Intrathecal morphine delivery at prepontine cistern to control refractory cancer-related pain: a case report of extensive metastatic and refractory cancer pain.

BACKGROUND: Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. CASE PRESENTATION: The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. CONCLUSIONS: The patient achieved a good quality of life during the one-month follow-up period.

Intrathecal Therapeutics: Device Design, Access Methods, and Complication Mitigation.

INTRODUCTION: The intrathecal space remains underutilized for diagnostic testing, invasive monitoring or as a pipeline for the delivery of neurological therapeutic agents and devices. The latter including drug infusions, implants for electrical modulation, and a means for maintaining the physiologic pressure column. The reasons for this are many but include unfamiliarity with the central nervous system and the historical risks that continue to overshadow the low complication rates in modern clinical series. MATERIALS AND METHODS: Our intent in this review is to explore the access devices currently on the market, assess the risk associated with breaching the intrathecal space, and propose a research model for bringing to patients the next generation of intrathecal hardware. For this purpose, we reviewed both historical and contemporary literature that pertains to the access devices and catheters intended for both temporary and permanent implantation and the complications thereof. RESULTS: There are few devices that are currently marketed in the United States or Europe for intrathecal use. Most hew to a relatively fixed design pattern predicated on the dimensions and properties of the thecal sac. All are typically composed of soft silicone, and employ a Tuohy needle for access despite design limitations. In general, these catheters are engineered for durability, ease of use, and regional deployment. Devices on the market with steerability or targeted intrathecal fixation are not yet available. Complications, once a legitimate concern, are now quite rare when recommended techniques are followed. CONCLUSIONS: Over the next decade, advances in intrathecal catheter design, access techniques, imaging, and greater understanding of the spinal cord neurophysiology will usher in an era where the intrathecal space is recognized as a highly valued diagnostic and therapeutic target. We anticipate that this will occur in several concurrent phases, each with the potential to accelerate the growth of the others.

Intrathecal miR-183 delivery suppresses mechanical allodynia in mononeuropathic rats.

Members of the miR-183 family are unique in that they are highly abundant in sensory organs. In a recent study, significant downregulation was observed for miR-96 and miR-183 in the L5 dorsal root ganglion (DRG) 2 weeks after spinal nerve ligation (SNL). In this study, we focused on miR-183, which is the most regulated member of the miR-183 family, to look at the specific role on neuropathic pain. Persistent mechanical allodynia was induced with the L5 SNL model in 8-week-old male Sprague-Dawley rats. Paw withdrawal thresholds in response to mechanical stimuli were assessed with Von Frey filaments. Expression of miR-183 in the L5 DRG was assessed with quantitative real-time polymerase chain reaction (qPCR) analysis. Lentivirions expressing miR-183 were injected intrathecally into SNL rats. Changes in mechanical allodynia were assessed with Von Frey filaments. In addition, changes in the predicted target genes of miR-183 were assessed with qPCR. L5 SNL produced marked mechanical allodynia in the ipsilateral hindpaws of adult rats, beginning at postoperative day 1 and continuing to day 14. L5 SNL caused significant downregulation of miR-183 in adult DRG cells. Intrathecal administration of lentivirions expressing miR-183 downregulated SNL-induced increases in the expression of Nav1.3 and brain-derived neurotrophic factor (BDNF), which correlated with the significant attenuation of SNL-induced mechanical allodynia. Our results show that SNL-induced mechanical allodynia is significantly correlated with the decreased expression of miR-183 in DRG cells. Replacement of miR-183 downregulates SNL-induced increases in Nav1.3 and BDNF expression, and attenuates SNL-induced mechanical allodynia.

Oncolytic viral therapy: a review and promising future directions.

