Fanconi anemia and beta c 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 de ficiency of the beta-chain common to the GM-CSF/IL3/IL5 receptors (beta c-P AP) 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 c ell transplantation. However, there are important distinctions to be made b etween the two diseases: FANC seems to be a disorder with functional stem c ell deficiency. Thus, introduction of the wildtype cDNA should provide an i n vivo growth advantage to genetically corrected stem cells so that correct ed cells and their progeny may expand in vivo and slowly repopulate the ent ire hematopoietic system, In beta c-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 depe nd on the percentage of stem cells initially transduced as the current tech nology only allows for transduction of stem cells with low efficiency. The introduction of a second selectable cDNA into the vector might be used to p rovide selective growth for modified cells and thus overcome a low gene tra nsfer efficiency of stem cells. The correction of rare monogenetic diseases may serve as a model for gene t herapy prior to attempts to treat more common and complex polygenetic disea ses. The studies outlined here will be helpful envisioning new treatment st rategies for other inherited monogenetic diseases such as mucopolysaccharid osis, Gauchers disease or adrenoleukodystrophy.