Genomic instability markers in Fanconi anemia
Markers for genomic instability in Fanconi Anemia (FA) and other pathologies for therapeutic and diagnostic uses. In one embodiment, glycosphingolipid metabolism is altered in the FA deficient squamous cell carcinoma (SCC) cells, based on analysis of a metabolomics/lipidomics platform. The data indicated ganglioside metabolism was important in FA patients' susceptibility to SCC progression.
1. A method of treating at least one condition of a gene instability disorder in an individual having a gene instability disorder characterized by increased NeuACα2-3Galβ1-4Glcβ1-1ceramide (GM3), increased GM3 precursor, or increased GM3 metabolic product, the method comprising the step of administering a composition comprising an iminosugar-based GM3 synthase inhibitor selected from the group consisting of NB-DNJ and Genz529468 to treat the at least one condition, where the at least one condition is a skin abnormality or an abnormal cellular phenotype selected from the group consisting of diminished cellular adhesion, increased cellular migration, increased cellular invasiveness, and combinations thereof, where the gene instability disorder is selected from the group consisting of Fanconi Anemia (FA), ataxia telangiectasia (AT), AT-like disorder (ATLD), Nijmegen breakage syndrome (NBS), Werner's syndrome, Bloom's syndrome, Rothmund-Thompson syndrome, xeroderma pigmentosa (XP), Cockayne's syndrome (CS), and combinations thereof.
2. The method of claim 1 where the genetic instability disorder is Fanconi Anemia (FA).
3. The method of claim 1 where the composition is administered by a route selected from the group consisting of orally, rectally, nasally, topically, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, or a combination thereof.
4. The method of claim 1 where administering the composition results in increased cellular adhesion, decreased cellular migration, decreased cellular invasiveness, and/or decreased blistering compared to an individual not receiving the composition.
5. The method of claim 1 where the cell exhibiting the abnormal cellular phenotype is cancerous or non-cancerous.
6. The method of claim 5 where the cancerous cell is a squamous cell carcinoma (SCC) cell.
7. The method of claim 6 where the SCC cell is a head and neck squamous cell carcinoma (HNSCC) cell.
8. The method of claim 6 where administering the composition results in a decrease in metastasis of the SCC cell compared to an individual not receiving the composition.
9. The method of claim 1 where the cell exhibiting the abnormal cellular phenotype is a skin cell selected from the group consisting of keratinocytes, melanocytes, Merkel cells, Langerhans cells, and combinations thereof.
10. The method of claim 1 wherein the cell exhibiting the abnormal cellular phenotype is a keratinocyte.
11. The method of claim 9 where administering the composition results in a decreased susceptibility to blistering and/or a decreased susceptibility to infectious agents passing through the skin compared to an individual not receiving the composition.
12. A method of ameliorating at least one condition of a genetic instability disorder characterized by increased NeuACα2-3Galβ1-4Glcβ1-1ceramide (GM3), the method comprising administering a composition comprising a GM3 synthase inhibitor selected from the group consisting of NB-DNJ and Genz529468 under conditions sufficient to decrease GM3 and ameliorate the condition, where the at least one condition is a skin abnormality or an abnormal cellular phenotype selected from the group consisting of diminished cellular adhesion, increased cellular migration, increased cellular invasiveness, and combinations thereof, where the gene instability disorder is selected from the group consisting of Fanconi Anemia (FA), ataxia telangiectasia (AT), AT-like disorder (ATLD), Nijmegen breakage syndrome (NBS), Werner's syndrome, Bloom's syndrome, Rothmund-Thompson syndrome, xeroderma pigmentosa (XP), Cockayne's syndrome (CS), and combinations thereof.