PURPOSE:Due to the highly individualized clinical manifestation of Parkinson's disease (PD), personalized patient care may require domain-specific assessment of neurological disability. Evidence from magnetic resonance imaging (MRI) studies has proposed that heterogenous clinical manifestation corresponds to heterogeneous cortical disease burden, suggesting customized, high-resolution assessment of cortical pathology as a candidate biomarker for domain-specific assessment. METHOD:Herein, we investigate the potential of the recently proposed Mosaic Approach (MAP), a normative framework for quantifying individual cortical disease burden with respect to a population-representative cohort, in predicting domain-specific clinical progression. Using MRI and clinical data from 135 recently diagnosed PD patients from the Parkinson's Progression Markers Initiative, we first defined an extremity-specific motor score. We then identified cortical regions corresponding to "extremity functions" and restricted MAP, respectively, and contrasted the explanatory power of the extremity-specific MAP to unrestricted MAP. As control conditions, domain-related but less specific general motor function and nondomain-specific cognitive scores were considered. We also tested the predictive power of the restricted MAP in predicting disease progression over 1 and 3 years using support vector machines. The restricted, extremity-specific MAP yielded higher explanatory power for extremity-specific motor function at baseline as opposed to the unrestricted, whole-brain MAP. On the contrary, for general motor function, the unrestricted, whole-brain MAP yielded higher power. FINDING:No associations were found for cognitive function. The extremity-specific MAP predicted extremity-specific motor progression over 1 and 3 years above chance level. The MAP framework allows for domain-specific prediction of customized PD disease progression, which can inform machine learning, thereby contributing to personalized PD patient care.

* Velvio therapeutics aim at CNS reconstitution to renew stem cell populations in bone marrow, muscle and CNS, to reactivate normal cell functions (anti-senescence), to reactivate autophagy and normalize immune communication, to enhance stem cell friendly milieu (extracellular matrix), and to reverse scarring and fibrosis. Velvio has developed selective biomarkers to monitor regained functionalities and to bridge the time gap between therapy and recovery - these include MRI imaging, inflammatory cyto- and chemo/kines, and stem cell markers in peripheral blood. ALS (Amyotrophic Lateral Sclerosis) is a grave disease with still limited treatment options and a median survival of approx. 16 to 24 months after diagnosis. Long-time pulsed G-CSF - BM stem cell mobilization is safe 1 and highly effective 2 in ALS: Clinical pilot data in N=36 ALS patients revealed significant slowing of disease progression and significantly increased survival. Disease modelling and a biomarker panel identified and validated 15 long-time survivors with median OS of 3.8 yrs from start of treatment and a very limited disease progression of -0,12 ALS-FRS-R loss / month with G-CSF therapy in contrast to -0,9 ALS-FRS-R loss / month with best standard care. Among many other modes of action for G-CSF, it was nicely shown 3 that bone marrow cells drive central nervous system regeneration, here after radiation injury. With this impressive therapeutic potential in mind, we want to initiate a prospective pivotal adaptive clinical trial of G-CSF to achieve regulatory approval for 'early' ALS patients. The architecture of such a trial and the related expenditure will be discussed in the light of the high unmet medical need and the opportunity of using a 'repurposed' therapeutic compound employed over decades in hemato-oncology and intensive care medicine. Velvio believes that healthcare investors and regulatory authorities should not miss the opportunity for such a shortcut to establish a very efficacious new treatment option for desperate ALS patients.

