Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

Kimura, Seigo; Harashima, Hideyoshi

doi:10.3390/pharmaceutics12121216

Cited by 53 publications

(41 citation statements)

References 286 publications

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“…One possible approach is to deliver the genes encoding the Nbs using a viral vector-based system (47). The field of gene therapy for the nervous system has undergone explosive growth in the last 5 years (48,49), and gene therapy strategies have also been developed for PD (50)(51)(52)(53). Different approaches for the development of the Nbs into next-generation therapeutics to target LRRK2 in PD are currently being explored.…”

Section: Discussionmentioning

confidence: 99%

Nanobodies as allosteric modulators of Parkinson’s disease-associated LRRK2

Singh

Soliman

Guaitoli

et al. 2021

Preprint

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Mutations in the gene coding for Leucine-Rich Repeat Kinase 2 (LRRK2) are a leading cause of the inherited form of Parkinson′s disease (PD), while LRRK2 overactivation is also associated with the more common idiopathic form of PD. LRRK2 is a large multi-domain protein, including a GTPase as well as a Ser/Thr protein kinase domain. Common disease-causing mutations increase LRRK2 kinase activity, presenting LRRK2 as an attractive target for inhibitory drug design. Currently, drug development has mainly focused on ATP-competitive kinase inhibitors. Here, we report the identification and characterization of a variety of Nanobodies that bind to different LRRK2 domains and inhibit or activate LRRK2 activity in cells and in vitro. Importantly, diverse groups of Nanobodies were identified that inhibit LRRK2 kinase activity through a mechanism that does not involve binding to the ATP pocket or even to the kinase domain. Moreover, while certain Nanobodies completely inhibit the LRRK2 kinase activity, we also identified Nanobodies that specifically inhibit the phosphorylation of Rab protein substrates. Finally, in contrast to current type-I kinase inhibitors, the studied kinase-inhibitory Nanobodies did not induce LRRK2 microtubule association. These comprehensively characterized Nanobodies represent versatile tools to study the LRRK2 function and mechanism, and can pave the way toward novel diagnostic and therapeutic strategies for PD.

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Section: Discussionmentioning

confidence: 99%

Nanobodies as allosteric modulators of Parkinson’s disease-associated LRRK2

Singh

Soliman

Guaitoli

et al. 2021

Preprint

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“…Non-viral vectors with different transgene encapsulations exist, but despite that the first lipid nanoparticle-based RNA interference (RNAi) therapeutic drug was approved for treatment in 2018 (Kimura and Harashima, 2020), the viral vector-mediated gene transfers are still the preferred choice for gene therapies in the CNS. Finally, new genetic tools using in vivo gene therapy such as chemogenetics and optogenetics (Ingusci et al, 2019), have been developed as useful tools for basic scientific research, but could also refine gene therapy approaches to control neuronal activation for rare genetic disorders in the CNS in the future.…”

Section: In Vivo Vector-mediated Gene Therapymentioning

confidence: 99%

“…Delivery of genetic material is an important issue since accessibility of systemically administered treatments targeting the CNS has long been complicated by the tightly regulated blood-brain barrier (BBB) that controls passage into the CNS (Kimura and Harashima, 2020). Direct intracerebral injection into the parenchyma, although highly invasive, is one way to circumvent this problem, which also ensures a direct match between treatment delivery and the targeted region.…”

Section: Delivery Strategies For Gene Therapy To the Brain And Spinal Cordmentioning

confidence: 99%

“…If it is necessary to deliver treatment to larger parts of the brain or spinal cord, it is possible to apply multiple injection sites and/or viral vectors with a larger degree of spread and retrograde transport along neuronal processes (Kimura and Harashima, 2020). Another strategy for achieving a wide spread in the brain and spinal cord could be delivered through the CSF, by intracerebroventricular (ICV), intracisterna magna, or intrathecal injections (Hocquemiller et al, 2016;Taghain et al, 2020).…”

Section: Delivery Strategies For Gene Therapy To the Brain And Spinal Cordmentioning

confidence: 99%

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Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Jensen

Gøtzsche

Woldbye

2021

Front. Mol. Neurosci.

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In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.

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“…Although the factors responsible for the widespread failures of promising agents to translate into clinically effective DMTs are complex, a role for poor brain bioavailability has been suggested ( 2 ). This is particularly true for the growing pharmacopeia of molecular therapies including growth factors, enzymes, monoclonal antibodies, and genetic material, all too large to cross the specialized endothelia that compose the blood-brain barrier (BBB).…”

mentioning

confidence: 99%

Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases

Fishman

Fischell

2021

Front. Neurol.

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The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.

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Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

Cited by 53 publications

References 286 publications

Nanobodies as allosteric modulators of Parkinson’s disease-associated LRRK2

Nanobodies as allosteric modulators of Parkinson’s disease-associated LRRK2

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases

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