[초청강연] Patient-customized oligonucleotide therapy for ultra-rare genetic disease

제목: Patient-customized oligonucleotide therapy for ultra-rare genetic disease

High-throughput sequencing has revolutionized the diagnosis of rare genetic disorders. However, many patients still suffer due to a lack of therapeutic options for most of these conditions, which in aggregate impact tens of millions of individuals in the US alone. Here, we demonstrate a new pathway from genomic diagnosis to individualized therapy for an ultra-rare condition. 

A six-year-old girl developed progressive blindness, epilepsy, and neurologic regression. Genome sequencing revealed a maternally-inherited intronic retrotransposon insertion in MFSD8/CLN7, a key lysosomal gene. This created an exon trap, and in combination with a paternal known pathogenic point mutation in the same gene, resulted in Batten disease, a rare neurodegenerative disorder of lysosomal storage.

No treatments exist for CLN7 Batten disease. Unchecked, it is rapidly progressive and ultimately fatal. We therefore set out to develop an antisense oligonucleotide drug, customized to her maternally-inherited mutation, to correct the splice defect. Administration of this oligonucleotide to patient fibroblasts relieved the exon trap, and rescued lysosomal function as well.

In collaboration with the FDA, we orchestrated manufacturing and formulation of our oligonucleotide, which we named milasen. Eight months after her genomic diagnosis, and within one year of patient referral, we launched a single patient trial of intrathecal milasen administration. Through ten months of treatment, no safety or tolerability issues have arisen. No further clinical deterioration has been evident, and we observe striking reductions in seizure intensity and frequency. 

This study offers a possible template for the delivery of genetically targeted treatments in a safe and timely fashion.