Supplementary Data 1 from CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cells Show Differential Growth Characteristics and Molecular Profiles

COPYRIGHT © 2023 Bruun, Dietrich, Klingseisen and Bogdahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Cellular CNS repair strategies, technologies and therapeutic developments

Supplementary Table 5 from Transcriptional Profiles of CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cell Lines Suggest Different Cells of Origin

Supplementary Figure 1 from Temozolomide Preferentially Depletes Cancer Stem Cells in Glioblastoma

The hematopoietic granulocyte-colony stimulating growth factor (G-CSF, filgrastim) is an approved drug in hematology and oncology. Filgrastim's potential in neurodegenerative disorders is gaining increasingly more attention, as preclinical and early clinical studies suggest it could be a promising treatment option. G-CSF has had a tremendous record as a safe drug for more than three decades; however, its effects upon the central nervous system (CNS) are still not fully understood. In contrast to conceptual long-term clinical application with lower dosing, our present pilot study intends to give a first insight into the molecular effects of a single subcutaneous (s.c.) high-dose G-CSF application upon different regions of the rodent brain. We analyzed mRNA-and in some instances-protein data of neurogenic and non-neurogenic differentiation markers in different regions of rat brains five days after G-CSF (1.3 mg/kg) or physiological saline. We found a continuous downregulation of several markers in most brain regions. Remarkably, cerebellum and hypothalamus showed an upregulation of different markers. In conclusion, our study reveals minor suppressive or stimulatory effects of a single exceptional high G-CSF dose upon neurogenic and non-neurogenic differentiation markers in relevant brain regions, excluding unregulated responses or unexpected patterns of marker expression.

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.

Increasingly antisense oligonucleotides (ASOs) are developed for potential treatment of CNS disorders, and due to the inability to cross the blood brain barrier, they require direct administration into the cerebrospinal fluid (CSF). In this regard, intrathecal (i.th.) administration in cynomolgus monkeys (Macaca fascicularis) is a well-established approach for preclinical safety studies. Here, we present an innovative preclinical approach that is intended to support rapid entry into clinical development with ASOs targeting the CNS. The preclinical approach comprises one non-GLP study in 26 non-human primates, followed by a pivotal GLP repeated dose toxicity study in the same species. No pivotal rodent studies were conducted, and regulatory guidance to initiate this study was met by in vitro work. The non-GLP study consists of three separate phases: Phase A determines toxicity after i.th. administrations with five escalating dose levels in a single male and female animal, respectively. Dosing is conducted on days 1, 8, 15, 22, and 29 and the experiment is terminated 36 days after start of the study. The second phase (Phase B) investigates pharmacokinetics over a 2- or 4-week period at two dose levels following single administrations in eight (8) animals (4 females, 4 males). Finally, a third phase (Phase C) investigates toxicity and pharmacokinetics after repeated (9×) dosing over a 13-week period at two dose levels in sixteen (8 females, 8 males) animals. In each phase, clinical observations and physical/neurological parameters are investigated directly pre-dose, 4 h and 24 h post-dose, respectively. In all phases, CSF and blood samples are taken pre-dose and after each dosing, for determination of test article concentration, biomarkers of tolerability and biomarkers of pharmacology. In all phases, tissue samples from the liver, kidney, spinal cord, and brain are collected for determination of NVP-13 tissue concentrations. The above concept has successfully supported first-in-human clinical trials. The entire non-GLP program is completed within less than six months and requires fewer animals in comparison to the conduct of three independent studies.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

Granulocyte colony-stimulating factor (G-CSF) is a cytokine used in pharmaceutical preparations for the treatment of chemotherapy-induced neutropenia. Evidence from experimental studies indicates that G-CSF exerts relevant activities in the central nervous system (CNS) in particular after lesions. In acute, subacute, and chronic CNS lesions, G-CSF appears to have strong anti-inflammatory, antiapoptotic, antioxidative, myelin-protective, and axon-regenerative activities. Additional effects result in the stimulation of angiogenesis and neurogenesis as well as in bone marrow stem cell mobilization to the CNS. There are emerging preclinical and clinical data indicating that G-CSF is a safe and effective drug for the treatment of acute and chronic traumatic spinal cord injury (tSCI), which we summarize in this review.

