Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood

Vojnits, Kinga; Mahammad, Saleemulla; Collins, Tony; Bhatia, Mickie

doi:10.1002/sctm.19-0054

“…17,18 Peri.4U neurons are more peripheral-like, expressing βIII-tubulin, peripherin, MAP2, and vGLUT2, but have been minimally characterized with respect to functional properties. 10,19 Additionally, neurons derived from human fibroblasts, blood, and embryonic stem cells that express more canonical nociceptive markers, like ISL1, BRN3A, P2RX3, the NTRK receptors, and NF200, [20][21][22][23] have also been used to study chemotherapy toxicity. Although these human derived cells resemble the DRG sensory neurons that are targeted by chemotherapeutics, there is significant interindividual variation across donor samples that limits their routine use for mechanistic studies and confounds the evaluation of functional consequences of genetic variation associated with human CIPN.…”

Section: How Might This Change Clinical Pharmacol-ogy or Translational Science?mentioning

confidence: 99%

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Xiong

¹

,

Chua

²

,

Stage

³

et al. 2020

Clinical Translational Sci

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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell-derived sensory neuron (iPSC-SN) model was developed for the study of chemotherapy-induced neurotoxicity. The iPSC-SNs express proteins characteristic of nociceptor, mechanoreceptor, and proprioceptor sensory neurons and show Ca 2+ influx in response to capsaicin, α,β-meATP, and glutamate. The iPSC-SNs are relatively resistant to the cytotoxic effects of paclitaxel, with half-maximal inhibitory concentration (IC 50) values of 38.1 µM (95% confidence interval (CI) 22.9-70.9 µM) for 48-hour exposure and 9.3 µM (95% CI 5.7-16.5 µM) for 72-hour treatment. Paclitaxel causes dose-dependent and time-dependent changes in neurite network complexity detected by βIII-tubulin staining and high content imaging. The IC 50 for paclitaxel reduction of neurite area was 1.4 µM (95% CI 0.3-16.9 µM) for 48-hour exposure and 0.6 µM (95% CI 0.09-9.9 µM) for 72-hour exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites, and changes in glutamate-induced neuronal excitability were also observed with paclitaxel exposure. The iPSC-SNs were also sensitive to docetaxel, vincristine, and bortezomib. Collectively, these data support the use of iPSC-SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy-induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity associated with a number of drugs used for the treatment of solid tumors and hematological cancers. 1-3 Drugs with diverse mechanisms of action, including microtubule disruptors, proteasome inhibitors, and DNA-crosslinking agents, all cause significant peripheral neuropathy. CIPN typically presents as burning, tingling, or numbness in the hands and feet that occurs in a glove and stocking distribution. 2,4 In addition to negatively affecting a patient's quality of life, dose reductions, treatment delays, and discontinuation can impact the therapeutic effectiveness of these drugs. 2 Despite years of research, there

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“…Peri.4U ® neurons are more peripheral-like, expressing IIItubulin, peripherin, MAP2 and vGLUT2, but have been minimally characterized with respect to functional properties 10,19 . Additionally, neurons derived from human fibroblasts, blood and embryonic stem cells that express more canonical nociceptive markers like ISL1, BRN3A, P2RX3, the NTRK receptors and NF200 [20][21][22][23] have also been used to study chemotherapy toxicity. While these human derived cells resemble the DRG sensory neurons that are targeted by chemotherapeutics, there is significant interindividual variation across donor samples that limits their routine use for mechanistic studies and confounds the evaluation of functional consequences of genetic variation associated with human CIPN 24 .…”

Section: Introductionmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Xiong

¹

,

Chua

²

,

Stage

³

et al. 2020

Preprint

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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell-derived sensory neuron (iPSC-SN) model was developed for the study of chemotherapy-induced neurotoxicity. The iPSC-SNs express proteins characteristic of nociceptor, mechanoreceptor and proprioceptor sensory neurons and show Ca 2+ influx in response to capsaicin, ,-meATP and glutamate. iPSC-SNs are relatively resistant to the cytotoxic effects of paclitaxel, with IC 50 values of 38.1 M (95% CI: 22.9 -70.9 M) for 48 hr exposure and 9.3 M (95% CI: 5.7 -16.5 M) for 72 hr treatment. Paclitaxel causes dose-and time-dependent changes in neurite network complexity detected by III-tubulin staining and high content imaging. The IC 50 for paclitaxel reduction of neurite area was 1.4 M (95% CI: 0.3 -16.9 M) for 48 hr exposure and 0.6 M (95% CI: 0.09 -9.9 M) for 72 hr exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites and changes in glutamate-induced neuronal excitability were also observed with paclitaxel exposure. The iPSC-SNs were also sensitive to docetaxel, vincristine and bortezomib.Collectively, these data support the use of iPSC-SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy-induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.

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“… 119 Others have used peripheral blood mononuclear cell-derived, or IPSC-derived sensory neurons, to investigate chemotherapy-induced neuropathy, and offer their high throughput methods as drug-discovery and phenotypic screening platforms. 118 , 150 …”

Section: Using Human Induced Pluripotent Stem Cell-derived Nociceptors To Understand Nociceptor Functionmentioning

confidence: 99%

Studying human nociceptors: from fundamentals to clinic

Middleton

¹

,

Barry

²

,

Comini

³

et al. 2021

Brain

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Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood–brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.

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Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood

Cited by 25 publications

References 77 publications

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel

Studying human nociceptors: from fundamentals to clinic

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