Proof of concept personal RNA therapy for ultra-rare form of Batten’s disease

A year ago, we covered preliminary results of ultra-personalized gene therapy for a rare form of Batten disease. Team behind the treatment just published a peer-reviewed report, describing in detail the development and results of such, first in the world, drug.

Batten disease is a rare and fatal disorder of the nervous system. Patients typically die before adulthood. Mila – the recipient of custom-made therapy – was clinically diagnosed when she began to lose vision, regressed in development, and started to suffer from frequent seizures. At the age of 6, Mila was enrolled in a research study at Boston Children’s Hospital.

Scientists used basic tools of modern molecular biology to dissect details of the disorder. Whole genome sequencing found repeated sequences in the non-coding part of gene MFSD8 (another name: CLN7). Precise amplification with PCR revealed that discovered sequences surround 2,000-nucleotide fragment, which was probably inserted by one of the mobile elements in the human genome. Mila’s mutation was moved, long element, that interrupted gene important in nervous cells. Further analysis of RNA sequencing data showed the mechanism of disease: interruption causes the gene to be cut too early in the process of splicing. This observation suggested possible treatment – a molecule excluding aberrant element from the splicing.

We know molecules capable of completing that task. RNA strands (antisense oligonucleotides), chemically modified and synthesized in proper order, can attach to the erroneous sequence in the genome, modifying its splicing. There is already one approved drug – nusinersen for spinal muscular atrophy – and researchers followed its path. The new drug was named milasen.

The drug was developed in just one year. The team established cell culture from the patient’s cells to speed up the testing. They found 22-nucleotide long RNA, which increased the number of correct splicing processes by three times. After toxicological studies in animal models, Mila received the first dose at the beginning of 2018.

One year of treatment brought an 80% decrease in a cumulative time of seizures, as well as improvement in 5 out of 11 neurological subscores. The disease can be described as slowed down, but not cured – the brain volume is still decreasing.

The novel therapy serves as a model of ultra-personalized care for a patient with one-in-the-world mutations. Milasen will be probably never used again in another individual, but the diagnosis and development provide clear procedures for fast treatment with unique antisense oligonucleotides. And, as parents of Mila remark:

Milasen will not cure Mila. But Mila was 7 when she got her first dose. What if the next Mila is treated when she is 4 or 5?

Publication: Jinkuk Kim, Ph.D., Chunguang Hu, M.D., Ph.D., Christelle Moufawad El Achkar, M.D., Lauren E. Black, Ph.D., Julie Douville, Ph.D., Austin Larson, M.D., Mary K. Pendergast, J.D., Sara F. Goldkind, M.D., Eunjung A. Lee, Ph.D., Ashley Kuniholm, B.S., Aubrie Soucy, B.A., Jai Vaze, B.A., Nandkishore R. Belur, M.S., Kristina Fredriksen, B.S., Iva Stojkovska, B.S., Alla Tsytsykova, Ph.D., Myriam Armant, Ph.D., Renata L. DiDonato, B.S., Jaejoon Choi, Ph.D., Laura Cornelissen, Ph.D., Luis M. Pereira, Ph.D., Erika F. Augustine, M.D., Casie A. Genetti, M.S., Kira Dies, Sc.M., Brenda Barton, R.N., Lucinda Williams, D.N.P., Benjamin D. Goodlett, Ph.D., Bobbie L. Riley, M.D., Amy Pasternak, D.P.T., P.C.S., Emily R. Berry, D.P.T., Kelly A. Pflock, D.P.T., P.C.S., Stephen Chu, Pharm.D., Chantal Reed, Ph.D., Kimberly Tyndall, B.A., Pankaj B. Agrawal, M.B., B.S., M.M.Sc., Alan H. Beggs, Ph.D., P. Ellen Grant, M.D., David K. Urion, M.D., Richard O. Snyder, Ph.D., Susan E. Waisbren, Ph.D., Annapurna Poduri, M.D., M.P.H., Peter J. Park, Ph.D., Al Patterson, Pharm.D., Alessandra Biffi, M.D., Joseph R. Mazzulli, Ph.D., Olaf Bodamer, M.D., Ph.D., Charles B. Berde, M.D., Ph.D., and Timothy W. Yu, M.D., Ph.D (2019).Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. Doi:10.1056/NEJMoa1813279.
Quote: New York Times
Photo: TriLink Biotechnologies

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