Advances in amyotrophic lateral sclerosis (ALS) research: Research in ALS has gained unprecedented momentum in recent years fueled by important conceptual developments, establ ishment of internat ional consort ia , breakthrough genetic discoveries and relentless technological advances. The first genotypespecific pharmaceutical trials signal the paradigm shift from the notion of ‘one-drug-for-all’ to precision, individualized therapies. The once arcane presymptomatic phase of the disease is gradually unraveled by seminal studies of asymptomatic mutation carriers (Geevasinga et al., 2015; Querin et al., 2019). The meticulous analysis of data from large population-based registries has contributed to the identification of etiological factors, genetic risk profiles, epigenetic and environmental modifiers. Progression patterns have been characterized in vivo by robust clinical, neurophysiology and neuroimaging studies and led to the development of clinical staging systems and biomarkers with practical utility in clinical trials (Chipika et al., 2019). While ALS was once considered a ‘pure’ motor system disorder, it is now widely regarded as multisystem condition with frontotemporal, cerebellar, and subcortical grey matter involvement and a range of extrapyramidal, cognitive, and behavioral manifestations (Elamin et al., 2017). Disease-specific functional rating scales are now routinely used and screening instruments have been developed to assess the most commonly affected cognitive and behavioral domains in ALS. Advances in genetics paved the way for the first large presymptomatic studies which confirmed considerable cerebral and spinal cord alterations decades before symptom manifestation (Vucic et al., 2008; Querin et al., 2019). The characterization of genotype-associated molecular cascades, pathological signatures and clinical features were important milestones for the development of novel therapies, and the first antisense oligonucleotide trials are now underway. The datasets generated by multicenter initiatives offer unprecedented data mining opportunities; clustering patterns, prognostic determinants, and reliable diagnostic indicators were identified using machine-learning approaches that could not have previously been applied to smaller datasets. Technological advances in electrophysiology and the emergence of magnetoencephalography generated important functional insights (Bede et al., 2018). Novel imaging modalities, such as multivoxel spectroscopy, spinal cord imaging, diffusion kurtosis imaging captured pathological changes that were previously impossible to ascertain in vivo (Bede et al., 2017; Huang et al., 2020). Advanced neurophysiology techniques, such as transcranial magnetic stimulation or motor unit number estimation are now widely used in both clinical and academic settings and contribute to diagnostic clarification and the monitoring of individual patients. In response to the inevitable sample size limitations of single-center studies (Schuster et al., 2016), ambitious international initiatives such as Project MinE established large biobanks to conduct genetic studies with sufficient statistical power. Societies such as NISALS provide pioneering frameworks to conduct large multicenter neuroimaging studies. Barriers to drug development: Despite the coordinated work of large research centers, research consortia, patient charities, advocacy groups and pharmaco log ica l companies , relatively limited progress has been made in the development of effective disease-modifying therapies. The barriers to successful drug development in ALS include the marked clinical heterogeneity of the condition, the relatively late inclusion of patients into clinical trials, and an inadvertent selection bias to patients with limited cognitive impairment, who may live closer to research centers and who may have been diagnosed relatively early. Clinical heterogeneity in ALS is multidimensional and encompasses considerable di fferences in age of onset, progression rates, extra-motor manifestations, bulbar versus limb disability, lowerversus upper motor neuron predominance. The considerable differences in cl inical profi les necessitate individualized management and a series of welltimed multidisciplinary interventions such as feeding-tube placement, initiation of non-invasive ventilation and ultimately palliative measures tailored to the patient’s specific medical needs and care preferences. While the benefits of individualized clinical care in contrast to a blanket strategy are widely accepted, the ill-conceived expectation that a single drug may be useful for all patients with ALS prevails. It is increasingly clear that unique genotype-associated clinical profiles exist and patients with specific mutations may have relatively distinct disease trajectories. It is also apparent that considerable phenotypic differences exist in survival, progression rates and disability profiles. It is therefore likely that patients may benefit from individualized pharmacological intervent ions ta i lored to their genotype, phenotype and disease-stage as opposed to the notion of ‘one-drug-for-all’. Despite the enthusiasm generated by the first antisense oligonucleotide studies, it is noteworthy that the vast majority of patients with ALS are seemingly sporadic and test negative for large panels of mutations linked to ALS such as SOD1, ALS2, SETX, SPG11, FUS, VAPB, ANG, TARDBP, FIG4, OPTN, ATXN2, VCP, C9orf72, UBQLN2, SQSTM1, NEK1, FUS, TBK1 etc. Accordingly, the majority of patients with ALS are not candidates for genotypespecific interventions, cannot be included in presymptomatic studies and the risk of their relatives developing neurodegenerative change is unclear. Another barrier to successful clinical trial is the relatively late inclusion of patients into clinical trials due to stringent inclusion criteria. Large epidemiology studies in ALS have repeatedly demonstrated that the interval between symptom onset and diagnosis is in the range of 12–14 months which is a considerable delay with a multitude of adverse ramifications. Quantitative radiology studies have shown that by the time the diagnosis is confirmed, patients already exhibit considerable motor cortex, corticospinal tract and corpus callosum degeneration which are unlikely to be ameliorated by pharmacological intervention. The observation that significant pathological changes have already taken place by the time a patient fulfills diagnostic criteria suggests that the optimal therapeutic window is Perspective

