PRNP-Targeting siRNA Compositions for Blood-Brain Barrier Delivery
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Solution Overview
Problem
Prion diseases, caused by the misfolding of prion proteins, lack effective methods for reducing prion protein expression, particularly in the brain, to prevent disease onset or progression.
Innovation Solution
The use of small interfering RNA (siRNA) molecules to silence the PRNP gene, targeting specific regions of the prion protein mRNA transcript, thereby reducing prion protein expression in the brain through direct delivery to the central nervous system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If siRNA molecules are used to silence the PRNP gene, then prion protein expression is reduced, but delivery to the central nervous system becomes complex
Solution Approach 1:
The patent uses liposomal carriers as intermediaries to deliver siRNA molecules across the blood-brain barrier into the central nervous system. The liposomes protect the siRNA from degradation and facilitate its transport into target cells, resolving the delivery complexity issue while maintaining effective gene silencing.
Solution Approach 2:
The patent employs chemical modifications to the siRNA molecules, including 2'-O-methyl and phosphorothioate modifications, to enhance stability, cellular uptake, and brain penetration. These parameter changes in the molecular structure improve delivery efficiency without compromising the gene silencing function.
2Reliability
If siRNA molecules are administered to reduce prion protein levels, then disease progression is prevented, but selectivity toward PRNP over other CNS genes must be maintained
Solution Approach 1:
The patent designs siRNA molecules with highly specific sequences that target only the PRNP mRNA transcript. The antisense strand is engineered to have exact complementarity to a specific region of the PRNP transcript, ensuring that only the prion protein gene is silenced while other CNS genes remain unaffected, thus maintaining high gene selectivity.
3Reliability
If direct delivery to the CNS is implemented, then treatment effectiveness is improved, but administration complexity increases
Solution Approach 1:
The patent uses liposomal carriers as intermediaries to deliver siRNA molecules across the blood-brain barrier into the central nervous system. The liposomes protect the siRNA from degradation and facilitate its transport into target cells, resolving the delivery complexity issue while maintaining effective gene silencing.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The siRNA molecules effectively reduce prion protein levels, preventing disease onset or progression, and are well-tolerated, as evidenced by the presence of healthy adults with heterozygous loss of function prion mutations.
Implementation Method 1
The antisense strand has complementarity sufficient to hybridize to a region within a prion protein (PRNP) mRNA transcript
Implementation Method 2
small interfering RNA (siRNA)-mediated silencing of PRNP transcripts
Data Source
AI summary
The present disclosure provides single- or double-stranded interfering RNA molecules (e.g., siRNA) that target a PRNP gene. The interfering RNA molecules may contain specific patterns of nucleoside modifications and internucleoside linkage modifications, as pharmaceutical compositions including the same. The siRNA molecules may be branched siRNA molecules, such as di-branched, tri-branched, or tetra-branched siRNA molecules. The disclosed siRNA molecules may further feature a 5′ phosphorus stabilizing moiety and/or a hydrophobic moiety. Additionally, the disclosure provides methods for delivering the siRNA molecule of the disclosure to the central nervous system of a subject, such as a subject identified as having a prion disease or a high-penetrance PRNP mutation.