Oncolytic viral therapy is quickly emerging as a promising subset of immunotherapy, which theoretically can target tumor cells while sparing surrounding healthy cells by harnessing the replication machinery of viruses with tropism for tumor cells, resulting in direct oncolysis, and by transforming immunologically "cold" tumor into areas that elicit the host's immune response. This review provides an overview of oncolytic viral therapy until the present day, starting with the original concept in 1912. The general mechanism of oncolytic viruses (OVs) depends on selectively integrating them into tumor cells based on genetic engineering of viral genomic material, inducing oncolysis and eliciting the host's innate immune response. Moreover, a major component of oncolytic viral therapy has been herpes simplex virus, with talimogene laherparepvec being the only FDA-approved oncolytic viral therapy for the treatment of melanomas. This review explores the characteristics, advantages, disadvantages, and therapeutic uses of several DNA and RNA viral families. A snapshot of the oncolytic viral treatments used in the most recent and advanced clinical trials is also provided. Lastly, the challenges of implementing oncolytic viral therapy are explored, both at a molecular and clinical level, with a highlight of promising future directions. In particular, the lack of an optimal delivery method based on tumor type for oncolytic viral therapy poses a significant obstacle, even in clinical studies. Intrathecal continuous delivery of OVs is a promising prospect, potentially by adapting the novel continuous irrigation and drainage IRRAflow catheter. Further exploration and testing of the IRRAflow catheter should be undertaken.

The safety profile of mesenchymal stem cell therapy administered through intrathecal injections for treating neurological disorders: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Based on previous in vivo studies and human trials, intrathecal cell delivery is a safe and relevant therapeutic tool for improving patient's quality of life with neurological conditions. We aimed to characterise the safety profile of intrathecally delivered Mesenchymal stem cells (MSCs). METHODS: Ovid MEDLINE, Embase, Scopus, Cochrane Library, KCI-Korean Journal Database, and Web of Science. Databases were searched from their inception until April 13, 2023. Randomised Controlled Trials (RCTs) that compared intrathecal delivery of MSCs to controls in adult populations were included. Adverse events (AEs) were pooled and meta-analysed using DerSimonian-Laird random effects models with a correction factor 0.5 added to studies with zero count cells. Pooled AEs were described using Risk ratio (RR) and 95% confidence intervals (95% CI). Then, a random-effects meta-regress model on study-level summary data was performed to explore the relationship between the occurrence of AEs and covariates thought to modify the overall effect estimate. Finally, publication bias was assessed. RESULTS: 303 records were reviewed, and nine RCTs met the inclusion criteria and were included in the quantitative synthesis (n = 540 patients). MSCs delivered intrathecally, as compared to controls, were associated with an increased probability of AEs of musculoskeletal and connective tissue disorders (categorised by Common Terminology Criteria for Adverse Events-CTCAE version 5.0) (RR: 1.61, 95% CI 1.19-2.19, I2 = 0%). The random-effects meta-regress model suggested that fresh MSCs increased the probability of occurrence of AEs compared to cryopreserved MSCs (RR: 1.554; p-value = 0.048; 95% CI 1.004-2.404), and the multiple-dose, decreased the probability of AEs by 36% compared to single doses (RR: 0.644; p-value = 0.048; 95% CI 0.416-0.996); however, univariate random effects meta-regression models revealed a not significant association between the occurrence of AEs from MSCs intrathecal delivery and each covariate. CONCLUSIONS: Intrathecal delivery of MSCs was associated with a slight increase in AEs associated with musculoskeletal and connective tissue disorders, albeit without serious AEs. We conclude that intrathecal MSCs delivery is safe for patients with neurological conditions. However, further high-quality, large-scale RCTs are needed to confirm these findings.

A mechanistic pharmacokinetic model for intrathecal administration of antisense oligonucleotides.