Constant physiological remodeling and repair are increasingly dysfunctional in several essential brain systems during neurodegenerative disorders. Once chronic neuroinflammatory mechanisms are activated, a machinery of major cytokines - among them an upregulated TGF-β system - are pushing this process forward. By hitting the TGF-β system as such crucial single target, our aim was to reach many critical downstream mechanisms of neurodegeneration at one time for a long-term treatment approach.

Background: There is an urgent demand for therapeutic options in patients with amyotrophic lateral sclerosis (ALS). Filgrastim (Granulocyte-Colony Stimulating Factor, G-CSF) is a hematopoietic growth factor with excellent safety and tolerability, routinely applied in oncology, intensive care, and stem cell mobilization for bone marrow transplantation. Preliminary pre-clinical and clinical evidence indicated potential efficacy in ALS. Methods: We offered ALS patients filgrastim as a new treatment approach (mostly five days per month, median duration 17 cycles, up to 76 cycles) and analyzed disease course, survival, and potential biomarkers in a total of 36 patients (mean age 52 years, CI 48-56, 29·7% female). The PRO-ACT database, which collects outcome data from 23 clinical trials performed with ALS patients worldwide, served as historical control and reference for modelling in this observational study. Findings: Long-term filgrastim treatment was safe and well tolerated. All filgrastim treated patients progressed significantly slower and survived longer compared to patients from PRO-ACT, supported by different statistical approaches. Particularly, Cox proportional hazard (filgrastim versus PRO-ACT: Risk Ratio 0·52, p=0·0052) and matched pair analyses (filgrastim versus PRO-ACT, 596 versus 373 days of survival, p<0·001) revealed a significant survival benefit for filgrastim treated patients. Strong treatment response to filgrastim with a median survival of 3·8 years (n=15/36, p<0·001) was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profile, and reduced fractional anisotropy (1·5 Tesla cerebral MRI DTI). A non-linear principal component analysis (NLPCA)-based biomarker analysis discovered individual patient responses as early as within three months of starting filgrastim treatment. Interpretation: Filgrastim constitutes a safe and powerful treatment option in ALS patients. Strong responding patients were identified by cytokines, stem cell function, and brain MRI. Treatment benefit was associated with younger age, however, also apparent in some of the older patients.Funding Statement: German Ministry of Research (GO-Bio; funding for biomarker development in ALS), donation by RB Leipzig.Declaration of Interests: UB an LA hold patents for clinical application of G-CSF in ALS, Orphan Drug Status is granted for EU and US by EMA and FDA–all within NeuroVision Pharma GmbH, Murnau, Germany. All other authors declare that they do not have any conflicts of interest. Ethics Approval Statement: The ethics committee of the University of Regensburg approved a retrospective analysis (ethics approval: 15- 101-0106 and 14-101-0011).

