iPSCs and DRGs: stepping stones to new pain therapies

Alsaloum, Matthew; Waxman, Stephen G.

doi:10.1016/j.molmed.2021.11.005

Cited by 19 publications

(15 citation statements)

References 106 publications

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“…These include the culture of human nociceptors either from surgical or post-mortem tissue or using human-induced pluripotent stem cell-derived nociceptors. 145,147 Taken together, these approaches will permit a rational and highly personalized medicine approach that will dictate the most appropriate therapeutic approach for each individual patient. 7,148,149 Funding.…”

Section: The Way Forward? Bridging the Gap Between Basic Science And ...mentioning

confidence: 99%

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

Smith

2023

Can. J. Neurol. Sci.

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Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1β from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

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Section: The Way Forward? Bridging the Gap Between Basic Science And ...mentioning

confidence: 99%

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

Smith

2023

Can. J. Neurol. Sci.

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“…Also, the limited results of clinical trials with Na V channel blockers may reside in the differences between human and rodent DRG neurons. Hence, the development of iPSC-derived human sensory neurons, including those from SCN9A R 185 H patients may provide a new preclinical platform for the in vitro design of next pain therapies ( Alsaloum and Waxman, 2022 ). Altogether, the combination of rodent genetic models and other molecular, genetic, cellular, and pharmacological approaches will allow to identify additional components of chronic pain and to design new therapeutic strategies ( Calvo et al, 2019 ; Kingwell, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

Xue

Kremer

Moreno

et al. 2022

Front. Mol. Neurosci.

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The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9AR185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.

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“…They are generally classified based on age of onset, clinical features, type of inheritance, and genetic background [ 82 , 85 ]. To date, iPSC-derived nociceptor models offer particularly promising opportunities to explore personalized pharmacological treatments for those HSNs with a hypernormal pain phenotype such as gain-of-function mutations in the SCN9A gene, coding for the DRG, and sympathetic neuron-specific voltage-gated sodium channel Na v 1.7 [ 86 , 87 ].…”

Section: Modeling Hereditary Disorders Affecting Nociceptorsmentioning

confidence: 99%

“…Healthy nociceptors serve important roles as an important alarm system and in host defense by sensing physical and chemical stimuli including noxious heat, cold, pressure, and danger signals [ 99 ]. Nociceptive transduction, transformation, or transmission may be affected by monogenetic pathologies, and these can be sufficiently modeled in nociceptors derived from patient iPSC clones [ 70 , 86 , 100 , 101 ]. However, the pathogenesis of acquired pain disorders such as painful arthritis, complex regional pain syndrome (CRPS), or postherpetic neuralgia is more complex, and numerous studies have reported the contribution of immune and glia cells to nociceptor dysfunction in preclinical models of pathological pain.…”

Section: Modeling Complex Pathologiesmentioning

confidence: 99%

Towards bridging the translational gap by improved modeling of human nociception in health and disease

Zeidler

Kummer

Kress

2022

Pflugers Arch - Eur J Physiol

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Despite numerous studies which have explored the pathogenesis of pain disorders in preclinical models, there is a pronounced translational gap, which is at least partially caused by differences between the human and rodent nociceptive system. An elegant way to bridge this divide is the exploitation of human-induced pluripotent stem cell (iPSC) reprogramming into human iPSC-derived nociceptors (iDNs). Several protocols were developed and optimized to model nociceptive processes in health and disease. Here we provide an overview of the different approaches and summarize the knowledge obtained from such models on pain pathologies associated with monogenetic sensory disorders so far. In addition, novel perspectives offered by increasing the complexity of the model systems further to better reflect the natural environment of nociceptive neurons by involving other cell types in 3D model systems are described.

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iPSCs and DRGs: stepping stones to new pain therapies

Cited by 19 publications

References 106 publications

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

Towards bridging the translational gap by improved modeling of human nociception in health and disease

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