Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors

Abstract

BackgroundSmall fiber neuropathy (SFN) is a severe and disabling chronic pain syndrome with no causal and limited symptomatic treatment options. Mechanistically based individual treatment is not available. We report an in-vitro predicted individualized treatment success in one therapy-refractory Caucasian patient suffering from SFN for over ten years.MethodsIntrinsic excitability of human induced pluripotent stem cell (iPSC) derived nociceptors from this patient and respective controls were recorded on multi-electrode (MEA) arrays, in the presence and absence of lacosamide. The patient's pain ratings were assessed by a visual analogue scale (10: worst pain, 0: no pain) and treatment effect was objectified by microneurography recordings of the patient's single nerve C-fibers.FindingsWe identified patient-specific changes in iPSC-derived nociceptor excitability in MEA recordings, which were reverted by the FDA-approved compound lacosamide in vitro. Using this drug for individualized treatment of this patient, the patient's pain ratings decreased from 7.5 to 1.5. Consistent with the pain relief reported by the patient, microneurography recordings of the patient's single nerve fibers mirrored a reduced spontaneous nociceptor (C-fiber) activity in the patient during lacosamide treatment. Microneurography recordings yielded an objective measurement of altered peripheral nociceptor activity following treatment.InterpretationThus, we are here presenting one example of successful patient specific precision medicine using iPSC technology and individualized therapeutic treatment based on patient-derived sensory neurons.

A Systematic Review of the Diagnostic Methods of Small Fiber Neuropathies in Rehabilitation

“…Gaillet et al [38] used a quantitative sensory testing at the four extremities with measurement of the average warm detection threshold (WDT) [68]. Namer et al [51] used temperature thresholds and the genetic examination of the mutation of SFN. Hoitsma et al [69] used the temperature threshold testing (TTT) for sensory fibers and cardiovascular autonomic testing for autonomic fibers, that resulted abnormal in their case report.…”

The Genetics of Neuropathic Pain from Model Organisms to Clinical Application

“…Beyond studying genetic variants, the use of iPSC-nociceptors as screening platforms may be a substantial step forward for drug development in NeuP (Cao et al., 2016, Weir et al., 2017). Once ion channel targets are identified, drugs can be screened for their selectivity and ability to modulate neuronal excitability (Namer et al., 2019).…”

Capturing Novel Non-opioid Pain Targets

“…Combining these tools and approaches with mathematical modeling will enable the identification of those networks of targets that dynamically drive distinct pain conditions in different disease states. These targets or pathways may then be combined with gene targeting or editing and human neuron models for target validation, particularly those including neurons differentiated from patient-derived induced pluripotent stem cells (86). The exploitation of human neurons for comprehensive disease-based phenotypic screens will need to be a key feature.…”