Vascular dementia (VaD) is the second leading form of memory loss after Alzheimer's disease (AD). Currently, there is no cure available. The etiology, pathophysiology and clinical manifestations of VaD are extremely heterogeneous, but the impaired cerebral blood flow (CBF) represents a common denominator of VaD. The latter might be the result of atherosclerosis, amyloid angiopathy, microbleeding and micro-strokes, together causing blood-brain barrier (BBB) dysfunction and vessel leakage, collectively originating from the consequence of hypertension, one of the main risk factors for VaD. At the histopathological level, VaD displays abnormal vascular remodeling, endothelial cell death, string vessel formation, pericyte responses, fibrosis, astrogliosis, sclerosis, microglia activation, neuroinflammation, demyelination, white matter lesions, deprivation of synapses and neuronal loss. The transforming growth factor (TGF) β has been identified as one of the key molecular factors involved in the aforementioned various pathological aspects. Thus, targeting TGF-β signaling in the brain might be a promising therapeutic strategy to mitigate vascular pathology and improve cognitive functions in patients with VaD. This review revisits the recent understanding of the role of TGF-β in VaD and associated pathological hallmarks. It further explores the potential to modulate certain aspects of VaD pathology by targeting TGF-β signaling.

Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFβ receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFβ signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFβ signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFβ signaling related disorders.

Reply : Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34+ hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34+ HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34+ HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.

Objective: To test the hypothesis, whether TGF-s receptor II (TGFRII) specific antisense-oligonucleotide (ASO)-mediated inhibition of TGF-s signaling will rescue adult neurogenesis and oppose neurodegeneration as studied in human neuronal progenitor cells (ReNcell CX®, Millipore). Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment so far. Actual research is elucidating molecular pathogenesis of this fatal disease. Most probably ALS patients have multifactorial mechanisms causing several additional hits. It is known that TGF-s is often elevated during pathogenesis of different disorders including neurodegenerative diseases or fibrosis. Often, these TGF-smediated alterations correlate with disease progression. ALS patients show high levels of circulating and CNS-tissue TGF-s that contribute to arrested neurogenesis. In addition, TGF-s is related to pathogenic modifications of extracellular matrix (ECM) and the actin-cytoskeleton. Thus, it is tempting to analyze if an (ASO)-mediated inhibition of TGF-s signaling has effects on stem cell proliferation and fibrotic processes in neuronal precursor cells. Design/Methods: To analyze an effective target downregulation TGFRII levels were determined. Inhibition of TGF-s signaling was confirmed by an evaluation of CTGF and pSmad2 levels. Expression of FN, ColIV and the modulation of actin-cytoskeleton (Phalloidin) was examined to clarify an involvement in anti-fibrotic effects in neuronal degeneration. In addition, proliferation of neuronal precursor cells and neurogenesis marker DCX were observed to examine if targeting the TGF-s system leads to a neuronal regeneration. Data were obtained by quantitative real-time RT-PCR, immunoblotting, immunocytochemistry and cell counting. Results: Results indicate that blocking cellular TGF-s signaling by selective ASO leads to reduction of fibrotic deposition and a re-modulation of actin-cytoskeleton. Furthermore, the application of ASO lead to a reactivation of adult neurogenesis in neuronal precursor cells and to an increase of DCX, a marker for neurogenesis. Conclusions: Targeting the TGF-s system by TGFRII-specific oligonucleotide is a promising therapeutic intervention to counteract neuronal degeneration in ALS. Study Supported by: GoBio Disclosure: Dr. Kuespert has nothing to disclose. Dr. Poellmann has nothing to disclose. Dr. Heydn has nothing to disclose. Dr. Zitzelsperger has nothing to disclose. Dr. Peters has nothing to disclose. Dr. Meyer has nothing to disclose. Dr. Bruun has nothing to disclose. Dr. Aigner has nothing to disclose. Dr. Bogdahn has nothing to disclose.