A number of gene therapy approaches have been developed for the treatment of genetic diseases, most of them based on the use of viral vectors. However, in general, they have not been successful and some complications, such as immune reactions induced by adenoviral vectors or random integration of retroviral vectors, have been reported frequently. To overcome these limitations, novel strategies have recently emerged. One of them is chimeraplasty, based on the correction of single-base mutations by mismatch repair mechanisms using chimeric RNA/DNA oligonucleotides, named chimeraplasts. Several papers have reported the use of this method to correct a number of pathological mutations underlying different diseases. In Gaucher disease, the most prevalent spingoliposis, mutation c.1448C->T (L444P), is one of the most common mutations in many populations. We have attempted to correct mutation c.1448C->T in fibroblasts from a Gaucher disease patient using a chimeraplast approach. Although we have shown that the chimeraplast reaches the fibroblast nucleus by colocalization with nuclear structures, no genomic correction was detected. To evaluate whether fibroblast and hepatocyte extracts are able to effect correction in vitro, we followed a cell-free extract assay using Escherichia coli cells. Our results show a very low efficiency (if any) of chimeraplast correction. A growing number of negative results for chimeraplast experiments have recently been reported. This promising technique has turned out to be inconsistent and impossible to replicate in most laboratories and many of the first successful results are now being questioned. Our negative data are consistent with this criticism.