A custom-designed antisense oligonucleotide has been used to treat a unique form of Batten disease in a single patient in a study recently published in the New England Journal of Medicine. The study sets a precedent for rapid development of individually tailored treatment on the basis of genetic sequencing.

The study was led by Timothy Yu at Boston Children’s Hospital in the USA, who first encountered the patient — a 6-year-old girl — through social media. She had been diagnosed with Batten disease, an autosomal recessive disorder; her symptoms included loss of vision, falls, dysarthria, dysphagia, seizures and cerebral and cerebellar atrophy.

Genetic testing had revealed one mutation in the MFSD8 gene, which is associated with Batten disease. However, a second mutation, which is expected when a recessive disorder has manifested, had not been found. Building on his background in whole-exome and genome sequencing and analysis, Yu and his colleagues set out to reach a molecular diagnosis.

“I had a long-standing interest in difficult-to-find mutations as a cause of ‘hidden heritability’, and I had always been curious about ‘half-diagnosed cases’ — those 10% of clinically diagnosed cases with what should be a recessive disease, but for which one mutation is missing,” explains Yu.

Whole-genome sequencing revealed a deep intronic mutation that had previously gone undetected. Yu’s team showed that this mutation altered the splicing of MFSD8 and reduced expression of the normal gene product. The underlying biology of this mutation was similar to that of the causal mutation in spinal muscular atrophy, a mutation that has been targeted successfully with the oligonucleotide nusinersen. On this basis, Yu and his team worked on the principles of nusinersen to develop a custom-designed oligonucleotide.

“We thought that if we could make a short synthetic stretch of RNA, just like nusinersen, utilizing the same chemical backbone and modifications, we ought to be able to find one that could block usage of our patient’s aberrant splice site and restore the full-length gene,” says Yu.

The team designed multiple oligonucleotides to target the MFSD8 splice variant and singled out the one that most effectively increased normal gene expression in fibroblasts from the patient. The oligonucleotide — which they called milasen — was developed for clinical administration, and permission was obtained from the FDA for its clinical investigation under an Expanded Access Investigational New Drug application.

Treatment of the patient with milasen led to stabilization of her scores on neurological and neuropsychiatric assessments — performance in these tests had previously been deteriorating. In addition, objective measures demonstrated that the number of seizures decreased.

it is possible to design, test and manufacture a drug customized to a patient’s genomic sequence

“The major finding here was that it is possible to design, test and manufacture a drug customized to a patient’s genomic sequence, and to do it all in a timeframe to be potentially useful for that patient. The speed with which these technologies can be brought to bear has the potential to change the paradigm — especially considering all of the devastating diseases for which even a proof-of-concept treatment has never been attempted,” points out Yu. “This type of work also proves the value of a molecular diagnosis. This case is obviously an extreme example, but it certainly drives home the point that it is critical to understand exactly what your mutations are, given the potential treatment ramifications.”