RNA Therapy for Peripheral Neuropathy: Scientific Advances and Clinical Perspectives

Abstract

Peripheral neuropathy is a prevalent and debilitating condition with diverse etiologies, leading to significant morbidity worldwide. Despite numerous therapeutic strategies, management remains challenging, especially in refractory cases. Emerging RNA-based therapies offer a novel and promising approach by targeting disease mechanisms at the molecular level. This review synthesizes the latest evidence on RNA therapy for peripheral neuropathy, evaluates its clinical relevance, and discusses current challenges and future directions for implementation in practice, emphasizing mechanistic insights, efficacy, safety, and guideline considerations.

Introduction

Peripheral neuropathy encompasses a spectrum of disorders affecting the peripheral nervous system, manifesting as sensory, motor, and autonomic dysfunction. Etiologies are diverse, ranging from diabetes mellitus to hereditary, toxic, and immune-mediated causes. Conventional treatments primarily focus on symptom relief and slowing disease progression, yet many patients experience suboptimal outcomes. The advent of RNA-based therapeutics, including small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and messenger RNA (mRNA), has revolutionized molecular medicine by enabling specific gene modulation. This article explores the role of RNA therapy in peripheral neuropathy, integrating recent research, mechanistic frameworks, and clinical guidance.

Epidemiology / Disease Burden

Peripheral neuropathy affects approximately 2-7% of the global population, with higher prevalence in elderly individuals and those with metabolic comorbidities. Diabetes is the leading cause, accounting for up to 50% of cases in developed countries. Other etiologies include hereditary neuropathies, such as Charcot-Marie-Tooth disease (CMT), autoimmune conditions (e.g., chronic inflammatory demyelinating polyneuropathy), infections, toxins, and chemotherapy-induced neuropathy. The disease imposes considerable burdens in terms of pain, disability, healthcare resource utilization, and reduced quality of life.

Pathophysiology

Peripheral neuropathy arises from complex pathogenic mechanisms that include axonal degeneration, demyelination, impaired axonal transport, mitochondrial dysfunction, and neuroinflammation. In diabetic neuropathy, hyperglycemia triggers oxidative stress, advanced glycation end-product formation, and microvascular compromise, leading to nerve injury. In hereditary neuropathies, specific genetic mutations disrupt myelin or axonal proteins. RNA-based therapies aim to intervene directly at the molecular level by silencing pathogenic genes, restoring protein function, or modulating aberrant signaling pathways, thus offering unprecedented precision in disease modification.

Risk Factors

Risk factors for peripheral neuropathy are multifaceted and include chronic hyperglycemia, advanced age, genetic predisposition, alcohol abuse, exposure to neurotoxic agents (such as chemotherapeutic drugs), vitamin deficiencies (notably B12), and underlying autoimmune or infectious diseases. Identification of modifiable risk factors remains crucial for prevention and early intervention, particularly in high-risk populations.

Clinical Features

Peripheral neuropathy typically presents with distal symmetric sensory loss, paresthesia, dysesthesia, and, in some cases, neuropathic pain. Motor involvement can lead to weakness, muscle atrophy, and gait disturbances, while autonomic dysfunction may manifest as orthostatic hypotension, gastrointestinal dysmotility, or urinary incontinence. The clinical spectrum varies according to the underlying etiology, pattern of nerve involvement, and disease duration.

Diagnosis

Diagnosis is based on a combination of clinical assessment, electrophysiological studies (nerve conduction velocity, electromyography), laboratory investigations to identify systemic causes, and, in select cases, nerve biopsy or genetic testing. Recent advances in molecular diagnostics, including next-generation sequencing and transcriptomic profiling, facilitate precise etiological classification and may inform suitability for RNA-based interventions. Early and accurate diagnosis is essential for optimizing therapeutic outcomes and preventing irreversible nerve damage.

Treatment & Management

Conventional management strategies for peripheral neuropathy include glycemic control in diabetic patients, removal of offending agents, symptomatic therapies (analgesics, anticonvulsants, antidepressants), physical rehabilitation, and disease-modifying immunotherapies for autoimmune etiologies. However, these approaches often yield incomplete relief, underscoring the need for targeted disease-modifying therapies. Multidisciplinary care involving neurologists, endocrinologists, pain specialists, and rehabilitation teams is recommended for comprehensive management.

Recent Advances / Emerging Therapies

RNA therapy represents a transformative frontier in the treatment of peripheral neuropathy. Several investigational and approved RNA-based agents target pathogenic transcripts implicated in hereditary and acquired neuropathies. For instance, patisiran (an siRNA) and inotersen (an ASO) have demonstrated efficacy in hereditary transthyretin-mediated amyloidosis with polyneuropathy, improving neurological function and quality of life. Other RNA therapeutics are being developed for CMT and chemotherapy-induced neuropathy, with ongoing clinical trials assessing safety, pharmacokinetics, and efficacy. Advantages of RNA therapies include high specificity, potential for personalized medicine, and the ability to address previously undruggable targets. Challenges remain regarding delivery to peripheral nerves, immunogenicity, long-term safety, and cost-effectiveness.

Guideline Recommendations

Current guidelines from neurology and rare disease societies acknowledge the role of RNA therapeutics in hereditary amyloid neuropathy and recommend their consideration in eligible patients. EMA and FDA approvals of patisiran and inotersen have established a precedent for RNA-based interventions in clinical practice. Guidelines emphasize patient selection based on genetic, clinical, and functional criteria, ongoing monitoring for adverse events (such as thrombocytopenia or hepatic dysfunction), and integration with multidisciplinary care. As more agents receive regulatory approval and evidence accumulates, guideline recommendations are expected to evolve, broadening indications and optimizing treatment algorithms.

Conclusion

RNA therapy offers a paradigm shift in the management of peripheral neuropathy by enabling precise molecular targeting of disease mechanisms. While current applications are primarily limited to hereditary amyloid neuropathy, ongoing research heralds broader indications in other neuropathic conditions. Clinicians should remain abreast of emerging evidence, evolving guidelines, and practical considerations when integrating RNA therapeutics into practice. Continued collaboration between researchers, clinicians, and regulatory bodies is essential to ensure safe, effective, and equitable access to these innovative therapies, ultimately improving outcomes for patients affected by peripheral neuropathy.