Fluid delivery system and method of treatment

Abstract

The disclosed system and method is a configurable central nervous system (CNS) delivery solution for therapeutic agents such as gene drugs. The system and method first inject a therapeutic bolus into the intrathecal space and then inject flush fluid to move the therapeutic bolus rostrally towards the target area and achieve the desired spread in the spine and / or brain. The second location can be a location caudal to the delivery location of the therapeutic bolus.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 201,941, filed May 19, 2021, which is incorporated by reference in its entirety.

[0002] Field of Disclosure FIELD OF THE DISCLOSURE The present disclosure relates generally to fluid delivery systems and methods of treatment, and more specifically to central nervous system fluid delivery systems and methods of treatment. [Background technology]

[0003] background Many systems in the human body rely on careful regulation of fluid pressure, volume, flow and metabolite balance. For example, the intrathecal space is a fluid-filled space located between the pia mater surrounding the spinal cord and the arachnoid membrane adjacent to the dura mater. The intrathecal space contains cerebrospinal fluid, which is typically a clear, water-like fluid with a viscosity close to that of water at body temperature. Alterations in intrathecal pressure can result in, for example, reduced local spinal tissue blood flow, reduced metabolite delivery to the spinal cord and changes in intracranial pressure. Delivery or removal of fluid to the intrathecal space is difficult because a needle (optionally associated with a catheter) is manually inserted into the patient's spinal column. Other risks associated with intrathecal drug administration include: a) infection associated with non-sterile instruments, b) inflammatory reaction of nerve tissue to foreign bodies, c) loss of fluid from the needle, resulting in reduced intrathecal and intracranial pressure and hypotensive headache, d) incorrect positioning of the needle outside the intrathecal space in the epidural space, e) injection of fluid / drug too rapidly, resulting in increased intrathecal and intracranial pressure, f) inflammatory reaction of nerve tissue due to injection of foreign fluid, g) nerve tissue damage from the needle, h) long-term leakage of cerebrospinal fluid from the needle hole, and many other problems. Combined, these risks are significant for intrathecal injection. The training and time required to manually adapt existing drug delivery devices to different anatomical sites and specific treatments represents a significant burden for clinicians.

[0004] However, intrathecal administration is a valuable tool for introducing therapeutic agents into the cerebrospinal fluid (CSF), allowing for the potential for widespread or localized biodistribution throughout the central nervous system. Indeed, therapeutic agents administered to the CSF distribute to the brain and spinal cord, thereby bypassing the blood-brain barrier, which potentially limits the range of drugs that can be delivered to CNS tissues. Summary of the Invention

[0005] summary According to a first example, a method for fluid delivery to a target region in a patient's central nervous system is described, the method including injecting a therapeutic bolus into the patient's intrathecal space at a first location and subsequently injecting a flush fluid into the patient's intrathecal space at a second location at one or more flush flow rates, the one or more flush flow rates being based on at least one of the patient's anatomical or physiological data.

[0006] In the above examples, the one or more flush flow rates may be calculated using: an estimated or measured steady-state fluid velocity of cerebrospinal fluid in the patient's intrathecal space between the first location and the target region, divided into one or more axial sections; and an estimated or measured axial cross-sectional area of ​​the one or more axial sections. Optionally, the one or more flush flow rates may be based on an average steady-state fluid velocity or a maximum steady-state fluid velocity in the one or more axial sections. Optionally, the one or more flush flow rates may be calculated using a predetermined percentage of the average steady-state fluid velocity or the maximum steady-state fluid velocity in the one or more axial sections.

[0007] In the above examples, the at least one of the patient's anatomical or physiological data may include one or more of the patient's age, the patient's sex, the patient's size, the patient's CSF volume, the patient's CSF dynamics, the patient's respiratory data, the patient's sleep data, the patient's anatomical geography, heart rate, or disease. Optionally, the one or more steady-state fluid velocities may be estimated by a central nervous system computational or in vitro model for the patient using the at least one of the patient's anatomical or physiological data as an input.

[0008] In the above example, the volume of flush fluid may correspond to a volume of cerebrospinal fluid between the first location and the target region. Optionally, the method may include imaging the patient to determine the volume of cerebrospinal fluid between the first location and the target region.