Intrathecal administration is an important mode for delivering biological agents targeting central nervous system (CNS) diseases. However, current clinical practices lack a sound theorical basis for a quantitative understanding of the variables and conditions that govern the delivery efficiency and specific tissue targeting especially in the brain. This work presents a distributed mechanistic pharmacokinetic model (DMPK) for predictive analysis of intrathecal drug delivery to CNS. The proposed DMPK model captures the spatiotemporal dispersion of antisense oligonucleotides (ASO) along the neuraxis over clinically relevant time scales of days and weeks as a function of infusion, physiological and molecular properties. We demonstrate its prediction capability using biodistribution data of antisense oligonucleotide (ASO) administration in non-human primates. The results are in close agreement with the observed ASO pharmacokinetics in all key compartments of the central nervous system. The model enables determination of optimal injection parameters such as intrathecal infusion volume and duration for maximum ASO delivery to the brain. Our quantitative model-guided analysis is suitable for identifying optimal parameter settings to target specific brain regions with therapeutic drugs such as ASOs.

Intrathecal liproxstatin-1 delivery inhibits ferroptosis and attenuates mechanical and thermal hypersensitivities in rats with complete Freund's adjuvant-induced inflammatory pain.

Previous studies have confirmed the relationship between iron-dependent ferroptosis and a peripheral nerve injury-induced neuropathic pain model. However, the role of ferroptosis in inflammatory pain remains inconclusive. Therefore, we aimed to explore whether ferroptosis in the spinal cord and dorsal root ganglion contributes to complete Freund's adjuvant (CFA)-induced painful behaviors in rats. Our results revealed that various biochemical and morphological changes were associated with ferroptosis in the spinal cord and dorsal root ganglion tissues of CFA rats. These changes included iron overload, enhanced lipid peroxidation, disorders of anti-acyl-coenzyme A synthetase long-chain family member 4 and glutathione peroxidase 4 levels, and abnormal morphological changes in mitochondria. Intrathecal treatment of liproxstatin-1 (a ferroptosis inhibitor) reversed these ferroptosis-related changes and alleviated mechanical and thermal hypersensitivities in CFA rats. Our study demonstrated the occurrence of ferroptosis in the spinal cord and dorsal root ganglion tissues in a rodent model of inflammatory pain and indicated that intrathecal administration of ferroptosis inhibitors, such as liproxstatin-1, is a potential therapeutic strategy for treating inflammatory pain.

Spinally delivered ampakine CX717 increases phrenic motor output in adult rats.

Ampakines are synthetic molecules that allosterically modulate AMPA-type glutamate receptors. We tested the hypothesis that delivery of ampakines to the intrathecal space could stimulate neural drive to the diaphragm. Ampakine CX717 (20 mM, dissolved in 10 % HPCD) or an HPCD vehicle solution were delivered via a catheter placed in the intrathecal space at the fourth cervical segment in urethane-anesthetized, mechanically ventilated adult male Sprague-Dawley rats. The electrical activity of the phrenic nerve was recorded for 60-minutes following drug application. Intrathecal application of CX717 produced a gradual and sustained increase in phrenic inspiratory burst amplitude (n = 10). In contrast, application of HPCD (n = 10) caused no sustained change in phrenic motor output. Phrenic burst rate, heart rate, and mean arterial pressure were similar between CX717 and HPCD treated rats. We conclude that intrathecally delivered ampakines can modulate phrenic motor output. This approach may have value for targeted induction of spinal neuroplasticity in the context of neurorehabiliation.

The AAV9 Variant Capsid AAV-F Mediates Widespread Transgene Expression in Nonhuman Primate Spinal Cord After Intrathecal Administration.

Intrathecal delivery of AAV9 into the subarachnoid space has been shown to transduce spinal cord and brain and be less affected by preexisting antibodies, which are lower in cerebral spinal fluid. Still, efficiency of transduction needs to be improved. Recently, we identified a new capsid from a library selection in mice, called AAV-F, that allowed robust transduction of the spinal cord gray matter after lumbar injection. In this study, we test transduction of spinal cord by AAV-F (n = 3) compared to AAV9 (n = 2), using a reporter gene, in cynomolgus monkeys after lumbar intrathecal injection. Using an automated image analysis (IA) approach to sensitively quantitate reporter gene expression in spinal cord, we found that AAV-F capsid mediated slightly higher transgene expression (both in percentages of cells and intensity of immunostaining) in motor neurons and interneurons, in the lumbar and thoracic regions, compared to AAV9. Interestingly, although AAV-F mediated higher transgene expression in spinal cord, the number of genomes in spinal cord and periphery were on average lower for AAV-F than AAV9, which suggest that lower numbers of genomes were able to mediate higher transgene expression in spinal cord with this capsid. In contrast, dorsal root ganglion transduction efficiency was lower for AAV-F compared to AAV9 on average. Interestingly, we also observed transduction of Schwann cells in sciatic nerve in two nonhuman primates injected with AAV-F, but none with AAV9. Overall, our data demonstrate the utility of automated IA for quantitation of AAV transduction in the spinal cord and the favorable on-target:off-target transduction profile suggests that the AAV-F capsid be considered for gene therapy applications focused on treating the spinal cord after intrathecal delivery.

