Pridopidine Composition Targeting S1R in Huntington's Disease
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Solution Overview
Problem
Current treatments for Huntington's disease focus primarily on alleviating symptoms like chorea but fail to address the progressive functional decline and cognitive impairment, with no therapy proven to modify the disease's inexorable progression.
Innovation Solution
An oral pharmaceutical composition comprising pridopidine or its pharmaceutically acceptable salts, combined with specific analog compounds, is administered to improve, maintain, or reduce impairment of functional capacity, motor function, and cognition by targeting the sigma-1 receptor (S1R) to provide neuroprotective effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If current medications are prescribed to ameliorate motor and emotional problems in HD, then symptom relief is achieved, but functional decline progression cannot be modified
Solution Approach 1:
The patent changes the therapeutic parameter from symptomatic management to disease-modifying treatment by using pridopidine, a sigma-1 receptor agonist, which has been shown to slow functional decline and improve motor symptoms in HD patients, thereby modifying the disease progression trajectory
Solution Approach 2:
The patent introduces pridopidine as an intermediary substance that acts on the sigma-1 receptor to produce neuroprotective effects, thereby mediating between the disease pathology and therapeutic outcome to achieve both symptom relief and progression modification
2Object-affected harmful factors
If tetrabenazine and deutetrabenazine are used to treat chorea, then chorea symptoms are alleviated, but no therapy proves able to modify progressive functional decline
Solution Approach 1:
The patent changes the therapeutic approach from transient symptom suppression to sustained functional capacity maintenance by using pridopidine, which has demonstrated ability to preserve functional capacity over time in HD patients, thereby extending the duration of beneficial effect
Solution Approach 2:
The patent applies preliminary neuroprotective action by using pridopidine to prevent further functional decline before it becomes irreversible, thereby maintaining functional capacity for longer periods compared to conventional symptomatic treatments
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 composition effectively reduces motor impairment symptoms and slows the functional decline in Huntington's disease patients, as evidenced by improved Unified Huntington's Disease Rating Scale (UHDRS) scores and maintained or enhanced functional capacity over 26 weeks of treatment.
Implementation Method 1
Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) is a highly selective S1R ligand with Ki=0.57 nM and S2R Ki of 5450 nM. Thus, pridopidine has 95-fold higher affinity for the S1R vs the S2R and is a highly selective S1R ligand.
Implementation Method 2
Pridopidine demonstrates neuroprotective properties mediated by the S1R in several in vivo and in vitro HD models, including a robust and dose-dependent neuroprotective effect against mutant huntingtin-(mHTT)-induced cell death in human HD induced pluripotent stem cells (iPSCs) and mouse HD cortical neurons
Implementation Method 3
Pridopidine also enhances secretion of the neuroprotective brain-derived neurotrophic factor (BDNF) in a neuroblastoma cell line, in a S1R-dependent manner. Furthermore, pridopidine restores spine density and aberrant calcium signaling
Data Source
Figure 1
AI summary
This invention is directed to a method of treating a human patient afflicted with Huntington disease and/or symptoms thereof, comprising administering to the patient a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and an analog thereof or a pharmaceutically acceptable salt thereof.