[0009] In the above examples, the method may include one or more of the following options: at least one of the patient's anatomical or physiological data may include data obtained from imaging and testing of the patient and calculations performed on the patient's imaging and testing; the target region may be the brain, the spinal column, or a combination thereof; the method may include measuring the patient's CSF pressure with a pressure sensor and ceasing injection of flush fluid or reducing one or more flush flow rates in response to determining that the CSF pressure exceeds or falls below a predetermined threshold; the method may include measuring the patient's CSF pressure with a pressure sensor and initiating injection of flush fluid in response to determining that the CSF pressure exhibits an ascending or descending phase of the waveform; the second location may be spaced caudally from the first location; or the first location and the second location may be in the same region of the intrathecal space.

[0010] In the above example, the method may include creating an access opening in the patient's lumbar region into the intrathecal space, inserting a catheter through the access opening, and threading the catheter rostrally within the intrathecal space, where injection of a therapeutic bolus and a flush fluid is performed through the catheter. In one option, the catheter may include a first lumen having a first fluid port and a second lumen having a second fluid port, the second fluid port spaced proximally from the first fluid port, and threading the catheter rostrally within the intrathecal space positions the first fluid port at a first location within the lumbar region to the cisterna magna region for injection of a therapeutic bolus, and positions the second fluid port at a second location within the lumbar region to the cisterna magna for injection of a flush fluid. Optionally, passing the catheter rostrally within the intrathecal space may position a first fluid port at a first location in the thoracic region up to the cervical region of the intrathecal space for injection of a therapeutic bolus, and a second fluid port at a second location in the lumbar region up to the cervical region of the intrathecal space for injection of a flush fluid; and / or passing the catheter rostrally within the intrathecal space may include moving a first lumen relative to a second lumen within the intrathecal space. In another option, the catheter may include a single lumen having a distal fluid port, and passing the catheter rostrally within the intrathecal space may include positioning a distal fluid port at a first location in the lumbar region up to the cisterna magna region for injection of a therapeutic bolus, and withdrawing the catheter to position a distal fluid port at a second location in the lumbar region up to the cisterna magna for injection of a flush fluid. Optionally, passing the catheter rostrally within the intrathecal space may include positioning a distal fluid port at a first location in the thoracic region up to the neck for injection of a therapeutic bolus, and withdrawing the catheter and positioning a distal fluid port at a second location in the lumbar region for injection of a flush fluid.

[0011] In some of the above examples, the method may include creating an access opening into the intrathecal space in the patient's lumbar region with an introducer needle, inserting a catheter through the access opening, and passing the catheter rostrally into the intrathecal space, where injection of a treatment bolus is performed through the introducer needle and injection of a flush fluid is performed through the catheter.

[0012] In some of the above examples, the method may include creating an access opening into the intrathecal space in the patient's lower back using a lumbar puncture needle, and injections of treatment bolus and flush fluids are performed in the lower back through the lumbar puncture needle.

[0013] In the above examples, the method may include one or more of the following options: injecting a flush fluid may include injecting an artificial cerebrospinal fluid or an anti-inflammatory fluid into the patient's intrathecal space at the second location at one or more flush flow rates; the method may include positioning the patient in a head-up tilted orientation prior to injection of the treatment bolus and injection of the flush fluid; the method may include positioning the patient in a head-down tilted orientation prior to injection of the treatment bolus and injection of the flush fluid, and the treatment bolus may include a buffer that is at least one of a temperature cooler than the patient's cerebrospinal fluid and a density greater than the patient's cerebrospinal fluid; at least one of the treatment bolus or the flush fluid may include an imaging agent; the treatment bolus may include a nucleic acid, a protein therapeutic, a cell therapy, a small molecule therapeutic, a viral vector encoding a therapeutic protein, or a combination thereof, and optionally the treatment bolus may include an antisense oligonucleotide, a cellular therapeutic, a small molecule therapeutic, a viral vector encoding a therapeutic protein, or a combination thereof. The therapeutic bolus may comprise a nucleic acid selected from the group consisting of a nucleotide, a ribozyme, miRNA, siRNA and shRNA, or a nucleic acid encoding a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (Cas) system, or a combination thereof; alternatively, the therapeutic bolus may comprise an antisense oligonucleotide targeting an mRNA encoding Huntington protein (HTT) or an antisense oligonucleotide targeting an mRNA encoding survival motor neuron-2 (SMN2); the therapeutic bolus may comprise an adeno-associated virus (AAV) vector DNA sequence, a recombinant AAV particle, or a combination thereof, optionally the AAV vector DNA sequence targets an mRNA encoding the MECP2 gene; alternatively, the therapeutic bolus may be injected according to a therapeutic platform having one of the following conventional gene replacement, x-reactivation, exon skipping or promoter modulation.

