Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy
Related Articles
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
AAV1.NT3 gene therapy mitigates the severity of autoimmune encephalomyelitis in the mouse model for multiple sclerosis
Multiple sclerosis (MS) is an immune-mediated chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than 2.5 million patients worldwide. Chronic demyelination in the CNS has an important role in perpetuating axonal loss and increases difficulty in promoting remyelination. Therefore, regenerative, and neuroprotective strategies are essential to overcome this impediment to rescue axonal integrity and function. Neurotrophin 3 (NT-3) has immunomodulatory and anti-inflammatory properties, in addition to its well-recognized function in nervous system development, myelination, neuroprotection, and regeneration. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of experimental autoimmune encephalomyelitis (EAE) mice, the chronic relapsing mouse model of MS, at 3 weeks post EAE induction. Measurable NT-3 levels were found in serum at 7-weeks post gene delivery. The treated cohort showed improved clinical scores and performed significantly better in rotarod, and grip strength tests compared to their untreated counterparts. Histopathologic studies showed improved remyelination and axon protection. These data correlated with reduced expression of the pro-inflammatory cytokines in brain and spinal cord, and increased percentage of regulatory T cells in the spleens and lymph nodes. Collectively, these findings demonstrate the translational potential of AAV-delivered NT-3 for chronic progressive MS.
International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma
T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.
Allogeneic mesenchymal stem cell therapy with laromestrocel in mild Alzheimer’s disease: a randomized controlled phase 2a trial
Alzheimer’s disease (AD) is characterized by progressive cognitive decline, severe brain atrophy and neuroinflammation. We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 2a clinical trial that tested the safety and efficacy of laromestrocel, a bone-marrow-derived, allogeneic mesenchymal stem-cell therapy, in slowing AD clinical progression, atrophy and neuroinflammation. Participants across ten centers in the United States were randomly assigned 1:1:1:1 to four infusion groups: group 1 (placebo; four monthly infusions, n = 12); group 2 (25 million cells, one infusion followed by three monthly infusions of placebo, n = 13); group 3 (25 million cells; four monthly doses, n = 13); and group 4 (100 million cells; four monthly doses, n = 11). The study met its primary end point of safety; the rate of treatment-emergent serious adverse events within 4 weeks of any infusion was similar in all four groups: group 1, 0% (95% CI 0–26.5%); group 2, 7.7% (95% CI 0.2–36%); group 3, 7.7% (95% CI 0.2–36%) and group 4, 9.1% (95% CI 0.2–41.3%). Additionally, there were no reported infusion-related reactions, hypersensitivities or amyloid-related imaging abnormalities. Laromestrocel improved clinical assessments at 39 weeks compared to placebo, as measured by a composite AD score (secondary end point was met: group 2 versus placebo change: 0.38; 95% CI −0.06–0.82), Montreal cognitive assessment and the Alzheimer’s Disease Cooperative Study Activities of Daily Living. At 39 weeks, Laromestrocel slowed the decline of whole brain volume compared to placebo (n = 10) by 48.4% for all treatment groups combined (groups 2–4: P = 0.005; n = 32) and left hippocampal volume by 61.9% (groups 2–4, P = 0.021; n = 32), and reduced neuroinflammation as measured by diffusion tensor imaging. The change in bilateral hippocampal atrophy correlated with the change in mini-mental state exam scores (R = 0.41, P = 0.0075) in all study patients (N = 42). Collectively these results support safety of single and multiple doses of laromestrocel treatment for mild AD and provide indications of efficacy in combating decline of brain volume and potentially cognitive function. Larger-scale clinical trials of laromestrocel in AD are warranted. ClinicalTrials.gov registration: NCT05233774.
Modulating neuroplasticity for chronic pain relief: noninvasive neuromodulation as a promising approach
Chronic neuropathic pain is a debilitating neuroplastic disorder that notably impacts the quality of life of millions of people worldwide. This complex condition, encompassing various manifestations, such as sciatica, diabetic neuropathy and postherpetic neuralgia, arises from nerve damage or malfunctions in pain processing pathways and involves various biological, physiological and psychological processes. Maladaptive neuroplasticity, known as central sensitization, plays a critical role in the persistence of chronic neuropathic pain. Current treatments for neuropathic pain include pharmacological interventions (for example, antidepressants and anticonvulsants), invasive procedures (for example, deep brain stimulation) and physical therapies. However, these approaches often have limitations and potential side effects. In light of these challenges, interest in noninvasive neuromodulation techniques as alternatives or complementary treatments for neuropathic pain is increasing. These methods aim to induce analgesia while reversing maladaptive plastic changes, offering potential advantages over conventional pharmacological practices and invasive methods. Recent technological advancements have spurred the exploration of noninvasive neuromodulation therapies, such as repetitive transcranial magnetic stimulation, transcranial direct current stimulation and transcranial ultrasound stimulation, as well as innovative transformations of invasive techniques into noninvasive methods at both the preclinical and clinical levels. Here this review aims to critically examine the mechanisms of maladaptive neuroplasticity in chronic neuropathic pain and evaluate the efficacy of noninvasive neuromodulation techniques in pain relief. By focusing on optimizing these techniques, we can better assess their short-term and long-term effects, refine treatment variables and ultimately improve the quality of neuropathic pain management.
Responses