Innovative Cholesterol-Conjugated HDOs Enable Systemic Delivery of ASOs Across Blood-Brain Barrier, Paving Way for Neurodegenerative Disease Therapies
Ionis Pharmaceuticals
RNA Drug Developer
Takeda
Biopharmaceutical Manufacturer
Tokyo Medical and Dental University
Tokyo Medical and Dental University (Japanese: 東京医科歯科大学, Tōkyō Ika Shika Daigaku; Chinese: 东京医科齿科大学) is a Japanese national university established in 1928, with its university-level education commencing in 1946. The university is commonly abbreviated as “Ika Shika Dai” or “Tokyo I-Shi Dai.” Its Faculty of Dentistry is the oldest public dental education institution in Japan and was one of the original six dental universities. In April 2004, it was incorporated as a National University Corporation. Currently, Tokyo Medical and Dental University comprises two undergraduate faculties, two graduate schools, two libraries, and two affiliated hospitals, along with numerous research institutes. The university operates across three campuses: the Yushima Campus (building area: 265,623 square meters), the Surugadai Campus (building area: 18,028 square meters), and the Kounodai Campus (building area: 13,900 square meters). Located in Bunkyo Ward, the cultural and educational center of Tokyo, the Yushima Campus serves as the main campus. It houses the Faculty of Medicine, the Faculty of Dentistry, the Graduate School of Medical and Dental Sciences, the Graduate School of Health Care Sciences, the affiliated hospital, and the Central Library. It is also home to the central administrative offices and various research centers. Separated from the Yushima Campus only by a canal, the Surugadai Campus is located in Chiyoda Ward, Tokyo. It hosts the International Exchange Center, the Institute of Biomaterials and Bioengineering, the Research Institute for Diseases of Old Age, and the Data Science Center. The Kounodai Campus, situated in Ichikawa City, Chiba Prefecture, accommodates the College of Liberal Arts, the International House, and international student dormitories. Guided by its educational philosophy, the university is dedicated to cultivating healthcare professionals who possess comprehensive refinement, rich humanistic sensibilities, outstanding creativity, and a broad global perspective.
Antisense oligonucleotide (ASO) therapy holds the potential to treat various neurodegenerative diseases by inhibiting the production of pathogenic proteins or non-coding RNAs at the genetic level. However, delivering sufficient levels of ASOs to the central nervous system (CNS) remains a significant challenge, as ASOs cannot effectively cross the blood-brain barrier. ASOs for treating CNS diseases typically require intrathecal injection for effective delivery, which poses considerable inconvenience for patients receiving treatment.
Recently, researchers from Tokyo Medical and Dental University (TMDU), Ionis Pharmaceuticals, and Takeda have collaborated to discover a novel method for delivering ASOs administered via subcutaneous or intravenous injection across the blood-brain barrier into the central nervous system. The researchers stated that this breakthrough is expected to revolutionize the treatment of neurodegenerative diseases. This study was published in *Nature Biotechnology*.
Generally, only hydrophobic molecules with a molecular weight of less than 450 Da can cross the blood-brain barrier. To improve the blood-brain barrier permeability of ASO therapy, researchers synthesized and evaluated 14 lipophilic conjugates. Ultimately, it was found that conjugating cholesterol to heteroduplex oligonucleotides (HDOs) composed of DNA and RNA effectively knocked down the expression of target genes in the brain in mouse and rat models following subcutaneous or intravenous injection.
Experimental results demonstrate that these cholesterol-conjugated HDOs are widely distributed in the brain, spinal cord, and peripheral tissues, exhibiting the highest accumulation in the CNS...
▲ HDOs capable of crossing the blood-brain barrier (BBB-HDOs) significantly inhibit target gene expression in the cerebral cortex (Image credit: Department of Neurology and Neurological Science, TMDU)
Furthermore, the research team further demonstrated that the ability of these HDOs to cross the blood-brain barrier did not compromise the integrity of the blood-brain barrier itself.
References:
[1] From blood to brain: Delivering nucleic acid therapy to the central nervous system. Retrieved August 14, 2021, from https://medicalxpress.com/news/2021-08-blood-brain-nucleic-acid-therapy.html
[2] Nagata et al., (2021). Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS. Nature Biotechnology, https://doi.org/10.1038/s41587-021-00972-x
(Original text abridged)
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