[0014] According to a second example, a method for fluid delivery to a target region in a patient's central nervous system is described, the method including injecting a therapeutic bolus into the patient's intrathecal space at a first location, and subsequently injecting a flush fluid into the patient's intrathecal space at a second location at one or more flush flow rates. The volume of the flush fluid corresponds to a volume of cerebrospinal fluid (CSF) between the first location. Optionally, the method may include imaging the patient to determine a volume of cerebrospinal fluid between the first location and the target region.

[0015] In the above examples, the one or more flush flow rates may be based on at least one of the patient's anatomical or physiological data. Optionally, the one or more flush flow rates may be calculated using an estimated or measured steady-state fluid velocity of cerebrospinal fluid in the patient's intrathecal space between the first location and the target region, which is divided into one or more axial sections, and an estimated or measured axial cross-sectional area of ​​the one or more axial sections. Optionally, the one or more flush flow rates may be based on an average steady-state fluid velocity or a maximum steady-state fluid velocity in the one or more axial sections, and further, if desired, the one or more flush flow rates may be calculated using a predetermined percentage of the average steady-state fluid velocity or the maximum steady-state fluid velocity in the one or more axial sections. Optionally, at least one of the patient's anatomical or physiological data may include data obtained from imaging and testing of the patient and calculations performed on the patient's imaging and testing;optionally, at least one of the patient's anatomical or physiological data may include one or more of the patient's age, the patient's sex, the patient's size, the patient's CSF volume, the patient's CSF dynamics, the patient's respiratory data, the patient's sleep data, the patient's anatomical geography, heart rate, or disease.Furthermore, if desired, the steady-state fluid velocity may be estimated by a central nervous system computational or in vitro model for the patient using at least one of the patient's anatomical or physiological data as input.

[0016] In the above examples, the method may include one or more of the following: the target region may be the brain, the spinal column, or a combination thereof; the method may include measuring the patient's CSF pressure with a pressure sensor and ceasing injection of flush fluid or reducing one or more flush flow rates in response to determining that the CSF pressure exceeds or falls below a predetermined threshold; the method may include measuring the patient's CSF pressure with a pressure sensor and initiating injection of flush fluid in response to determining that the CSF pressure exhibits an ascending or descending phase of the waveform; the second location may be spaced caudally from the first location; or the first location and second location may be in the same region of the intrathecal space.

[0017] In the above example, the method may include creating an access opening in the patient's lumbar region into the intrathecal space, inserting a catheter through the access opening, and passing the catheter rostrally within the intrathecal space, where injection of a therapeutic bolus and a flush fluid is performed through the catheter. Optionally, the catheter may include a first lumen having a first fluid port and a second lumen having a second fluid port, the second fluid port spaced proximally from the first fluid port, and passing the catheter rostrally within the intrathecal space positions the first fluid port at a first location within the lumbar region to the cisterna magna region for injection of a therapeutic bolus, and positions the second fluid port at a second location within the lumbar region to the cisterna magna for injection of a flush fluid. Optionally, passing the catheter rostrally within the intrathecal space may position a first fluid port at a first location in the thoracic region up to the cervical region of the intrathecal space for injection of a therapeutic bolus, and a second fluid port at a second location in the lumbar region up to the cervical region of the intrathecal space for injection of a flush fluid. Optionally, passing the catheter rostrally within the intrathecal space may include moving a first lumen relative to a second lumen within the intrathecal space. In another option, the catheter may include a single lumen with a distal fluid port, and passing the catheter rostrally within the intrathecal space may include positioning a distal fluid port at a first location in the lumbar region up to the cisterna magna region for injection of a therapeutic bolus, and withdrawing the catheter to position a distal fluid port at a second location in the lumbar region up to the cisterna magna for injection of a flush fluid. Optionally, passing the catheter rostrally within the intrathecal space may include positioning a distal fluid port at a first location in the thoracic region up to the neck for injection of a therapeutic bolus, and withdrawing the catheter and positioning a distal fluid port at a second location in the lumbar region for injection of a flush fluid.