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas.

Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important.

Large-Volume Intrathecal Administrations: Impact on CSF Pressure and Safety Implications.

The increasing number of studies demonstrates the high potency of the intrathecal (IT) route for the delivery of biopharmaceuticals to the central nervous system (CNS). Our earlier data exhibited that both the infused volume and the infusion rate can regulate the initial disposition of the administered solute within the cerebrospinal fluid (CSF). This disposition is one of key factors in defining the subsequent transport of the solute to its intended target. On the other hand, fast additions of large volumes of liquid to the CSF inevitably raise the CSF pressure [a.k.a. intracranial pressure (ICP)], which may in turn lead to adverse reactions if the physiologically delimited threshold is exceeded. While long-term biological effects of elevated ICP (hydrocephalus) are known, the safety thresholds pertaining to short-term ICP elevations caused by IT administrations have not yet been characterized. This study aimed to investigate the dynamics of ICP in rats and non-human primates (NHPs) with respect to IT infusion rates and volumes. The safety regimes were estimated and analyzed across species to facilitate the development of translational large-volume IT therapies. The data revealed that the addition of a liquid to the CSF raised the ICP in a rate and volume-dependent manner. At low infusion rates (<0.12 ml/min in rats and <2 ml/min in NHPs), NHPs and rats displayed similar tolerance patterns. Specifically, safe accommodations of such added volumes were mainly facilitated by the accelerated pressure-dependent CSF drainage into the blood, with I stabilizing at different levels below the safety threshold of 28 ± 4 mm Hg in rats and 50 ± 5 mm Hg in NHPs. These ICPs were safely tolerated for extended durations (of at least 2-25 min). High infusion rates (including boluses) caused uncompensated exponential ICP elevations rapidly exceeding the safety thresholds. Their tolerance was species-dependent and was facilitated by the compensatory role of the varied components of craniospinal compliance while not excluding the possibility of other contributing factors. In conclusion, large volumes of liquids can safely be delivered via IT routes provided that ICP is monitored as a safety factor and cross-species physiological differences are accounted for.

Intra-CSF AAV9 and AAVrh10 Administration in Nonhuman Primates: Promising Routes and Vectors for Which Neurological Diseases?

The identification of the most efficient method for whole central nervous system targeting that is translatable to humans and the safest route of adeno-associated virus (AAV) administration is a major concern for future applications in clinics. Additionally, as many AAV serotypes were identified for gene introduction into the brain and the spinal cord, another key to human gene-therapy success is to determine the most efficient serotype. In this study, we compared lumbar intrathecal administration through catheter implantation and intracerebroventricular administration in the cynomolgus macaque. We also evaluated and compared two AAV serotypes that are currently used in clinical trials: AAV9 and AAVrh10. We demonstrated that AAV9 lumbar intrathecal delivery using a catheter achieved consistent transgene expression in the motor neurons of the spinal cord and in the neurons/glial cells of several brain regions, whereas AAV9 intracerebroventricular delivery led to a consistent transgene expression in the brain. In contrast, AAVrh10 lumbar intrathecal delivery led to rare motor neuron targeting. Finally, we found that AAV9 efficiently targets respiratory and skeletal muscles after injection into the cerebrospinal fluid (CSF), which represents an outstanding new property that can be useful for the treatment of diseases affecting both the central nervous system and muscle.

