Antisense Oligonucleotide Therapy for the Nervous System: From Bench to Bedside with Emphasis on Pediatric Neurology.

Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action. Chemical modifications in the phosphodiester bond, nucleotide sugar, and nucleobase can increase structural thermodynamic stability and prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, conjugated antibodies, and nanocarriers, may improve ASO delivery. To date, six ASOs have been approved by the US Food and Drug Administration (FDA) in three neurological disorders: spinal muscular atrophy, Duchenne muscular dystrophy, and polyneuropathy caused by hereditary transthyretin amyloidosis. Ongoing preclinical and clinical studies are assessing the safety and efficacy of ASOs in multiple genetic and acquired neurological conditions. The current review provides an update on underlying mechanisms, design, chemical modifications, and delivery of ASOs. The administration of FDA-approved ASOs in neurological disorders is described, and current evidence on the safety and efficacy of ASOs in other neurological conditions, including pediatric neurological disorders, is reviewed.

Clinical and imaging outcomes after intrathecal injection of umbilical cord tissue mesenchymal stem cells in cerebral palsy: a randomized double-blind sham-controlled clinical trial.

BACKGROUND: This study assessed the safety and efficacy of intrathecal injection of umbilical cord tissue mesenchymal stem cells (UCT-MSC) in individuals with cerebral palsy (CP). The diffusion tensor imaging (DTI) was performed to evaluate the alterations in white-matter integrity. METHODS: Participants (4-14 years old) with spastic CP were assigned in 1:1 ratio to receive either UCT-MSC or sham procedure. Single-dose (2 × 107) cells were administered in the experimental group. Small needle pricks to the lower back were performed in the sham-control arm. All individuals were sedated to prevent awareness. The primary endpoints were the mean changes in gross motor function measure (GMFM)-66 from baseline to 12 months after procedures. The mean changes in the modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and CP quality of life (CP-QoL) were also assessed. Secondary endpoints were the mean changes in fractional anisotropy (FA) and mean diffusivity (MD) of corticospinal tract (CST) and posterior thalamic radiation (PTR). RESULTS: There were 36 participants in each group. The mean GMFM-66 scores after 12 months of intervention were significantly higher in the UCT-MSC group compared to baseline (10.65; 95%CI 5.39, 15.91) and control (ß 8.07; 95%CI 1.62, 14.52; Cohen's d 0.92). The increase was also seen in total PEDI scores (vs baseline 8.53; 95%CI 4.98, 12.08; vs control: ß 6.87; 95%CI 1.52, 12.21; Cohen's d 0.70). The mean change in MAS scores after 12 months of cell injection reduced compared to baseline (-1.0; 95%CI -1.31, -0.69) and control (ß -0.72; 95%CI -1.18, -0.26; Cohen's d 0.76). Regarding CP-QoL, mean changes in domains including friends and family, participation in activities, and communication were higher than the control group with a large effect size. The DTI analysis in the experimental group showed that mean FA increased (CST 0.032; 95%CI 0.02, 0.03. PTR 0.024; 95%CI 0.020, 0.028) and MD decreased (CST -0.035 × 10-3; 95%CI -0.04 × 10-3, -0.02 × 10-3. PTR -0.045 × 10-3; 95%CI -0.05 × 10-3, -0.03 × 10-3); compared to baseline. The mean changes were significantly higher than the control group. CONCLUSIONS: The UCT-MSC transplantation was safe and may improve the clinical and imaging outcomes. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov ( NCT03795974 ).

Neurological manifestations as the predictors of severity and mortality in hospitalized individuals with COVID-19: a multicenter prospective clinical study.

BACKGROUNDS: The reports of neurological symptoms are increasing in cases with coronavirus disease 2019 (COVID-19). This multi-center prospective study was conducted to determine the incidence of neurological manifestations in hospitalized cases with COVID-19 and assess these symptoms as the predictors of severity and death. METHODS: Hospitalized males and females with COVID-19 who aged over 18 years were included in the study. They were examined by two neurologists at the time of admission. All survived cases were followed for 8 weeks after discharge and 16 weeks if their symptoms had no improvements. RESULTS: We included 873 participants. Of eligible cases, 122 individuals (13.97%) died during hospitalization. The most common non-neurological manifestations were fever (81.1%), cough (76.1%), fatigue (36.1%), and shortness of breath (27.6%). Aging, male gender, co-morbidity, smoking, hemoptysis, chest tightness, and shortness of breath were associated with increased odds of severe cases and/or mortality. There were 561 (64.3%) cases with smell and taste dysfunctions (hyposmia: 58.6%; anosmia: 41.4%; dysguesia: 100%). They were more common among females (69.7%) and non-smokers (66.7%). Hyposmia/anosmia and dysgeusia were found to be associated with reduced odds of severe cases and mortality. Myalgia (24.8%), headaches (12.6%), and dizziness (11.9%) were other common neurological symptoms. Headaches had negative correlation with severity and death due to COVID-19 but myalgia and dizziness were not associated. The cerebrovascular events (n = 10) and status epilepticus (n = 1) were other neurological findings. The partial or full recovery of smell and taste dysfunctions was found in 95.2% after 8 weeks and 97.3% after 16 weeks. The parosmia (30.9%) and phantosmia (9.0%) were also reported during 8 weeks of follow-up. Five cases with mild headaches and 5 cases with myalgia were reported after 16 weeks of discharge. The demyelinating myelitis (n = 1) and Guillain-Barré syndrome (n = 1) were also found during follow-up. CONCLUSION: Neurological symptoms were found to be prevalent among individuals with COVID-19 disease and should not be under-estimated during the current pandemic outbreak.