[0018] In some of the above examples, the method may include creating an access opening into the intrathecal space in the patient's lumbar region with an introducer needle, inserting a catheter through the access opening, and passing the catheter rostrally into the intrathecal space, where injection of a treatment bolus is performed through the introducer needle and injection of a flush fluid is performed through the catheter.

[0019] In some of the above examples, the method may include creating an access opening into the intrathecal space in the patient's lower back using a lumbar puncture needle, and injections of treatment bolus and flush fluids are performed in the lower back through the lumbar puncture needle.

[0020] In the above examples, the method may include one or more of the following: injecting a flush fluid may include injecting an artificial cerebrospinal fluid or an anti-inflammatory fluid into the patient's intrathecal space at the second location at one or more flush flow rates; the method may include positioning the patient in a head-up tilted orientation prior to injection of the treatment bolus and injection of the flush fluid; the method may include positioning the patient in a head-down tilted orientation prior to injection of the treatment bolus and injection of the flush fluid, and the treatment bolus may include a buffer that is at least one of a temperature cooler than the patient's cerebrospinal fluid and a density greater than the patient's cerebrospinal fluid; at least one of the treatment bolus or the flush fluid may include an imaging agent; the treatment bolus may include a nucleic acid, a protein therapeutic, a cell therapy, a small molecule therapeutic, a viral vector encoding a therapeutic protein, or a combination thereof; the treatment bolus may include an antisense oligonucleotide, a ligand, a ligand-binding domain ... The therapeutic bolus may comprise a nucleic acid selected from the group consisting of a ribozyme, miRNA, siRNA and shRNA, or a nucleic acid encoding a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (Cas) system, or a combination thereof, and optionally the therapeutic bolus may comprise an antisense oligonucleotide targeting an mRNA encoding the Huntington protein (HTT) or an antisense oligonucleotide targeting an mRNA encoding survival motor neuron-2 (SMN2); the therapeutic bolus may comprise an adeno-associated virus (AAV) vector DNA sequence, a recombinant AAV particle, or a combination thereof, and optionally the AAV vector DNA sequence may target an mRNA encoding the MECP2 gene; alternatively, the therapeutic bolus may be infused according to a therapeutic platform having one of the following: conventional gene replacement, x-reactivation, exon skipping, or promoter modulation.

[0021] According to a third example, a fluid delivery system is described, the fluid delivery system including a pump device, the pump device including a first syringe configured to contain a treatment bolus, a second syringe configured to contain a flush fluid, and one or more drivers configured to cause the treatment bolus and the flush fluid to be ejected from the first and second syringes, respectively. The fluid delivery system further includes a fluid delivery device fluidly coupled to the syringes and a controller. The controller is configured to control operation of the pump device to eject a treatment bolus from the first syringe and deliver the treatment bolus to the fluid delivery device for a first injection into the intrathecal space of the patient at a first location, and subsequently control operation of the pump device to eject flush fluid from the second syringe and deliver flush fluid to the fluid delivery device at one or more flush flow rates for a second injection into the intrathecal space of the patient at a second location, the one or more flush flow rates being based on at least one of the patient's anatomy or physiology. Optionally, the first location can be in the lumbar region to the patient's cisternal region for injection of a therapeutic bolus, and the second location can be in the lumbar region to the patient's cisternal region for injection of a flush fluid. If desired, the first location can be in the thoracic region to the neck for injection of a therapeutic bolus, and the second location can be in the lumbar region to the neck.

[0022] In the above examples, the fluid delivery device may include a catheter, the catheter including a first lumen having a first fluid port, the first lumen sized to position the first fluid port at a first location, and the catheter including a second lumen having a second fluid port, the second lumen sized to position the second fluid port at a second location. Optionally, the first lumen may be movably received within the second lumen. Optionally, the system may include a valve configured to allow the length of the first lumen to be adjusted relative to the second lumen while maintaining a fluid seal of the second lumen.

[0023] In some of the above examples, the fluid delivery system may include an introducer needle fluidly coupled to a plurality of syringes, the introducer needle including a lumen having a fluid port, and the fluid delivery system may include a catheter, the catheter fluidly coupled to a plurality of syringes and configured to be threaded through the lumen of the introducer needle, the catheter including a lumen having a fluid port, and the controller is then configured to control operation of the pump device to eject a therapeutic bolus from the first syringe and deliver the therapeutic bolus to the catheter for a first injection through the fluid port of the catheter into the intrathecal space of the patient at a first location, and subsequently control operation of the pump device to eject flush fluid from the second syringe at one or more flush flow rates and deliver flush fluid to the introducer needle for a second injection through the fluid port of the introducer needle into the intrathecal space of the patient at a second location.

