Safe and Effective Cynomolgus Monkey GLP—Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide “NVP-13”, targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

Sociosexual behavior requires both activating and repressive roles of Tfap2e/AP-2ε in vomeronasal sensory neurons

Neuronal identity dictates the position in an epithelium, and the ability to detect, process, and transmit specific signals to specified targets. Transcription factors (TFs) determine cellular identity via direct modulation of genetic transcription and recruiting chromatin modifiers. However, our understanding of the mechanisms that define neuronal identity and their magnitude remains a critical barrier to elucidate the etiology of congenital and neurodegenerative disorders. The rodent vomeronasal organ provides a unique system to examine in detail the molecular mechanisms underlying the differentiation and maturation of chemosensory neurons. Here we demonstrated that the identity of postmitotic/maturing VSNs and vomeronasal dependent behaviors can be reprogrammed through the rescue of AP-2ε expression in the AP-2ε Null mice and by inducing ectopic AP-2ε expression in mature apical VSNs. We suggest that the transcription factor AP-2ε can reprogram VSNs bypassing cellular plasticity restrictions, and that it directly controls the expression of batteries of vomeronasal genes.

Nanotech-based food: An initiative for alternative pharmaceuticals

Nanotechnology opens many avenues in the food sector and offers applications associated with food production, processing, cultivation, and packaging. Nanofood employs nano-techniques like nano-encapsulation and conjugation of various phytochemicals, antioxidants, probiotics, minerals, vitamins, etc. into nanovehicles. Food fortification strategies are then implemented to incorporate nano-processed substances. Nanofood is mostly used for improving health and as a supplementation method in various diseases ranging from liver diseases to neurodegenerative disorders. Here, we focus on recent studies that exhibit comparable results for nanofood and conventional medicines and subsiding the limitations of traditional therapies. Nanofood hold a potential in management of various health problems and the possibilities of using nanofood as alternative to medicine in clinical conditions like cancers and inflammatory bowel disease. With further advances in nanotechnology and expansion in the scope of current nanofood industry in addition to proper regulations set in place, nanofood may offer a wide variety of advantages in safety, long-term stability, etc.

Advance Care Planning in Neurodegenerative Disorders: A Scoping Review

Advance care planning (ACP) is increasingly acknowledged as a key step to enable patients to define their goals/preferences for future medical care, together with their carers and health professionals. We aimed to map the evidence on ACP in neurodegenerative disorders. We conducted a scoping review by searching PubMed (inception-December 28, 2020) in addition to trial, review, and dissertation registers. From 9367 records, we included 53 studies, mostly conducted in Europe (45%) and US-Canada (41%), within the last five years. Twenty-six percent of studies were qualitative, followed by observational (21%), reviews (19%), randomized controlled trials (RCTs, 19%), quasi-experimental (11%), and mixed-methods (4%). Two-thirds of studies addressed dementia, followed by amyotrophic lateral sclerosis (13%), and brain tumors (9%). The RCT interventions (all in dementia) consisted of educational programs, facilitated discussions, or videos for patients and/or carers. In conclusion, more research is needed to investigate barriers and facilitators of ACP uptake, as well as to develop/test interventions in almost all the neurodegenerative disorders. A common set of outcome measures targeting each discrete ACP behavior, and validated across the different diseases and cultures is also needed.

The risk of all-cause mortality, heart outcomes, cancer, and neurodegenerative disorders with cobalt-chrome-containing total hip arthroplasty implants

Aims A recent report from France suggested an association between the use of cobalt-chrome femoral heads in total hip arthroplasties (THAs) and an increased risk of dilated cardiomyopathy and heart failure. Cobalt-chrome is a commonly used material in orthopaedic implants. If the reported association is causal, the consequences would be significant given the millions of joint replacements and other orthopaedic procedures in which cobalt-chrome is used annually. We examined whether cobalt-chrome-containing THAs were associated with an increased risk of all-cause mortality, heart outcomes, cancer, and neurodegenerative disorders in a large national database. Methods Data from the National Joint Registry was linked to NHS English hospital inpatient episodes for 374,359 primary THAs with up to 14.5 years follow-up. We excluded any patients with bilateral THAs, knee replacements, indications other than osteoarthritis, aged under 55 years, and diagnosis of one or more outcome of interest before THA. Implants were grouped as either containing cobalt-chrome or not containing cobalt-chrome. The association between implant construct and the risk of all-cause mortality and incident heart failure, cancer, and neurodegenerative disorders was examined. Results There were 158,677 individuals (42.4%) with an implant containing cobalt-chrome. There were 47,963 deaths, 27,332 heart outcomes, 35,720 cancers, and 22,025 neurodegenerative disorders. There was no evidence of an association that patients with cobalt-chrome implants had higher rates of any of the outcomes. Conclusion Cobalt-chrome-containing THAs did not have an increased risk of all-cause mortality, or clinically meaningful heart outcomes, cancer or neurodegenerative disorders into the second decade post-implantation. Our findings will help reassure clinicians and the increasing number of patients receiving primary THA worldwide that the use of cobalt-chrome containing implants is not associated with significant adverse systemic effects.

Impact of the COVID-19 Pandemic on Chronic Neurological Disorders: Focus on Patients with Dementia

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) represents a public health problem worldwide. COVID-19 triggers a maladaptive cytokine release commonly referred to as cytokine storm syndrome with increased production of pro-inflammatory cytokines, which also appears to contribute to chronic neuro-inflammation and neurodegenerative disorders’ appearance, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, SARS-CoV-2 might enter the central nervous system through binding with the angiotensin converting enzyme 2 receptors which are highly expressed in glial cells and neurons. For this reason, an association between COVID-19, its dependent cytokine storm, and the development and/or progression of neurodegenerative disorders might be evaluated. Therefore, the aim of this review was to assess the impact of COVID-19 on neurodegenerative disorders focusing on the possible increased mortality risk and/or deterioration of clinical course of pre-existing chronic neurological diseases in patients with dementia.