An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.

Introduction: Leukodystrophies constitute heterogenous group of rare heritable disorders primarily affecting the white matter of central nervous system. These conditions are often under-appreciated among physicians. The first clinical manifestations of leukodystrophies are often nonspecific and can occur in different ages from neonatal to late adulthood periods. The diagnosis is, therefore, challenging in most cases.Area covered: Herein, the authors discuss different aspects of leukodystrophies. The authors used MEDLINE, EMBASE, and GOOGLE SCHOLAR to provide an extensive update about epidemiology, classifications, pathology, clinical findings, diagnostic tools, and treatments of leukodystrophies. Comprehensive evaluation of clinical findings, brain magnetic resonance imaging, and genetic studies play the key roles in the early diagnosis of individuals with leukodystrophies. No cure is available for most heritable white matter disorders but symptomatic treatments can significantly decrease the burden of events. New genetic methods and stem cell transplantation are also under investigation to further increase the quality and duration of life in affected population.Expert opinion: The improvements in molecular diagnostic tools allow us to identify the meticulous underlying etiology of leukodystrophies and result in higher diagnostic rates, new classifications of leukodystrophies based on genetic information, and replacement of symptomatic managements with more specific targeted therapies.Abbreviations: 4H: Hypomyelination, hypogonadotropic hypogonadism and hypodontia; AAV: Adeno-associated virus; AD: autosomal dominant; AGS: Aicardi-Goutieres syndrome; ALSP: Axonal spheroids and pigmented glia; APGBD: Adult polyglucosan body disease; AR: autosomal recessive; ASO: Antisense oligonucleotide therapy; AxD: Alexander disease; BAEP: Brainstem auditory evoked potentials; CAA: Cerebral amyloid angiopathy; CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy; CARASIL: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CGH: Comparative genomic hybridization; ClC2: Chloride Ion Channel 2; CMTX: Charcot-Marie-Tooth disease, X-linked; CMV: Cytomegalovirus; CNS: central nervous system; CRISP/Cas9: Clustered regularly interspaced short palindromic repeat/CRISPR-associated 9; gRNA: Guide RNA; CTX: Cerebrotendinous xanthomatosis; DNA: Deoxyribonucleic acid; DSB: Double strand breaks; DTI: Diffusion tensor imaging; FLAIR: Fluid attenuated inversion recovery; GAN: Giant axonal neuropathy; H-ABC: Hypomyelination with atrophy of basal ganglia and cerebellum; HBSL: Hypomyelination with brainstem and spinal cord involvement and leg spasticity; HCC: Hypomyelination with congenital cataracts; HEMS: Hypomyelination of early myelinated structures; HMG CoA: Hydroxy methylglutaryl CoA; HSCT: Hematopoietic stem cell transplant; iPSC: Induced pluripotent stem cells; KSS: Kearns-Sayre syndrome; L-2-HGA: L-2-hydroxy glutaric aciduria; LBSL: Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate; LCC: Leukoencephalopathy with calcifications and cysts; LTBL: Leukoencephalopathy with thalamus and brainstem involvement and high lactate; MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke; MERRF: Myoclonic epilepsy with ragged red fibers; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MLD: metachromatic leukodystrophy; MRI: magnetic resonance imaging; NCL: Neuronal ceroid lipofuscinosis; NGS: Next generation sequencing; ODDD: Oculodentodigital dysplasia; PCWH: Peripheral demyelinating neuropathy-central-dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschprung disease; PMD: Pelizaeus-Merzbacher disease; PMDL: Pelizaeus-Merzbacher-like disease; RNA: Ribonucleic acid; TW: T-weighted; VWM: Vanishing white matter; WES: whole exome sequencing; WGS: whole genome sequencing; X-ALD: X-linked adrenoleukodystrophy; XLD: X-linked dominant; XLR: X-linked recessive.

RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant.

BACKGROUND: Ribonucleases (RNases) are crucial for degradation of ribosomal RNA (rRNA). RNASET2 as a subtype of RNASEs is a 256 amino acid protein, encoded by RNASET2 gene located on chromosome six. Defective RNASET2 leads to RNASET2-deficient leukoencephalopathy, a rare autosomal recessive neurogenetic disorder with psychomotor delay as its main clinical symptom. The clinical findings can be similar to congenital cytomegalovirus (CMV) infection and Aicardi-Goutieres syndrome (AGS). METHODS: Herein, we presented a patient with motor delay, neurological regression, infrequent seizures and microcephaly at 5 months of age. Brain imaging showed white matter involvement, calcification and anterior temporal cysts. Basic metabolic tests, serum and urine CMV polymerase chain reaction (PCR) were requested. According to clinical and imaging findings, screening of RNASET2 and RMND1 genes were performed. The clinical data and magnetic resonance imaging (MRI) findings of previous reported individuals with RNASET2-deficient leukodystrophy were also reviewed and compared to the findings of our patient. RESULTS: Brain MRI findings were suggestive of RNASET2-deficient leukoencephalopathy, AGS and CMV infection. Basic metabolic tests were normal and CMV PCR was negative. Molecular study revealed a novel homozygous variant of c.233C > A; p.Ser78Ter in exon 4 of RNASET2 gene compatible with the diagnosis of RNASET2-deficient leukoencephalopathy. CONCLUSIONS: RNASET2-deficiency is a possible diagnosis in an infant presented with a static leukoencephalopathy and white matter involvement without megalencephaly. Due to overlapping clinical and radiologic features of RNASET2-deficient leukoencephalopathy, AGS and congenital CMV infections, molecular study as an important and helpful diagnostic tool should be considered to avoid misdiagnosis.