A novel treatment for familial adenomatous polyposis (FAP) patients by adenomatous polyposis coli (APC) nonsense mutation read-through

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome that strongly predisposes to the development of multiple adenomas in the colon and rectum. These adenomas will progress to adenocarcinoma if not removed. Most of the classic FAP cases can be attributed to mutations in the APC gene, where adenoma progression occurs due to inactivation of the non-mutated allele by somatic mutations or loss of heterozygosity (LOH). Approximately 30% of the germline APC mutations are single nucleotide changes that result in premature stop codons (nonsense mutations).

Read-through of nonsense mutations by different compounds or antibiotics is a potential therapeutic strategy to overcome genetic disorders. Here we present the results of a clinical trial in which 9 FAP patients harboring APC nonsense mutations, treated with the read-through inducing antibiotic- Erythromycin for 4 months with 500mgX2/d in adults and 250 to 500mgbid (according to weight at enrollment)in children. Endoscopic assessment of polyps was performed at baseline and after 4 and 12 months. The majority of patients (6/9) exhibited wide range of polyp burden reduction after 4 months of treatment (12.5-72.3% reduction) and after 1 year (12.5-77.3% reduction). Molecular and genetic analyses of the adenomas obtained from these patients revealed a reduction in the number of APC somatic mutations and the restoration of APC tumor suppressing activity. Thus, read-through of APC nonsense mutations should be considered as a potential chemopreventive strategy in this subset of FAP patients and in CRC patients harboring nonsense mutations in the APC gene.