Specific Delivery Platform Provides Promising Gene Therapy Against Neurodegenerative Diseases

Specific group of drugs – heteroduplex oligonucleotides are found to cross the blood-brain barrier effectively with intravenous or subcutaneous dosing when conjugated with cholesterol as per the researchers from Tokyo Medical and Dental University (TMDU), Takeda Pharmaceutical Co., Ltd. and Ionis Pharmaceuticals, USA.

Antisense oligonucleotide (ASO) therapy comprises of molecules that can target disease at the genetic level. The blood-brain barrier (BBB) is a physiological barrier of blood vessels that run through the brain, and is responsible for the selective passage of molecules in and out of the brain.

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‘Specific group of drugs – antisense oligonucleotides (ASOs) are found to efficiently cross the blood-brain barrier with intravenous or subcutaneous dosing when conjugated with cholesterol. This may revolutionize the management of several neurodegenerative diseases. ’

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Due to BBB, achieving the delivery of this ASO therapy with systemic dosing and adequate concentrations in the central nervous system (CNS) has been difficult.

Innovative ASO Therapy

To overcome the hurdle, the study team has now designed a suitable drug delivery platform of ASO therapy – the DNA/RNA heteroduplex oligonucleotide (HDO) technology that is capable of highly efficient RNA degradation in vivo.

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“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,” says Tetsuya Nagata, the First author of the study.

The drug efficacy was confirmed across species and against many neurodegenerative diseases such as myotonic dystrophy type 1, Alexander disease, and amyotrophic lateral sclerosis. The drugs ameliorate the diseases at the genetic level by suppressing the production of harmful proteins or non-coding RNAs.

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“Our innovative therapeutic platform for blood-to-brain delivery of ASOs may revolutionize the management of neurodegenerative diseases. Future research will help define the specific molecular pathways thus optimizing the delivery of ASO pharmacotherapy to the CNS,” says Takanori Yokota, the senior author of the study.

Source-Medindia

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