A road less travelled: the centenary of cisterna magna puncture

Lutters, Bart; Koehler, Peter J.

doi:10.1093/brain/awaa254

Cited by 5 publications

(7 citation statements)

References 10 publications

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“…In humans, the CM is an established route used for CSF collection and drug injection into the central nervous system (CNS) ( Ayer, 1920 ; Lutters and Koehler, 2020 ). Recently, it has been proposed as an efficient route for CNS gene therapy in non-human primates ( Hinderer et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Blanc

Bemelmans

Affortit

et al. 2022

Front. Cell Dev. Biol.

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Viral-mediated gene augmentation, silencing, or editing offers tremendous promise for the treatment of inherited and acquired deafness. Inner-ear gene therapies often require a safe, clinically useable and effective route of administration to target both ears, while avoiding damage to the delicate structures of the inner ear. Here, we examined the possibility of using a cisterna magna injection as a new cochlear local route for initiating binaural transduction by different serotypes of the adeno-associated virus (AAV2/8, AAV2/9, AAV2/Anc80L65). The results were compared with those following canalostomy injection, one of the existing standard inner ear local delivery routes. Our results demonstrated that a single injection of AAVs enables high-efficiency binaural transduction of almost all inner hair cells with a basal-apical pattern and of large numbers of spiral ganglion neurons of the basal portion of the cochlea, without affecting auditory function and cochlear structures. Taken together, these results reveal the potential for using a cisterna magna injection as a local route for binaural gene therapy applications, but extensive testing will be required before translation beyond mouse models.

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Section: Discussionmentioning

confidence: 99%

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Blanc

Bemelmans

Affortit

et al. 2022

Front. Cell Dev. Biol.

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“…Intrathecal delivery of AAV9-gene therapies has been employed in clinical trials for the treatment of giant axonal neuropathy [7] and spinal muscular atrophy [17]. Although infusions into the CM are not frequently used in clinical practice for procedural risk of pontomedullary tissue damage compared to cauda equinal lumbar puncture, ICM injections provide direct access to central CSF flux and brain entry, particularly in small animal models in which CSF fluid dynamics hinder therapeutic diffusion [18]. Also, ICM injections are less invasive and can accommodate significantly higher-volume infusions than intracerebroventricular injections.…”

Section: Discussionmentioning

confidence: 99%

Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9

et al. 2021

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The development of high efficiency, central nervous system (CNS) targeting AAV-based gene therapies is necessary to address challenges in both pre-clinical and clinical investigations. The engineered capsids, AAV.PHP.B and AAV.PHP.eB, show vastly improved blood-brain barrier penetration compared to their parent serotype, AAV9, but with variable effect depending on animal system, strain, and delivery route. As most characterizations of AAV.PHP variants have been performed in mice, it is currently unknown whether AAV.PHP variants improve CNS targeting when delivered intrathecally in rats. We evaluated the comparative transduction efficiencies of equititer doses (6 × 1011vg) of AAV.PHP.eB-CAG-GFP and AAV9-CAG-GFP when delivered into the cisterna magna of 6–9-month old rats. Using both quantitative and qualitative assessments, we observed consistently superior biodistribution of GFP+ cells and fibers in animals treated with AAV.PHP.eB compared to those treated with AAV9. Enhanced GFP signal was uniformly observed throughout rostrocaudal brain regions in AAV.PHP.eB-treated animals with matching GFP protein expression detected in the forebrain, midbrain, and cerebellum. Collectively, these data illustrate the benefit of intracisternal infusions of AAV.PHP.eB as an optimal system to distribute CNS gene therapies in preclinical investigations of rats, and may have important translational implications for the clinical CNS targeting.

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“…However, this route is less commonly performed clinically due to needle proximity to the brainstem and cerebellum. Nonetheless, in a recent review, authors describe ongoing work to improve methods for performing injections into the cisternal lumen and lumbar space, dating back to 1920 ( Lutters and Koehler, 2020 ). While improvements have been made to the clinical workflow over the course of the past century, one key element that has been relatively ignored is the lack of commercially available devices optimized for CSF delivery – particularly those that could be used to target regions proximal to motor-sensitive anatomy like the CM.…”

Section: Discussionmentioning

confidence: 99%

Pre-clinical delivery of gene therapy products to the cerebrospinal fluid: challenges and considerations for clinical translation

Salegio,

Hancock,

Korszen

2023

Front. Mol. Neurosci.

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While the majority of gene therapy studies in neurological indications have focused on direct gene transfer to the central nervous system (CNS), there is growing interest in the delivery of therapeutics using the cerebrospinal fluid (CSF) as a conduit. Historically, direct CNS routes-of-administration (RoAs) have relied on tissue dynamics, displacement of interstitial fluid, and regional specificity to achieve focal delivery into regions of interest, such as the brain. While intraparenchymal delivery minimizes peripheral organ exposure, one perceived drawback is the relative invasiveness of this approach to drug delivery. In this mini review, we examine the CSF as an alternative RoA to target CNS tissue and discuss considerations associated with the safety of performing such procedures, biodistribution of therapeutics following single administration, and translation of findings given differences between small and large animals. These factors will help delineate key considerations for translating data obtained from animal studies into clinical settings that may be useful in the treatment of neurological conditions.

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A road less travelled: the centenary of cisterna magna puncture

Cited by 5 publications

References 10 publications

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9

Pre-clinical delivery of gene therapy products to the cerebrospinal fluid: challenges and considerations for clinical translation

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