Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy are three demyelinating acquired ...neuropathies, with distinct responses to immunotherapy. In placebo‐controlled, double‐blind, randomized trials, intravenous immunoglobulin (IVIg) has been effective for CIDP and MMN, and plasmapheresis has been effective for CIDP. Corticosteroids have been beneficial in controlled trials for CIDP. Other agents, including cyclophosphamide, rituximab, azathioprine, cyclosporine, interferons, fludarabine, mycophenolate mofetil, and etanercept, have been reported to benefit some patients with inflammatory demyelinating neuropathies in case series and case reports. This review examines the use and toxicity associated with these immunotherapy medications in treating patients with chronic immune‐mediated demyelinating neuropathies. Muscle Nerve, 2009
Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering ...RNA targeting transthyretin messenger RNA, to treat the disease.
Autoimmune neuropathy may present acutely or with a more progressive and/or relapsing and remitting course. Acute inflammatory neuropathy or Guillain-Barré syndrome (GBS) has variable presentations ...but by far the most common is acute inflammatory demyelinating polyradiculoneuropathy which is characterized by rapidly progressive proximal and distal symmetric weakness, sensory loss, and depressed reflexes. The most common chronic autoimmune neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy, which in its most typical form is clinically similar to acute inflammatory demyelinating polyradiculoneuropathy (proximal and distal symmetric weakness, sensory loss, and depressed reflexes) but differs in that onset is much more gradual, i.e., over at least 8 weeks. While the majority of GBS cases result from a postinfectious activation of the immune system, presumably in a genetically susceptible host, less is understood regarding the etiopathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy. Both acute and chronic forms of these inflammatory neuropathies are driven by some combination of innate and adaptive immune pathways, with differing contributions depending on the neuropathy subtype. Both disorders are largely clinical diagnoses, but diagnostic tools are available to confirm the diagnosis, prognosticate, detect variant forms, and rule out mimics. Given the autoimmune underpinnings of both disorders, immunosuppressive and immunomodulating treatments are typically given in both diseases; however, they differ in their response to treatment.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial ...has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol mg: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A.
In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set.
High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI - 0.68 to - 0.06; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated.
The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.
Transthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) ...fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
Intravenous immunoglobulin (IVIG) is a therapeutic biologic agent that has been prescribed for over two decades to treat various neuromuscular conditions. Most of the treatments are given off‐label, ...as little evidence from large randomized trials exists to support its use. Recently, IGIV‐C has received an indication for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). Because of the lack of evidence, an ad hoc committee of the AANEM was convened to draft a consensus statement on the rational use of IVIG for neuromuscular disorders. Recommendations were categorized as Class I–IV based on the strength of the medical literature. Class I evidence exists to support the prescription of IVIG to treat patients with Guillain–Barré syndrome (GBS), CIDP, multifocal motor neuropathy, refractory exacerbations of myasthenia gravis, Lambert–Eaton syndrome, dermatomyositis, and stiff person syndrome. Treatment of Fisher syndrome, polymyositis, and certain presumed autoimmune neuromuscular disorders is supported only by Class IV studies, whereas there is no convincing data to substantiate the treatment of inclusion body myopathy (IBM), idiopathic neuropathies, brachial plexopathy, or diabetic amyotrophy using IVIG. Treatment with IVIG must be administered in the context of its known adverse effects. There is little evidence to advise the clinician on the proper dosing of IVIG and duration of therapy. Muscle Nerve, 2009
Introduction: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients ...with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated.
Methods: Patients received either patisiran 0.3 mg/kg (n = 148) or placebo (n = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL.
Results: At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares LS mean difference: −21.1; p = 1.10 × 10
−10
; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2; p = 1.4 × 10
−12
), EuroQoL-visual analog scale (LS mean difference: 9.5; p=.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0; p = 4.07 × 10
−16
) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: −7.5; p=.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation.
Conclusion: The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.
The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation ...while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.
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