Topics in Pediatric Leukemia -- Fanconi's Anemia: New Insights

Noah Federman, MD; Kathleen M. Sakamoto, MD, PhD

Gene Therapy

Somatic mosaicism, which has been reported in FA patients, supports the modality of gene therapy as a therapeutic option. In FA mosaic patients, there is reversion of a pathogenic allele in a single hematopoietic progenitor cell to a wild-type one, thereby conferring a survival advantage to that cell. The patients with this mosaicism remain in remission from bone marrow failure.^[24] This indicates that correction of a single progenitor cell may be all that is required to restore adequate hematopoiesis.

As mentioned before, phenotypic correction of hematopoietic progenitors has been achieved in FANCA knockout mice with retroviral vectors.^[25] However, retroviral vectors in human patients have proven ineffective because FA human bone marrow cells grow poorly in vitro, are fragile, and are refractory to retroviral vector transduction.^[26] Clinical trials with retroviral vectors in FA patients have been disappointing. Lentiviral vectors, on the other hand, are being used in animal models with some success. FANCA and FANCC knockout mice bone marrow cells have been transduced with lentiviruses, and the deriving hematopoietic cells have become resistant to DNA crosslinking agents.^[27]

Lentiviral vector gene therapy, although still in a very experimental phase, carries some promise for patients, as it can transduce quiescent hematopoietic progenitors in the absence of cytokines or other growth factors.

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Cite this: Topics in Pediatric Leukemia -- Fanconi's Anemia: New Insights - Medscape - Apr 06, 2005.

Introduction
Clinical Features
New Insights Into the Genetic and Molecular Basis of FA
Diagnosis
Management
Gene Therapy
Conclusion
References

Congenital Anomalies Associated With FA
Congenital Anomaly	Approximate Percentage of FA Patients Affected
Skeletal (radial ray, hip, rib, and vertebral) anomalies	70%
Skin pigmentation (café au lait, hypopigmentation)	60%
Short stature	60%
Eyes (hypertelorism, hypotelorism, microphthalmia, ptosis, or epicanthal folds)	35% to 40%
Genitourinary anomalies (ectopic kidney, horseshoe kidney, dysplastic kidney, or hypospadias)	35%
Neurologic anomalies (microcephaly, mental retardation, hydrocephalus, or deafness)	30%
Gastrointestinal anomalies (imperforate anus, esophageal atresia, duodenal atresia)	10% to 15%
Cardiac anomalies (patent ductus arteriosus, atrial septal defects, ventricular septal defects, tetralogy of Fallot)	10% to 15%
No anomalies	30%

FA = Fanconi's anemia

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