From blood to brain: Delivering nucleic acid therapy to the CNS

Date:
August 12, 2021
Source:
Tokyo Medical and Dental University
Summary:
Researchers have developed a drug delivery platform wherein
heteroduplex oligonucleotide drugs conjugated with cholesterol
are able to cross the blood-brain barrier and achieve therapeutic
concentrations in the central nervous system even with intravenous
or subcutaneous dosing. The ability to target gene expression
in the central nervous system through systemically administered
nucleic acid therapy holds great promise for the treatment of
neurogenerative disease.



FULL STORY ========================================================================== Researchers from Tokyo Medical and Dental University (TMDU), Takeda Pharmaceutical Co., Ltd. and Ionis Pharmaceuticals, USA, show that
heteroduplex oligonucleotide drugs conjugated with cholesterol cross the blood-brain barrier effectively with intravenous or subcutaneous dosing.


========================================================================== Antisense oligonucleotide (ASO) therapy has the potential to ameliorate
many neurodegenerative diseases at the genetic level to suppress the
production of harmful proteins or non-coding RNAs. Previously, achieving delivery of ASO with adequate concentrations in the central nervous
system (CNS) with systemic dosing was difficult. Now, researchers from
Japan and the USA have developed a drug delivery platform that overcomes
this hurdle.

Evolution has equipped the brain with protection against both mechanical
and molecular injury. The blood-brain barrier (BBB) is a selectively semipermeable barricade of endothelial cells lining the capillaries;
working with specific transporter proteins, it functions as a fastidious gatekeeper between the circulation and the CNS, barring foreign molecules, including drugs.

ASOs are pharmaceutical molecules that can target disease at the genetic
level.

They comprise a few dozen base pairs arranged in an 'antisense' or reverse order and prevent production of pathogenic proteins through binding to the 'sense' strand of mRNA targets. Single-stranded ASOs show great promise
against CNS disorders such as spinal muscular atrophy. However, they
do not enter the CNS effectively following systemic administration and
require direct intrathecal injection. This may be hazardous particularly
for patients with lumbar spinal deformity or on blood-thinners.

The research team had recently developed DNA/RNA heteroduplex
oligonucleotide (HDO) technology capable of highly efficient RNA
degradation in vivo. First author Tetsuya Nagata explains, "We found
that cholesterol conjugated HDO (Chol-HDO), unlike cholesterol-ASO,
efficiently reached the CNS following subcutaneous or intravenous administration in experimental animals. The Chol- HDO platform showed significant dose-dependent target gene reductions with prolonged
action in all CNS regions and cell types." Further, the researchers
confirmed that this beneficial outcome was not at the expense of
vascular barrier integrity. They also investigated the pharmacokinetics
of multiple injections as well as subcutaneous dosing (which may be self-administered). Additionally, the effects were confirmed across
species and against other neurogenerative disease gene targets such as
myotonic dystrophy type 1, Alexander disease and amyotrophic lateral
sclerosis.

"Systemic doses being higher, adverse effects such as mild decrease in platelets were expected," says Nagata. "However, divided or subcutaneous
dosing can rescue these. We may also strategize by initiating treatment
with intrathecal dosing to rapidly achieve therapeutic concentrations,
followed by intravenous or subcutaneous maintenance as needed." "Our innovative therapeutic platform for blood-to-brain delivery of ASOs may revolutionize management of neurodegenerative diseases," senior author
Takanori Yokota claims. "Future research will help define the specific molecular pathways thus optimizing delivery of ASO pharmacotherapy to
the CNS." The article, "Systemically administered DNA/RNA heteroduplex oligonucleotides achieve blood to brain delivery and efficient gene
knockdown in the CNS" was published in Nature Biotechnology.

========================================================================== Story Source: Materials provided by
Tokyo_Medical_and_Dental_University. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Tetsuya Nagata, Chrissa A. Dwyer, Kie Yoshida-Tanaka, Kensuke Ihara,
Masaki Ohyagi, Hidetoshi Kaburagi, Haruka Miyata, Satoe Ebihara,
Kotaro Yoshioka, Takashi Ishii, Kanjiro Miyata, Kenichi Miyata,
Berit Powers, Tomoko Igari, Syunsuke Yamamoto, Naoto Arimura,
Hideki Hirabayashi, Toshiki Uchihara, Rintaro Iwata Hara, Takeshi
Wada, C. Frank Bennett, Punit P. Seth, Frank Rigo, Takanori
Yokota. Cholesterol-functionalized DNA/RNA heteroduplexes cross the
blood-brain barrier and knock down genes in the rodent CNS. Nature
Biotechnology, 2021; DOI: 10.1038/s41587-021- 00972-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210812123119.htm

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