Fanconi anemia and βc deficiency-associated pulmonary alveolar proteinosis as two hereditary diseases of childhood which are potentially curable by stem cell gene therapy but require different therapeutic approaches

Fanconi anemia (FANC) and pulmonary alveolar proteinosis associated with deficiency of the β-chain common to the GM-CSF/IL3/IL5 receptors (βc-PAP) are rare inherited disorders of childhood or adolescence. Hematopoietic stem cell gene therapy aiming at reintroducing the wildtype cDNA as a new concept for the treatment of hereditary diseases may be applicable to FANC and PAP, as both disorders can be successfully treated by allogeneic stem cell transplantation. However, there are important distinctions to be made between the two diseases: FANC seems to be a disorder with functional stem cell deficiency. Thus, introduction of the wildtype cDNA should provide an in vivo growth advantage to genetically corrected stem cells so that corrected cells and their progeny may expand in vivo and slowly repopulate the entire hematopoietic system. In βc-PAP, the defect has no major impact on proliferation or differentiation of stem cells. Therefore, introduction of the wildtype gene will probably not provide any selective growth advantage and the percentage of corrected cells in the hematopoietic compartment depend on the percentage of stem cells initially transduced as the current technology only allows for transduction of stem cells with low efficiency. The introduction of a second selectable cDNA into the vector might be used to provide selective growth for modified cells and thus overcome a low gene transfer efficiency of stem cells. The correction of rare monogenetic diseases may serve as a model for gene therapy prior to attempts to treat more common and complex polygenetic diseases. The studies outlined here will be helpful envisioning new treatment strategies for other inherited monogenetic diseases such as mucopolysaccharidosis, Gauchers disease or adrenoleukodystrophy.