Systemic injection of AAV9-GDNF provides modest functional improvements in the SOD1G93A ALS rat but has adverse side effects

Gm, Thomsen; Alkaslasi, Mor R.; Vit, Jean-Philippe; Lawless, George M.; Godoy, Marlesa; Gowing, Genevíève; Shelest, Oksana; Svendsen, CN

doi:10.1038/gt.2017.9

Cited by 40 publications

(28 citation statements)

References 52 publications

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“…In most of these studies, results consist of correlations between transgene expression levels and clinical outcome measures. However, this level of insight may prove insufficient when sub-therapeutic effects are the outcome, or conversely when adverse events occur in vivo (Gicquel, Maizonnier et al, 2017, Mendell, Campbell et al, 2010, Thomsen, Alkaslasi et al, 2017, strongly arguing for a deeper understanding of disease mechanisms. Therefore, the identification of disease-associated gene dysregulation and signalling pathways that are notor only partiallycorrected after gene transfer is of considerable interest.…”

Section: Introductionmentioning

confidence: 99%

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Dupont

Guo

Lawlor

et al. 2018

Preprint

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Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Previous work from our laboratory on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrects structural abnormalities within the muscle and restores contractile function, with affected dogs surviving more than four years post injection. This exceptional therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology, and to what extent the whole muscle transcriptome is restored to normal after gene transfer.Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously-described canine cohort showing dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice, but also identified new transcripts linked to XLMTM pathology.We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created new metrics to pinpoint potential biomarkers of disease progression and correction.

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Section: Introductionmentioning

confidence: 99%

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Dupont

Guo

Lawlor

et al. 2018

Preprint

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“…In terms of GDNF, we reported previously that general over‐expression administered by early systemic injection of AAV9‐GDNF had only modest effects on ALS disease progression in the SOD1 rat . Clearly the appropriate delivery method, tissue targeting, and targeting of specific cell types within the tissue are critical for maximizing the potential for GDNF‐mediated therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis

et al. 2018

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Early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (ALS). As such, the cortex represents a critical area of ALS research and a promising therapeutic target. In the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) were transplanted into the SOD1 G93A ALS rat cortex, where they migrated, matured into astrocytes, and released GDNF. This protected motor neurons, delayed disease pathology and extended survival of the animals. These same cells injected into the cortex of cynomolgus macaques survived and showed robust GDNF expression without adverse effects. Together this data suggests that introducing cortical astrocytes releasing GDNF represents a novel promising approach to treating ALS. STEM CELLS 2018;36:1122-1131 SIGNIFICANCE STATEMENTStudies suggest that upper motor neurons in the cortex are affected in amyotrophic lateral sclerosis (ALS) patients and in the SOD1 rat. As such, this study assessed the effects of transplanting neural progenitor cells secreting a powerful growth factor, glial cell line-derived neurotrophic factor (GDNF) (hNPC GDNF ) into the motor cortex of the SOD1 rat. For the first time, it is shown that the cells survived, matured into astrocytes, and released GDNF in the brain. Critically, these cells in the cortex were able to protect both upper and lower motor neurons, delay disease pathology and extend survival of the ALS rats. Furthermore, these cells injected into the cortex of cynomolgus macaques survived and showed robust GDNF expression without adverse effects, suggesting that this novel approach is a promising therapeutic strategy for the treatment of ALS patients.

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“…This leads to progressive muscle atrophy and, finally, to respiratory failure, which is the most common cause of the death in ALS [32,33]. In some studies in animal models of ALS, GFLs improved the disease manifestations, although the effect could be dependent on the delivery site, concern only some symptoms and be variable in the degree of improvement [34][35][36], complicating the interpretation of the data and clinical translation. GDNF delivered to patients using stem cells was found to be safe and well-tolerated in a recent small-scale clinical trial, but the efficacy data are yet to be published [37].…”

Section: Introductionmentioning

confidence: 99%

Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration

Sidorova

Saarma

2020

IJMS

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Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson’s disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer’s disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients’ selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.

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Systemic injection of AAV9-GDNF provides modest functional improvements in the SOD1G93A ALS rat but has adverse side effects

Cited by 40 publications

References 52 publications

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

Transplantation of Neural Progenitor Cells Expressing Glial Cell Line-Derived Neurotrophic Factor into the Motor Cortex as a Strategy to Treat Amyotrophic Lateral Sclerosis

Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration

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