Calcium channel 3.2 inhibitory peptides and uses thereof
Inventors
Assignees
Publication Number
US-12365898-B2
Publication Date
2025-07-22
Expiration Date
2042-06-29
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Abstract
Aspects of the disclosure relate to constructs comprising one or more Cav3.2 inhibitory polypeptide that blocks Cav3.2 T-type calcium channel activity and nociceptive dorsal root ganglion (DRG) neuron excitation. Also provided herein are methods for treating pain in a subject in need thereof. In particular, provided herein are methods comprising administering Cav3.2 inhibitory peptide constructs to a dorsal root ganglion of the subject, whereby expression of the Cav3.2 inhibitory polypeptides partially or fully inhibits Cav3.2 T-type calcium channel activity in the DRG.
Core Innovation
The invention provides inhibitory polypeptides, specifically peptide aptamers, that bind with high affinity and selectively inhibit human Cav3.2 T-type calcium channel activity. These inhibitory polypeptides are derived from intrinsically disordered regions (IDRs) of the native Cav3.2 protein, particularly from intracellular loops and termini. The peptides can be linked to scaffolds or tags to form fusion proteins for enhanced function and delivery.
The problem addressed by the invention is the unmet need for safe, selective, and effective treatments for chronic pain, particularly neuropathic pain, by targeting Cav3.2 calcium channels. Existing therapies, including systemic small molecule blockers like ethosuximide and ABT-639, lack specificity and cause significant side effects. Current pain treatments, especially opioid-based ones, carry risks of misuse, overdose, and addiction. Difficulties in developing peripheral selective Cav3.2 inhibitors have limited clinical success.
The invention overcomes these issues by combining in silico identification of functional inhibitory peptides from disordered protein regions and targeted delivery methods using adeno-associated virus (AAV) vectors for sustained expression in the dorsal root ganglia (DRG). This strategy allows selective inhibition of Cav3.2 channels in peripheral sensory neurons, reducing neuronal excitability and nociceptive signaling, thereby attenuating pain with minimal off-target effects. The constructs enable local administration directly to the DRG, improving therapeutic specificity and safety.
Claims Coverage
The claims disclose multiple inventive features related to fusion proteins comprising Cav3.2 inhibitory polypeptides, nucleic acid constructs encoding such proteins, viral vectors for delivery, pharmaceutical compositions, and methods for treating pain by inhibiting Cav3.2 activity.
Fusion protein comprising inhibitory polypeptides linked to a scaffold or tag
A fusion protein that includes at least one inhibitory polypeptide selected from SEQ ID NOs: 1, 2, 4, and 5 linked by a linker sequence to a polypeptide scaffold or tag, wherein the fusion protein does not include a Cav3.2 transmembrane domain and specifically binds and inhibits human Cav3.2 protein function.
Fusion protein comprising two or more inhibitory polypeptides
A fusion protein comprising two or more inhibitory polypeptides from SEQ ID NOs: 1-5 linked by additional linker sequences, with at least one polypeptide selected from SEQ ID NOs: 1, 2, 4, and 5.
Pharmaceutical compositions with fusion proteins
Pharmaceutical compositions comprising the described fusion proteins and pharmaceutically acceptable carriers.
Nucleic acid constructs encoding fusion proteins with heterologous promoters
Nucleic acid constructs that encode the fusion proteins and include a heterologous promoter sequence to drive expression.
Vectors comprising nucleic acid constructs
Vectors, including viral vectors, that comprise nucleic acid constructs encoding the fusion proteins.
Adeno-associated virus (AAV) vectors for fusion protein delivery
AAV vectors comprising heterologous nucleic acid sequences encoding the fusion proteins operably linked to regulatory sequences for expression in host cells, including various AAV serotypes (types 1-11).
Methods of treating pain by administering fusion proteins or vectors
Methods of treating pain in subjects by administering therapeutically effective amounts of the fusion proteins or AAV particles encoding them, optionally by targeted delivery or injection into dorsal root ganglia to inhibit Cav3.2 T-type calcium channel activity and reduce nociceptive neuron excitation.
The claims cover fusion proteins composed of Cav3.2 inhibitory peptides linked to scaffolds or tags, nucleic acid constructs and vectors for expression of these proteins, pharmaceutical compositions including such proteins or vectors, and therapeutic methods of treating pain via inhibition of Cav3.2 channel activity localized to dorsal root ganglia.
Stated Advantages
High transduction efficiency including expression in neuronal somata and axonal terminals.
Selective targeting of peripheral sensory neurons with minimal impact on motor neurons.
Restricted transgene expression to targeted segmental level and side of injection reducing systemic exposure.
Injection method avoids damage to dorsal root ganglia compared to peripheral nerves or CNS injections.
Very low doses of viral vector are required, enabling feasible clinical translation at low cost and minimizing neutralizing antibody formation.
The inhibitory polypeptides selectively inhibit Cav3.2 T-type calcium channel activity without affecting other ion channels such as Nav1.7 or voltage-gated potassium channels.
Documented Applications
Treatment of chronic pain, including neuropathic pain, by targeted inhibition of Cav3.2 T-type calcium channels in dorsal root ganglion neurons.
Gene therapy delivery using AAV vectors for sustained expression of Cav3.2 inhibitory peptide aptamers in the peripheral nervous system.
Use in pain models such as the tibial nerve injury (TNI) neuropathic pain rat model demonstrating analgesic efficacy.
Potential screening platform for small molecule inhibitors of Cav3.2 channels based on peptide aptamers.
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