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Patient-Customized Anti-Sense Therapy Possibly Successful for Young Girl with MFSD8/CLN7 Batten Disease, an Ultra-Rare and Generally Fatal Genetic Disease

On October19 at that 2018 ASHG Annual Meeting in San Diego, scientists from Boston Children’s Hospital & collaborating institutions reported apparently successful treatment of a six-year-old girl’s (Mila) Batten disease with an antisense oligonucleotide customized to the girl’s specific disease-causing alteration in the intron of the MFSD8/CLN7 gene, a key lysosomal gene. The alteration was due to the insertion of a retrotranspon into the intron. The text of ASHG presentation abstract is given below. Links to articles on work are provided at the end. The ASHG abstract was titled “Patient-Customized Oligonucleotide Therapy for an Ultra-Rare Genetic Disease” And was #3570 in the ASHG’s meeting program. The presentation was given in the ASHG’s Late-Breaking Abstract Session. Here is the text of the presentation abstract: “Next generation sequencing has revolutionized the diagnosis of rare genetic diseases. However, many patients still suffer from a lack of therapeutic options for most of these conditions, which in aggregate impact tens of millions of individuals globally. Here, we demonstrate a dramatically new pathway for the treatment of even ultra-rare genetic diseases. A six year old girl (Mila) developed progressive blindness, epilepsy, and neurocognitive regression. Whole-genome sequencing and RNA-seq revealed a maternally inherited retrotransposon inserted into an intron of MFSD8/CLN7, a key lysosomal gene. The insertion was found to cause exon trapping, leading to gene inactivation. This mutation, in combination with a paternal missense mutation in the same gene, caused Batten Disease, a rare, recessive disorder of neuronal lysosomal storage. No treatments exist for CLN7 Batten disease. Unchecked, it is rapidly progressive and ultimately fatal. We therefore set out to rapidly develop a novel antisense oligonucleotide drug, customized to her mutation. In vitro administration of this oligonucleotide to patient-derived cells relieved the exon trap, and reversed lysosomal dysfunction as well. In communication with the FDA, we arranged the manufacturing and formulation of our oligonucleotide drug, which we named milasen. In January of this year – only one year from first patient contact – we launched a single patient treatment trial of milasen, under an Individual Patient Expanded Access IND. In this ongoing trial, milasen treatment appears to have arrested further clinical deterioration, and has been associated with striking reductions in seizure intensity and frequency. No safety or tolerability issues have arisen. This study illustrates an end-to-end pathway from genomic diagnosis to precision therapy, and offers a possible template for future treatments of even ultra-rare genetic diseases, in a safe and timely fashion.” Photo shows Mila resting in a hospital bed on February 1, 2018, after receiving the experimental treatment for her Batten disease. (Photo by Mila’s mother, Julia Vitarello).

[ASHG abstract] [Science magazine article] [Stat article] [FOX 5 article] [Daily Mail article] [Inquisitr article] [ASHG 2018 Annual Meeting]