[0024] In the above examples, the fluid delivery system may include one or more of the following: the catheter may include an atraumatic tip; the second location may be spaced caudally from the first location; the first location and the second location may be in the same region of the intrathecal space; the controller may be built into the pump device; and the system may include a display configured to provide a user interface.

[0025] In some of the above examples, the fluid delivery device may include a lumbar puncture needle fluidly coupled to a plurality of syringes, the lumbar puncture needle including a lumen having a fluid port, and the controller is then configured to control operation of the pump device to eject a therapeutic bolus from a first syringe and deliver the therapeutic bolus to the lumbar puncture needle for a first injection through the fluid port of the lumbar puncture needle into the intrathecal space of the patient at a first location, and to control operation of the pump device to eject flush fluid from a second syringe at one or more flush flow rates and deliver flush fluid to the lumbar puncture needle for a second injection through the fluid port of the lumbar puncture needle into the intrathecal space of the patient at a second location.

[0026] In the above examples, the fluid delivery system may include a pressure sensor configured to measure the patient's cerebrospinal fluid (CSF) pressure, and the controller is configured to communicate with the pressure sensor and at least one of: stop the first infusion or the second infusion in response to determining that the CSF pressure exceeds a predetermined threshold, reduce one or more flush flow rates in response to determining that the CSF pressure exceeds a predetermined threshold, or initiate the second infusion in response to determining that the CSF pressure exhibits an ascending or descending phase of the waveform. Optionally, the pressure sensor may be aligned with or coupled to the catheter along its length so as to be positioned within the patient's intrathecal space.

[0027] In the above example, the one or more flow rates may be calculated using an estimated or measured steady-state fluid velocity of cerebrospinal fluid in the intrathecal space of the patient between the first location and the target region divided into one or more axial sections, and an estimated or measured axial cross-sectional area of ​​the one or more axial sections. Optionally, the one or more flush flow rates may be based on an average steady-state fluid velocity or a maximum steady-state fluid velocity in the one or more axial sections. Furthermore, if desired, the one or more flush flow rates may be calculated using a predetermined percentage of the average steady-state fluid velocity or the maximum steady-state fluid velocity in the one or more axial sections. Optionally, at least one of the patient's anatomical or physiological data may include data obtained from imaging and testing of the patient and calculations performed on the imaging and testing of the patient, and / or the patient's age, the patient's sex, the patient's size, the patient's CSF volume, the patient's CSF dynamics, the patient's respiratory data, the patient's sleep data, the patient's anatomical geography, heart rate, or disease. Optionally, the steady-state fluid velocity may be estimated by a central nervous system computational or in vitro model for the patient, using at least one of the patient's anatomical or physiological data as input.

[0028] In the above examples, the fluid delivery system may include one or more of the following: the target area may be the brain, spinal column, or a combination thereof; the flush fluid may be an artificial cerebrospinal fluid or an anti-inflammatory fluid; the treatment bolus may include a buffer that is at least one of a temperature cooler than the patient's cerebrospinal fluid and / or denser than the patient's cerebrospinal fluid; at least one of the treatment bolus or the flush fluid may include an imaging agent; the treatment bolus comprises a nucleic acid, a protein therapeutic, a cell therapy, a small molecule therapeutic, a viral vector encoding a therapeutic protein, or a combination thereof, optionally the treatment bolus comprises a nucleic acid selected from the group consisting of antisense oligonucleotides, ribozymes, miRNA, siRNA, and shRNA, or a clustered regularly interspaced short palindromic sequence. The therapeutic bolus may comprise a nucleic acid encoding a critical intracellular repeat (CRISPR) associated protein (Cas) system, or a combination thereof, or the therapeutic bolus may comprise an antisense oligonucleotide targeting an mRNA encoding Huntington protein (HTT) or an antisense oligonucleotide targeting an mRNA encoding survival motor neuron-2 (SMN2); the therapeutic bolus may comprise an adeno-associated virus (AAV) vector DNA sequence, a recombinant AAV particle, or a combination thereof, optionally the AAV vector DNA sequence targets an mRNA encoding the MECP2 gene; or the therapeutic bolus may be injected according to one of the therapeutic platforms having conventional gene replacement, x-reactivation, exon skipping, or promoter modulation.

