Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD. <<<

Terrains in a 3D world can be undulating. Yet, most prior research has exclusively investigated spatial representations on a flat surface, leaving a 2D cognitive map as the dominant model in the field. Here, we investigated whether humans represent a curved surface by building a dimension-reduced flattened 2D map or a full 3D map. Participants learned the location of objects positioned on a flat and curved surface in a virtual environment by driving on the concave side of the surface (Experiment 1), driving and looking vertically (Experiment 2), or flying (Experiment 3). Subsequently, they were asked to retrieve either the path distance or the 3D Euclidean distance between the objects. Path distance estimation was good overall, but we found a significant underestimation bias for the path distance on the curve, suggesting an influence of potential 3D shortcuts, even though participants were only driving on the surface. Euclidean distance estimation was better when participants were exposed more to the global 3D structure of the environment by looking and flying. These results suggest that the representation of the 2D manifold, embedded in a 3D world, is neither purely 2D nor 3D. Rather, it is flexible and dependent on the behavioral experience and demand. <<<