Preselective gene therapy for Fabry disease

Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells

“…In the heart, one of the most critically affected organs in Fabry patients, a-gal A activities increased up to 124% of normal levels, and Gb3 levels also decreased to the normal range in the therapeutically treated group. Notably, in the kidney, which has been one of the most affected and challenging organs to correct for Fabry disease using ERT and gene therapy approaches, 13,14,22,23 a-gal A activities increased to B25% of normal levels, which is likely to be therapeutically relevant (Table 1). Even though Gb3 levels in kidneys of these treated animals did not fully reduce to the normal range, substantial and significant decreases of Gb3 levels were observed ( Table 2).…”

“…These levels were higher and more stable than those we previously observed using a therapeutic recombinant oncoretrovirus 13 even with pre-selection of functionally transduced cells before transplantation. 14 Increased a-gal A activity and reduced Gb3 levels in the organs of treated Fabry mice…”

“…24,25 Another important finding from this study was that the variability of the levels of disease correction between each animal was very small; we previously saw relatively large variations between organ and Gb3 levels in oncoretrovirally treated Fabry mice. 13,14 At the point of killing, we collected BMMNCs from the primary transplanted Fabry mice. A portion of these cells were seeded into Methocult for short-term colony assays.…”

“…In contrast to our earlier RVs, 14 we employed a recombinant LV that engineered expression of a-gal A (LV/a-gal A) in a monocistronic format. As we had previously observed high gene transfer levels using this vector system, we did not use a cell surface marker that could be used for enrichment of transduced cells.…”

“…[11][12][13][14] A major hurdle to application of this approach in clinical studies for Fabry disease and other LSDs, however, is to accomplish efficient gene transfer into true HSPCs, which can then be transplanted to achieve stable, robust and long-term expression of corrective genes in progeny cells. This is a challenging task for the RVs currently in clinical trials.…”