Visualization of intrathecal delivery by PET-imaging.

BACKGROUND: Intrathecal (IT) delivery is useful in both basic research and clinical treatments. Here we aim to test a new minimally invasive distribution route to the subarachnoid space (SAS) and the flow of IT administrations. We placed a radioligand into SAS during positron emission tomography (PET) scanning as a proof of concept. NEW METHOD: We injected a 11C-labeled PET-tracer using a surgically placed catheter in the cisterna magna of anesthetized female pigs. The pigs were scanned for 1.5-2 hours in a PET/CT-scanner. The pressure from continuous infusion of artificial CSF (aCSF) promoted distribution of the tracer. The procedure was done under continuous intracranial pressure (ICP) monitoring. The catheter was made accessible both by externalization through the skin and through a subcutaneously placed sterile titanium port connected to the catheter. After image reconstruction, we used PMOD software to assess the tracer distribution throughout SAS. Internalisation of the catheter to a port enables survival studies. Previous studies performing ventriculography have placed a catheter trough brain cortex and parenchyma; such procedures may affect any behavioural or neurological evaluation, and have an increased risk of bleeding per- and post-operatively (Kaiser & Frühauf, 2007). RESULTS: The PET-CT visualized tracer was evenly distributed in the SAS. Furthermore, the ICP measurement made it possible to adjust infusion speed within acceptable pressure levels. CONCLUSION: This new method can be useful for testing distribution of PET-tracers, antibiotics, chemotherapeutics and a wide range of other pharmaceuticals targeting the CNS and spinal cord in large animal models, and potentially later in human.

Slow Infusion of Recombinant Adeno-Associated Viruses into the Mouse Cerebrospinal Fluid Space.

Recombinant adeno-associated viruses (rAAVs) are the leading in vivo gene delivery platform, and have been extensively studied in gene therapy targeting various tissues, including the central nervous system (CNS). A single-bolus rAAV injection to the cerebrospinal fluid (CSF) space has been widely used to target the CNS, but it suffers from several drawbacks, such as leakage to peripheral tissues. Here, a protocol is described using an osmotic pump to infuse rAAV slowly into the mouse CSF space. Compared to the single-bolus injection technique, pump infusion can lead to higher CNS transduction and lower transduction in the peripheral tissues.

Atlanto-occipital catheterization of young rats for long-term drug delivery into the lumbar subarachnoid space combined with in vivo testing and electrophysiology in situ.

BACKGROUND: Catheterization has been widely used in neuroscience and pain research for local drug delivery. Though different modifications were developed, the use of young animals for spinal catheterization remains limited because of a little success rate. A reliable technique is needed to catheterize young animals aimed for in vivo testing combined with spinal cord electrophysiology, often limited by animal age, to facilitate pain research. NEW METHODS: We describe intrathecal catheterization of young rats (3-week-old) through atlanto-occipical approach for long-lasting drug delivery into the lumbar subarachnoid space. The technique represents a surgical approach of minimized invasiveness that requires PE-10 catheter and few equipment of standard laboratory use. RESULTS: Behavioral assessments revealed that spinal catheterization does not change peripheral sensitivity of different modalities (thermal and mechanical) and gives no rise to locomotive deficit or anxiety-like behavior in young rats. The long-term administration of genetic material (oligodeoxynucleotides given up to 4days), examined both in vivo and in situ, produced no adverse effects on basal peripheral sensitivity, but changed the AMPA receptor-mediated currents in sensory interneurons of the spinal cord. COMPARISON WITH EXISTING METHODS: Dissimilar to already described methods, the method is designed for the use of young rats for behavioral testing in vivo and/or spinal cord electrophysiology in situ. CONCLUSIONS: A practical method for spinal catheterization of young animals designed for studies in vivo and in situ is proposed. The method is rapid and effective and should facilitate investigation of therapeutic effects on both systemic and subcellular levels, as an advantage over the existing methods.