[0029] According to a fourth example, a catheter is described, the catheter including a first lumen having a first fluid port and a second lumen having a second fluid port, the second lumen having an annular configuration with a distal opening sized to telescopically receive the first lumen therethrough. Optionally, the distal tips of the first and second lumens may have an atraumatic configuration; the catheter may include a pressure sensor coupled along its length for positioning within a patient during use of the catheter; and / or the catheter may include a valve configured to allow the length of the first lumen to be adjusted relative to the second lumen while maintaining a fluid seal of the second lumen. [Brief description of the drawings]

[0030] [Figure 1] FIG. 1 is a diagram of an exemplary fluid delivery system, according to various embodiments. [Diagram 2] FIG. 2 is a cross-sectional view of an exemplary pump device for a fluid delivery system, according to various embodiments. [Diagram 3] FIG. 3 is a cross-sectional view of a distal tip of a catheter for a fluid delivery system, according to various embodiments. [Figure 4] FIG. 4 is a cross-sectional view of a catheter having first and second lumens in a telescopic relationship relative to one another, according to various embodiments. [Diagram 5] FIG. 5 is a cross-sectional view of a catheter having first and second lumens in side-by-side relationship, according to various embodiments. [Figure 6] FIG. 6 is a cross-sectional view of a needle having a lumen and a catheter passed through the lumen of the needle, according to various embodiments. [Figure 7] FIG. 7 is a cross-sectional view of a lumbar puncture needle and a portion of the intrathecal space, according to various embodiments. [Figure 8] FIG. 8 is a perspective view of a plug-in port for attachment to a patient's bone, according to various embodiments. [Figure 9]FIG. 9 is a schematic diagram of the plug-in port of FIG. 8 attached to a bone to access the intramedullary space. [Figure 10] FIG. 10 is a diagram of an axial cross section of the central nervous system for determining an infusion flow rate based on average steady state fluid velocity, according to various embodiments. [Figure 11] FIG. 11 is a diagram of an axial cross section of the central nervous system for determining an infusion flow rate based on maximum steady-state velocity, according to various embodiments. [Figure 12] FIG. 12 is a diagram of the central nervous system showing exemplary cross-sectional drug masses following lumbar puncture injection. [Figure 13] FIG. 13 is a diagram of the central nervous system showing an exemplary cross-sectional drug mass after algorithmic injection, according to various embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Detailed Description The systems and methods described herein are configurable central nervous system (CNS) delivery solutions for therapeutic agents such as genetic medicines. In addition to the therapeutic bolus delivered into the intrathecal space, the systems and methods described herein utilize a flush that can be performed caudal to the delivery location of the therapeutic bolus to move the therapeutic bolus rostrally toward the target area such as the brain, spinal column, or both, and achieve the desired spread in the spinal column and / or brain. Advantageously, the configuration and delivery location of the flush can be configured to deliver more than 100 times the therapeutic dose to the brain than typical intrathecal drug delivery via lumbar puncture, and reduce the drug dose to the spinal cord by 100 times compared to lumbar puncture. The flush can also be configured to allow a larger amount of the therapeutic bolus to move rostrally from the delivery location and thus spread in the spinal column and brain, or can be configured to deliver the therapeutic bolus entirely to the spinal column by limiting the extent or location of the flush (caudal vs. rostral, or vice versa). Thus, the system and method can be customized for different therapies to deliver drugs or other therapeutic agents to desired regions of the spine and / or brain in desired amounts. The system and method can be customized to be patient or group specific and can be customized for a particular therapy. For example, the location and injection of the fluid delivery device can be based on one or more of the patient's age, patient's sex, patient's size, patient's CSF volume, patient's CSF dynamics and breathing or sleep, patient's anatomical geography, heart rate, or physiological parameters such as illness.

[0032] The systems and methods may include a first injection of a therapeutic bolus at a first location from the lumbar region to the cisternal region, followed by a second injection of a flush fluid at a second location from the lumbar region to the cisternal region. In one example, the second injection may be performed at one or more flush flow rates based on at least one of anatomical or physiological data of the patient. In another example, the second injection may be of a volume corresponding to a CSF volume between the target region for the therapeutic bolus and the first location.

