Best practices for the use of intracerebroventricular drug delivery devices

Slavc, Irene; Cohen‐Pfeffer, Jessica; Gururangan, Sridharan; Krauser, Jeanne; Lim, Daniel; Maldaun, Marcos Vinícius Calfat; Schwering, Christoph; Shaywitz, Adam J.; Westphal, Manfred

doi:10.1016/j.ymgme.2018.05.003

Cited by 48 publications

(65 citation statements)

References 39 publications

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“…In addition, the infusion of mAbs unexpectedly stopped after 7 days of ICV deliverance in one mouse (#13); surprisingly, the animal survived, suggesting that the duration of ICV infusion could be shortened in some cases, naturally taking into consideration clinical status of the patient. ICV delivery is a safe administration route that distributes compounds throughout the brain, and despite the need of accurate neurosurgical techniques and to follow best practice requirements, it is extensively used in human neurology (Cohen‐Pfeffer et al , 2017; Slavc et al , 2018; Duma et al , 2019). Notwithstanding, other routes to the CNS, such as intralumbar, should not be excluded and need to be assessed.…”

Section: Resultsmentioning

confidence: 99%

A combination of two human monoclonal antibodies cures symptomatic rabies

et al. 2020

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Rabies is a neglected disease caused by a neurotropic Lyssavirus, transmitted to humans predominantly by the bite of infected dogs. Rabies is preventable with vaccines or proper post‐exposure prophylaxis (PEP), but it still causes about 60,000 deaths every year. No cure exists after the onset of clinical signs, and the case‐fatality rate approaches 100% even with advanced supportive care. Here, we report that a combination of two potent neutralizing human monoclonal antibodies directed against the viral envelope glycoprotein cures symptomatic rabid mice. Treatment efficacy requires the concomitant administration of antibodies in the periphery and in the central nervous system through intracerebroventricular infusion. After such treatment, recovered mice presented good clinical condition, viral loads were undetectable, and the brain inflammatory profile was almost normal. Our findings provide the unprecedented proof of concept of an antibody‐based therapeutic approach for symptomatic rabies.

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Section: Resultsmentioning

confidence: 99%

A combination of two human monoclonal antibodies cures symptomatic rabies

et al. 2020

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“…An additional disadvantage of this administration route for CNS disorders is that delivering large amounts of virus into the An ICV injection consists of delivering the drug directly into the CSF through the lateral ventricles providing the broadest CNS distribution. Although this technique is relatively safe and effective, and is routinely undertaken by neurosurgeons [75], it is not without risks and complications including infections, intracerebral hemorrhage, subcutaneous CSF leaks and increased intracranial pressure [75][76][77][78]. However, these rare complications are most often associated with chronic delivery of biologics, and single-delivery AAV treatments will likely be safer.…”

Section: Route Of Administrationmentioning

confidence: 99%

Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases

Pérez

Shutterly²,

Chan

et al. 2020

Brain Sciences

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Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.

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“…For application of ICV chemotherapy, strict antiseptic rules had been implemented at our hospital. 25 While no infectious complications occurred, non-infectious complications were observed in three patients (two patients with pericatheter leucencephalopathy, one patient with surgical scar dehiscence and CSF leak); however, these complications were manageable and longterm sequelae could be avoided.…”

Section: Discussionmentioning

confidence: 91%

HDMTX-based polychemotherapy including intraventricular therapy in elderly patients with primary CNS lymphoma: a single center series

Seidel

Kowalski

Margold

et al. 2020

Ther Adv Neurol Disord

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Background: To investigate outcome and toxicity of high-dose systemic methotrexate (HDMTX)-based polychemotherapy and intracerebroventricular (ICV) chemotherapy via an Ommaya reservoir in elderly patients with primary central nervous system lymphoma (PCNSL). Methods: We performed a retrospective analysis on patients ⩾65 years with first diagnosis of PCNSL admitted to our center between January 2015 and December 2019. These patients were treated with a standardized chemotherapy protocol in case of absent contraindications for HDMTX-based chemotherapy. The protocol contained induction therapy with systemic rituximab, methotrexate and ifosfamide and consolidation treatment with systemic cytarabine (AraC) and ICV methotrexate, prednisolone and AraC. Results: Of a total of 46 patients seen in this period, 3 did not qualify for HDMTX. Thus, 43 patients were included in this analysis. Median age was 74 years (range 65–86), median Karnofsky performance score was 50 (range 20–90). Of the 43 patients, 32 (74.4%) completed treatment including ICV therapy. Complete remission/complete remission unconfirmed was achieved in 26 of 43 patients (60.5%), partial response (PR) in 3 (7%); 5 (11.6%) had progressive disease, and 3 (7.0%) died due to treatment-related complications; in the remaining 6 (14.0%) therapy could not be completed. Median progression free survival was 16 months (95% confidence interval 8–24 months) and median overall survival had not been reached after a median follow up of 23 months (range 1–52 months); the 75th percentile survival time was 12 months. No Ommaya reservoir infection was observed. Complications of ICV treatment were pericatheter leucencephalopathy in two patients and surgical scar dehiscence with cerebrospinal fluid leak in one patient. Conclusion: Toxicity of HDMTX plus ICV chemotherapy for elderly patients with PCNSL was manageable and outcome was excellent for patients treated with this protocol.

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Best practices for the use of intracerebroventricular drug delivery devices

Cited by 48 publications

References 39 publications

A combination of two human monoclonal antibodies cures symptomatic rabies

A combination of two human monoclonal antibodies cures symptomatic rabies

Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases

HDMTX-based polychemotherapy including intraventricular therapy in elderly patients with primary CNS lymphoma: a single center series

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