Transdermal spinal catheter placement in piglets: Description and validation of the technique.

BACKGROUND: The swine species represents a perfect model for translational medicine due to its physiological and anatomical resemblance to humans. The development of techniques for spinal catheter insertion in swine is significantly useful but, at the moment, the only technique described requires laminectomy as a surgical approach. NEW METHOD: The proposed techniques represent a transdermal approach for catheter placement in piglets. The study was divided into Phase I (anatomical study on 8 cadavers) and Phase II (in vivo application of the technique in 20 anaesthetised 30-day old piglets). A spinal needle was introduced between the L2 and L3 spinous processes with a ventro-cranial orientation until cerebro-spinal fluid leakage. It was then replaced with a Tuohy needle, used to introduce the catheter into the intrathecal space. Before inserting the catheter, the approximate length from the insertion point to the external projection of the Cisterna Magna was measured using the gradation markings on the device. RESULTS: The technique described allowed spinal catheter placement in all piglets. In Phase I, the correct placement was confirmed using fluoroscopy while, in Phase II, cerebrospinal fluid leakage from the needle was relied on. No clinical alterations were detected either during the procedure or during the following days. COMPARISON WITH EXISTING METHOD: This technique is easy and requires less skilled operators when compared to the other existing method which involves a surgical approach. Moreover, being less invasive, it potentially leads to fewer complications. CONCLUSIONS: In conclusion, the technique can be performed safely in piglets, and provides an easier and less invasive approach for spinal catheter insertion.

Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries.

The environment within the spinal cord after injury, which changes in the progression from the acute to chronic stages, limits the extent of regeneration. The delivery of inductive factors to promote regeneration following spinal cord injury has been promising, yet, few strategies are versatile to allow delivery during acute or chronic injury that would facilitate screening of candidate therapies. This report investigates the intrathecal delivery of lentiviruses for long-term expression of regenerative factors. Lentivirus-filled sponges were inserted into the intrathecal space surrounding the spinal cord, with transgene expression observed within multiple cell types that persists for 12 weeks for both intact and injured spinal cord, without any apparent damage to the spinal cord tissue. Sponges loaded with lentivirus encoding for Sonic hedgehog (Shh) were investigated for acute (delivered at 0 weeks) and chronic (at 4 weeks) injuries, and for multiple locations relative to the injury. In an acute model, sponges placed directly above the injury increased oligodendrocyte and decreased astrocyte presence. Sponges placed caudal to the injury had reduced impact on oligodendrocytes and astrocytes in the injury. In a chronic model, sponges increased oligodendrocyte and decreased astrocyte presence. Furthermore, the effect of Shh was shown to be mediated in part by reduction of Bmp signaling, monitored with an Msx2-sensitive reporter vector. The implantation of lentivirus-loaded biomaterials intrathecally provides the opportunity to induce the expression of a factor at a specified time without entering the spinal cord, and has the potential to promote gene delivery within the spinal cord, which can influence the extent of regeneration.

The effect of intrathecal delivery of bone marrow stromal cells on hippocampal neurons in rat model of Alzheimer's disease.

OBJECTIVES: Intracerebral injection of bone marrow stromal cells (BMSCs) is being investigated as a therapeutic tool to prevent Alzheimer's disease (AD). Our aim was to investigate the effects of BMSCs by intrathecal injection in AD rat model. MATERIALS AND METHODS: BMSCs were obtained from the bone marrow of Wistar rat and transplanted into AD rat model via intrathecal injection. The rat model had received an injection of ß amyloid into the hippocampus for histological and immunohistochemical studies. RESULTS: Histological examination of the brains in transplanted rats compared to controls demonstrated the migration of BrdU-labeled BMSCs from the site of delivery, confirmed the differentiation of BMSCs transplanted cells into the cholinergic neurons, and increased number of healthy and decreased number of dark neurons. CONCLUSION: Our results showed that BMSCs intratechal administration could be a promising method for treatment of Alzheimer's disease in rat model.