaps were simulated between the implant and the craniectomy margins. RESULTS: Our mathematical model showed that when local and general discontinuities were included in the test scenarios, there was an increase in the load coming to bear on the cranioplasty implant, which amounted to 80 and 50 %, respectively. CONCLUSIONS: The fragility of custom-made PHA cranioplasty implants increases if the surgeon fails to achieve a precise design and validation, and/or an accurate surgical procedure. Nevertheless, careful attention during these phases helps to maintain the strength of the implant, given the more favorable mechanical conditions, without interfering with its biomimetic capacity.