Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction

Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease

“…We theorize that the lack of rescue may be explained by GALC levels that are too low, expressed in the wrong cell type, or present at the wrong time period. Furthermore, cross-correction of GALC 27 (and other lysosomal hydrolases 28 ) may not be very efficient in vivo, and therefore, the function of GALC may be restricted to the subset of cells that directly express it. A similar correlate exists regarding refractory moribund pathology observed in HSCT-treated twitcher and KD patients despite the detection of substantial GALC activity 29 – 32 .…”

Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

“…Thus, it may seem that significant overexpression of the enzyme in genetically modified cells can ensure the spread of the enzyme over long distances along the nervous system and provide a significant therapeutic effect. However, recent articles on another LSD showed that this might not have a big impact and in case of hematopoietic stem cell transplantation as the therapeutic effect of cells expressing the normal enzyme can be mediated by phagocytic response of healthy macrophages, rather than cross-correction (138).…”

In vitro Validation of Chimeric β-Galactosylceramidase Enzymes With Improved Enzymatic Activity and Increased Secretion

“…Neri et al, 2011;Ricca et al, 2015), suggesting a tight regulation of GALC expression that is only partially elucidated in these cell types. This limitation to GALC overexpression coupled to moderate enzyme secretion by transduced cells and/or insufficient uptake by GLD cells (cross-correction) suggested by previous studies (Ricca et al, 2015;Weinstock et al, 2020) may explain the partial effect of conventional HSCT and the little advantage of HSC-GT in GLD mice (Galbiati et al, 2009;Gentner et al, 2010;Rafi et al, 2015a). Thus, in GLD more than in other LSDs, it is crucial to maximize GALC expression by transduced cells and/or to enhance tissue bioavailability to improve the efficacy of GT approaches.…”

“…Ex vivo LV-mediated GT with autologous hematopoietic stem/progenitor cells (HSPCs) engineered to express the therapeutic gene product (HSC-GT) provides a therapeutic benefit in LSD mouse models (Biffi et al, 2006;Langford-Smith et al, 2012;Visigalli et al, 2016;Ellison et al, 2019) and ameliorates the clinical conditions of patients in several genetic diseases (Cartier et al, 2009;Aiuti et al, 2013;Ferrua et al, 2019;Marktel et al, 2019) including metachromatic leukodystrophy (MLD) (Biffi et al, 2013;Sessa et al, 2016), which shares with GLD the early onset and severe neurological involvement. The moderate benefit of HSC-GT in GLD mice might depend on the poor GALC overexpression achieved in HSPCs and progeny, possibly coupled to modest enzyme secretion and/or insufficient uptake by GLD cells (crosscorrection), particularly in the CNS (Gentner et al, 2010;Ungari et al, 2015;Weinstock et al, 2020). Combined cell/GT strategies designed to address the complex multi-organ GLD pathology significantly increase the lifespan of GLD models (Hawkins-Salsbury et al, 2015;Rafi et al, 2015b;Ricca et al, 2015).…”