Background & Aims
Painful diabetic neuropathy (PDN), contrasting with painless peripheral DN, manifests as intractable type of pain arising as a direct consequence of abnormalities of the somatosensory system in diabetic patients and predominantly affects the feet and legs1, 2. It is characterized by sensations such as burning, tingling, numbness, and severe pain, particularly in the lower extremities. The pathophysiological mechanisms of PDN are not yet fully understood, despite pain being one of its primary symptom. There is evidence that the pathophysiologic mechanisms underlying PDN are similar to those of other neuropathic pain disorders. These mechanisms are broadly characterized as peripheral and central sensitization3, 4. KLS-2031 is a multifactorial gene therapy designed to modulate major pathological mechanisms of neuropathic pain, including neuroinflammation, neuronal death, and hyperexcitability of sensory fibers. This study investigated the potential of KLS-2031 as a novel therapy for PDN.
Methods
The streptozotocin (STZ)-induced diabetic neuropathic pain (NP) model was utilized to examine the efficacy of KLS-2031 for treatment of PDN, and KLS-2031 was administered via transforaminal epidural injection into the bilateral lumbar vertebra 4 (L4) intervertebral foramen for its targeted delivery to dorsal root ganglia (DRG). The analgesic effect of KLS-2031 was assessed using the von Frey filament test in bilateral hind paws. The study evaluated the effects of KLS-2031 on neuroinflammation, neuronal cell death, and peripheral nerve denervation by measuring the expression of ionized calcium binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), activated caspase3, and protein gene product 9.5 (PGP9.5) using fluorescent immunohistochemistry (IHC). Statistical significance was determined by Student’s t-test or M-U test or One-way ANOVA analysis.
Results
KLS-2031 exhibited a significant long-term analgesic effect in the STZ model with a single injection. It also significantly reduced mechanical allodynia even when administered to rats 4 or 6 weeks after STZ injection, models similar to severe diabetic neuropathy conditions. KLS-2031 restored pathological features of DPN such as neuroinflammation and neuronal cell death in the nervous system. Additionally, it reduced peripheral sensory nerve loss in the hind paw.
Conclusions
Based on these results, the AAV-mediated gene combination approach KLS-2031 has a strong analgesic effect and can restore the pathophysiology of neuropathic pain. The efficacy of KLS-2031 is attributed to its multi-target approach, which simultaneously modulates several pathologies in the DRG and spinal cord (SC). These results suggest that KLS-2031 is a novel, effective, and promising therapy for PDN.
References
1. International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: International Diabetes Federation; 2013.
2. Schreiber AK, Nones CF, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: Physiopathology and treatment. World J Diabetes. 2015 Apr 15;6(3):432-44.
3. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–962.
4. Tesfaye S, Boulton AJ, Dickenson AH. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care. 2013;36:2456–2465.
Presenting Author
Soon-Oh Hong
Poster Authors
Sujeong Kim
Ph.D
Kolon Life Science
Lead Author
Kyung-Ran Kim
Ph.D.
Kolon Life Science
Lead Author
Hyelin Ji
Kolon Life Science
Lead Author
Yusin Lee
Kolon Life Science
Lead Author
Yunjung Choi
Ph.D.
Kolon Life Science
Lead Author
Hyejin Lee
Kolon Life Science
Lead Author
Soon-Oh Hong
Kolon Life Science
Lead Author
Topics
- Models: Chronic Pain - Inflammatory