Neuron-Targeted Oligonucleotide Conjugates for BBB-Selective Delivery
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Solution Overview
Problem
Current nucleic acid-based therapeutic approaches for brain pathologies face challenges in delivering therapeutic agents specifically to target cell types within the central nervous system due to the blood-brain barrier, and existing antidepressants and Parkinson's disease treatments lack specificity in targeting neurotransmitter receptors or dopaminergic cells, leading to slow response times and side effects.
Innovation Solution
Development of nucleic acid constructs that include a nucleic acid specific for a target gene and a selective inhibitor of a neurotransmitter transporter, allowing for targeted delivery to cells expressing these transporters, such as serotonin or dopamine transporters, using conjugates with inhibitors like sertraline or dopamine reuptake inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemically administered nucleic acid-based therapies are used to treat brain pathologies, then the therapeutic agents can potentially reach the CNS, but they cannot be delivered to specific cell types within the brain due to the blood-brain barrier
Solution Approach 1:
The patent uses neurotransmitter transporter molecules as intermediary carriers to mediate the delivery of nucleic acid-based therapeutic agents across the blood-brain barrier. The conjugate design includes a targeting moiety that binds specifically to transporters such as the serotonin transporter (SERT) or dopamine transporter (DAT) on the surface of specific neuronal cells. This intermediary mechanism allows the therapeutic agent to be transported into the CNS and delivered to specific cell types that express these transporters, overcoming both the BBB obstruction and the lack of cell-type specificity.
2Reliability
If existing antidepressants and Parkinson's disease treatments are used, then they can treat the diseases, but they lack specificity in targeting neurotransmitter receptors or dopaminergic cells, leading to side effects
Solution Approach 1:
The patent applies local quality by designing a conjugate where the therapeutic nucleic acid component is specifically localized to cells expressing particular neurotransmitter transporters. The targeting moiety ensures that the therapeutic agent is delivered only to neurons that express SERT, DAT, or other specific transporters, rather than affecting all neuronal cells uniformly. This localized delivery approach maintains therapeutic efficacy while minimizing side effects by avoiding off-target effects on non-target cell types.
3Reliability
If existing antidepressants and Parkinson's disease treatments are used, then they can treat the diseases, but they lack specificity, leading to slow response times
Solution Approach 1:
The patent employs neurotransmitter transporter molecules as specific intermediary carriers to rapidly deliver therapeutic agents directly to target neuronal cells. By utilizing the endogenous transporter systems that are already present on the surface of dopaminergic and serotonergic neurons, the conjugate achieves rapid and specific entry into target cells. This intermediary mechanism accelerates the therapeutic response time compared to non-specific delivery approaches, as the transporters provide a direct pathway to the target cells without requiring diffuse distribution throughout the CNS.
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 constructs achieve selective delivery to specific cell types within the CNS, enhancing therapeutic efficacy by directly targeting neurotransmitter receptors or dopaminergic cells, accelerating response times and reducing side effects.
Implementation Method 1
a selectivity agent which binds specifically to one or more of a neurotransmitter transporter
Implementation Method 2
WO 2009 79790 describe conjugates comprising siRNA and a series of peptides collectively known as Angiopeps which are capable of crossing the blood-brain barrier by receptor-mediated transcytosis
Data Source
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AI summary
The invention provides a conjugate comprising (i) a nucleic acid which is complementary to a target nucleic acid sequence and which expression prevents or reduces expression of the target nucleic acid and (ii) a selectivity agent which is capable of binding with high affinity to a neurotransmitter transporter. The conjugates of the present invention are useful for the delivery of the nucleic acid to a cell of interests and thus, for the treatment of diseases which require a down-regulation of the protein encoded by the target nucleic acid as well as for the delivery of imaging agents to the cells for diagnostic purposes.