Adeno-Associated Virus-Based Gene Therapy for CNS Diseases

Hocquemiller, Michaël; Giersch, Laura; Audrain, Mickaël; Parker, Samantha; Cartier, Nathalie

doi:10.1089/hum.2016.087

Cited by 240 publications

(225 citation statements)

References 217 publications

(146 reference statements)

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“…The other important issue regarding gene therapy is its clinical translation, as three possible routes of adeno-associated virus (AAV) vector administration have been described (intramuscular (IM), intravenous (IV) and intracerebroventricular (ICV) 46. Recently, many gene therapy studies have been conducted in the context of neuromuscular disorders, and very encouraging results have been achieved in the treatment of SMA and in human clinical trials.…”

mentioning

confidence: 99%

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Saladini

Nizzardo

Govoni

et al. 2019

J Cellular Molecular Medi

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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.

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mentioning

confidence: 99%

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Saladini

Nizzardo

Govoni

et al. 2019

J Cellular Molecular Medi

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“…A transient, early increase in gene (Dyn) expression is typical for high copy numbers of delivered AAV vectors. Only a fraction of the initially transduced AAV genomes persist long‐term as nuclear episomes (Murlidharan et al , ; Hocquemiller et al , ). Importantly, the early increase in neuronal Dyn did not lead to increased Dyn levels in the cerebrospinal fluid (CSF) at 1.5 months after AAV‐pDyn transduction (Fig H).…”

Section: Resultsmentioning

confidence: 99%

Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy

et al. 2019

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Focal epilepsy represents one of the most common chronic CNS diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical challenges. In the quest of novel, disease‐modifying treatment strategies of neuropeptides represent promising candidates. Here, we provide the “proof of concept” that gene therapy by adeno‐associated virus (AAV) vector transduction of preprodynorphin into the epileptogenic focus of well‐accepted mouse and rat models for temporal lobe epilepsy leads to suppression of seizures over months. The debilitating long‐term decline of spatial learning and memory is prevented. In human hippocampal slices obtained from epilepsy surgery, dynorphins suppressed seizure‐like activity, suggestive of a high potential for clinical translation. AAV‐delivered preprodynorphin expression is focally and neuronally restricted and release is dependent on high‐frequency stimulation, as it occurs at the onset of seizures. The novel format of “release on demand” dynorphin delivery is viewed as a key to prevent habituation and to minimize the risk of adverse effects, leading to long‐term suppression of seizures and of their devastating sequel.

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“…AAV mediates long-term and efficient target gene expression, infects and stably integrates into dividing and non-dividing cells, and stimulates low immune response without resulting in human diseases; 10 therefore, it evokes more and more interests and usage in treating various diseases. Recently, rAAV vectors have been used to treat eye diseases, 11,12 brain diseases, 13,14 muscle diseases, 15 blood diseases, [16][17][18] cancers 19 and so on. [20][21][22][23] In particular, the European Medicines Agency (EMA) had approved the first ever gene therapy of modified adeno-associated virus AAV-LPL S447X for the clinical use to treat a rare inherited metabolic disease called lipoprotein lipase deficiency in the Western world in 2013, 24 which greatly stimulates the enthusiasm using AAV as the targeted gene carrier for gene therapy.…”

Section: Introductionmentioning

confidence: 99%

Preclinical study of rAAV2-sTRAIL: pharmaceutical efficacy, biodistribution and safety in animals

et al. 2017

Cancer Gene Ther

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The recombinant sTRAIL has been in clinical trial for various human malignancies. However, the half-life time of sTRAIL is very short, which might be an important factor influencing its clinical efficacy for cancer therapy. We previously reported the recombinant adeno-associated virus (AAV)-encoding sTRAIL 95-281 -mediated sTRAIL expression in vivo up to 8 months and suppressed tumor growth markedly in mouse xenografts. In the present study, we further evaluated the clinical potency for cancer gene therapy and the safety in mouse and non-human primates. The mouse models with HCT-116, NCI-H460 and BEL-7402 cancers were injected intraperitoneally with a single dose of 1.0 × 10 11 , 1.0 × 10 10 and 1.0 × 10 9 vg of rAAV2-sTRAIL 95-281 virus, respectively. The cynomolgus monkeys were injected (i.m.) with a single dose of rAAV2-sTRAIL 95-281 of 1 × 10 11 , 3 × 10 11 and 1 × 10 12 vg, corresponding to 6-, 20-and 60-fold of intended use dosage for humans, respectively. The efficacy, pharmacology and toxicity of rAAV-sTRAIL in the animals were analyzed accordingly. The tumor inhibitory rates reached 44-76%, 48-52% and 55-74% in the three tumor models, respectively, and they had no influence on mouse spontaneous activity. Administration (s.c.) of a single dose of rAAV2-sTRAIL 95-281 virus of 1.0 × 10 9 or 1.0 × 10 10 vg in mice with implanted tumor led to mainly distribution in the spleen, liver, implanted tumor, blood, injected site of muscle and bone marrow. Two weeks later, there was no rAAV2-sTRAIL 95-281 detected in blood and bone marrow, and it significantly decreased in other tissues and organs and then gradually cleared away in 4-12 weeks after administration. There was no rAAV2-sTRAIL accumulation in the animal's body and no influence on the body weights. Administration (i.v.) did not cause animal death, and no dose-related abnormal clinical symptoms were found in the mice. There were no abnormal tissue and organ found in all animals. Long-term toxicity test in cynomolgus monkeys did not cause rAAV2-sTRAIL 95-281 -related toxic and side effects, except that anti-AAV and anti-sTRAIL antibodies were generated. In conclusion, these data demonstrated that administration of rAAV2-sTRAIL 95-281 in mice and in cynomolgus monkeys is safe without obvious toxic and side effects to the animals, and throw light on pharmacokinetics and safety in human clinical trials for cancer gene therapy.

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Adeno-Associated Virus-Based Gene Therapy for CNS Diseases

Cited by 240 publications

References 217 publications

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy

Preclinical study of rAAV2-sTRAIL: pharmaceutical efficacy, biodistribution and safety in animals

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