Adolore BioTherapeutics Announces Gene Therapy Reducing Pain by Activating Kv7 Channels

Adolore BioTherapeutics, a biotechnology company devoted to creating innovative gene therapy treatments for chronic pain without the use of opioids, has recently published a pivotal manuscript in the peer-reviewed journal, Frontiers in Molecular Neuroscience. The paper, titled "rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels," underscores the efficacy of their proprietary gene therapy in mitigating chronic pain by targeting specialized pain-sensing neurons, or nociceptors.

Dr. Roy Clifford Levitt, Clinical Professor at the University of Miami and Principal Investigator for the NIH, NINDS HEAL Award, which supports the development of Adolore's ADLR-1001 for osteoarthritis (OA) knee pain, highlighted the breakthrough findings. The study demonstrated that an increase in the expression of human carbonic anhydrase-8 variant peptides (CA8*) in nociceptors leads to a decrease in their excitability. This mechanism is linked to the prolongation of their afterhyperpolarization (AHP), attributed to the activation of Kv7 voltage-gated potassium channels. The specificity of this gene therapy was confirmed through the use of a null-mutant CA8* gene therapy vector and a selective Kv7 channel antagonist, XE-991.

Dr. Levitt emphasized the importance of Kv7 channels as analgesic targets, noting that their activation can result in significant non-opioid-based pain relief. The findings suggest that CA8 gene therapy achieves analgesia by reducing cytoplasmic free calcium, thereby prolonging AHP and diminishing neuronal excitability. This research supports the continued preclinical development of ADLR-1001 toward an Investigational New Drug (IND) application and subsequent clinical trials.

The key highlights of the study are as follows:
- CA8* gene therapy (rdHSV-CA8*) leads to a prolonged AHP in nociceptors, lowering their excitability and decreasing pain signaling.
- The activation of Kv7 voltage-gated potassium channels by rdHSV-CA8* is crucial to this effect.
- The inhibition of Kv7 channels with XE-991 reverses the prolonged AHP caused by rdHSV-CA8*.
- The selective upregulation of Kv7 M-currents was observed in neurons infected with rdHSV-CA8*, but not in control neurons.
- These results confirm that rdHSV-CA8* specifically activates Kv7 channels in nociceptors, reducing pain signal propagation.

Adolore is advancing two preclinical gene therapy programs using CA8* peptides: ADB-101 for erythromelalgia, a rare pain condition, and ADB-102 for chronic knee pain due to osteoarthritis. These programs are moving towards IND filings and first-in-human studies, leveraging compelling preclinical data. The development of ADLR-1001 for osteoarthritis knee pain is fully funded by a grant from the NIH/NINDS HEAL program, with a first-in-human study expected to commence in 2026.

CA8* gene therapies represent a new class of treatments that inhibit neuronal calcium channels and activate Kv7 potassium channels. These therapies can be administered locally and are designed to provide long-lasting relief without the systemic exposure that led to the withdrawal of oral small molecule Kv7 activators from the market. The targeted non-opioid mechanism of CA8* addresses various types of pain, including neuropathic, inflammatory, and nociceptive pain, covering a wide range of chronic pain conditions such as osteoarthritis, lower back pain, cancer pain, diabetic neuropathy, and post-herpetic neuralgia.

Adolore BioTherapeutics is leveraging its proprietary gene therapy platform to develop long-acting, locally administered pain treatments. Their innovative approach aims to replace opioids with safer alternatives, addressing the pressing need for effective chronic pain therapies.