[0033] 1-5 illustrate an exemplary fluid delivery system 100 suitable for the methods of treatment described herein. The exemplary system 100 includes a pump device 102, a fluid delivery device 104, such as a catheter and / or needle, and a controller 108 configured to control infusion through the fluid delivery device 104 by operation of the pump device 102, optionally including a pressure sensor. In some examples, the controller 108 may be further configured to monitor CSF pressure, such as intrathecal and intracranial pressure, during infusion based on data from the optional pressure sensor 106. The controller 108 may be a component of the pump device 102 or may be a separate component, as desired.

[0034] 1 is an example of a pump device 102 constructed according to the teachings of the present disclosure and positioned near a patient 110 to perform infusion of fluid through an access location 112 in the patient 110. For example, the access location 112 may be a lumbar puncture hole to access an intrathecal space 114 of the patient 110. Once the pump device 102 is fluidly coupled to the intrathecal space 114 via the catheter 104, a clinician would activate the pump device 102 to begin delivery (i.e., infusion) of fluid to the intrathecal space 114. Notably, once activated, the pump device 102 delivers fluid to the intrathecal space 114 based on a programmed algorithmic injection profile, which will be described in more detail below. It will be appreciated that the pump device 102 may be programmed with algorithmic injection developed off-site or on-site.

[0035] 2 shows further details about an exemplary pump device 102. The pump device 102 in this example generally includes a housing 116, a number of syringes 118 adapted to be carried by (e.g., partially disposed within) the housing 116 and fluidly coupled to the intrathecal space 114. In this example, the housing 116 may have a tabletop configuration or a handheld configuration, as desired.

[0036] In the embodiment shown, the pump device 102 may include two syringes 118 carried by and partially disposed within the housing 116. Of course, it will be understood that the multiple syringes 118 may include more than two syringes 118 (e.g., three or four syringes 118). In either case, each of the multiple syringes 118 includes a barrel 120 that is partially disposed within the housing 116 and adapted to hold and / or receive a fluid relying on an injection or aspiration action, each of the multiple syringes 118 includes a plunger rod 122 movably disposed within the barrel 120, and includes a stopper 124 adjacent to or attached to a proximal end of the plunger rod 122 and disposed within the barrel 120. At least one actuator 126 disposed within the housing 116 is coupled to the multiple syringes 118. The pump device 102 may include multiple actuators 126, one coupled to each of the multiple syringes 118, such that in the illustrated example, two actuators 126 are employed. However, in other examples, more or fewer actuators 126 may be employed. Each actuator 126 may include a driver 128 that is operably coupled to the plunger rod 122 to drive its movement via a connecting structure such as a shaft, gear train, or the like. Among other things, the driver 128 controls the position of the plunger rod 122, which in turn controls the flow of fluid to and / or from the intrathecal space 114 by translating the plunger rod 122 and the stopper 124 toward or away from the proximal end of each barrel 120.

[0037] As explained above, the system 100 also includes a controller 108 for controlling operation of the pump device 102 and, optionally, monitoring data from the pressure sensor 106. The controller 108 may be disposed within the housing 106, e.g., internally, or may be external and in communication with the pump device 102. The controller 108 is communicatively coupled to and controls the position of the actuator 126, which ultimately controls the movement of the plunger rod 122 to inject fluid into and / or aspirate fluid from the intrathecal space 114.

[0038] The controller 108 includes a processor 130 that implements algorithmic injection stored in the memory 132 of the controller 108. The algorithmic injection stored in the memory 132 includes an injection protocol for at least one of the syringes 118. Generally speaking, the processor 130 communicates with the actuators 126 to effectuate the algorithmic injection. For example, the controller 108 may be communicatively coupled to the actuators 126 using a hardware-implemented scheme that may include the use of any desired hardware, software, and / or firmware to implement the hardware-implemented communications, including, for example, any communication using standard 4-20 mA communications and / or any smart communications protocols such as FOUNDATION® Fieldbus communications protocols, HART® communications protocols, RS-485, RS-232, and the like. In another example, the controller 108 may be communicatively coupled to the actuators 126 using a wireless communications scheme facilitated using the wireless HART® protocol, the Ember protocol, the WiFi protocol, IEEE wireless standards, and the like.

[0039] The processor 130 may be a general purpose processor, a digital signal processor, an ASIC, a field programmable gate array, a graphic processing unit, an analog circuit, a digital circuit, or any other known or later developed processor. The processor 130 operates according to algorithmic instructions stored in the memory 132. The memory 132 may be a volatile or non-volatile memory. The memory 132 may include one or more of read only memory ("ROM"), random access memory ("RAM"), flash memory, electronically erasable programmable read only memory ("EEPROM"), or other types of memory. The memory 132 may include optical, magnetic (hard drive), or any other form of data storage.

[0040] The algorithmic injection is a set of executable instructions that control at least one of the syringes 118 to facilitate injection of a plurality of fluids 134, 136 into the patient 110 using the pump device 102. The algorithmic injection may be stored in the memory 132 as computational logic 138 including one or more injection and aspiration routines or subroutines embodied as computer readable instructions stored in the memory 132. The controller 108, and in particular its processor 130, executes the logic 138 to cause the processor 130 to derive the algorithmic injection and to control the actuator 126 in accordance with the algorithmic injection to facilitate the desired injection and / or aspiration of a particular fluid 134, 136 into the patient 110. In particular, the algorithmic injection may identify, among other parameters, whether each syringe 118 should inject fluid 134, 136 into the intrathecal space 114 (or whether it should aspirate fluid 134, 136 from the intrathecal space 114), the timing of injection and / or aspirate (i.e., when the plunger rod 122 should be moved), the volume of fluid 134, 136 to be injected from the barrel 120 into the intrathecal space 114, the flow rate for injecting fluid 134, 136 from the barrel 120 into the intrathecal space 114, the volume of fluid 134, 136 to be aspirated from the intrathecal space 114 into the barrel 120, and the flow rate for aspirating fluid 134, 136 from the intrathecal space 114 into the barrel 120.

[0041] In some cases, algorithmic infusion may be stored in memory external to the controller 108 and sent to the controller 108 prior to operation of the pump device 102. For example, algorithmic infusion may be stored in memory of a desktop computer that communicates with the controller 108 wirelessly using any of the wireless communication protocols or hardware-implemented communication protocols described above, or through a hardware-implemented connection. In other examples, infusion and aspiration profiles may be stored in memory of a mobile electronic device, smartphone, or server located remotely from the controller 108. Additionally, algorithmic infusion may be stored in external memory and transferred to the memory 132 of the controller 108 through a hardware-implemented connection. For example, algorithmic infusion may be stored on an external hard drive, solid state drive ("SSD"), portable digital storage device, cloud, personal cloud, or USB flash drive, and then transferred to the memory 132.

[0042] An exemplary hand-held automatic infusion pump device is disclosed in US Pat. No. 10,675,438, which is incorporated herein by reference in its entirety.

[0043] 1 and 3-6 illustrate an exemplary fluid delivery device 104 suitable for the systems and methods described herein. As described in more detail below, an exemplary algorithmic injection may include a first injection of a first fluid at a first location and a second injection of a second fluid at a second location caudal to the first location. In one example, the first location may range from the lumbar to the cisternal region of the patient. In another example, the first location may range from the thoracic to the cervical region of the patient. In one example, the second location may range from the lumbar to the cisternal region of the patient. In another example, the second location may range from the lumbar to the cervical region of the patient.

[0044] In some examples, the fluid delivery device 104 may be a catheter 104a. In these examples, the catheter 104a may be insertable and include an atraumatic tip 140 for implanting the catheter 104a within the intrathecal space 114 and threading the tip 140 to a desired location along the spinal column. For example, the tip 140 may have a tapered configuration (e.g., a frusto-conical shape with a distal port) or a curved configuration for atraumatic insertion. The catheter 104a may include one or more fluid ports 142 at its tip 140 to distribute fluid rostrally within the intrathecal space 114. The fluid ports 142 may optionally include a distal port extending axially through the tip 140 and / or one or more lateral ports extending through a sidewall of the catheter 104a.

[0045] In a first example, the catheter 104a may include a single lumen 144 with a fluid port 142 at the tip 140 of the catheter 104a. In this configuration, a clinician may pass through the catheter 104, place the catheter tip 140 at a first location, inject a first fluid, withdraw the catheter 104a, place the catheter tip 140 at a second location, and inject a second fluid.

[0046] In other configurations shown in Figures 3-5, the catheter 104a may include a second lumen 146 having a second fluid port 148 spaced rearward along the length of the catheter 104a from the tip 140. The first and second lumens 144, 146 may be aligned as desired or may be concentric (e.g., the first lumen 144 extends within the second lumen 146). Additionally, the first and second lumens 144, 146 and their fluid ports 142, 148 may be fixed relative to one another. Alternatively, the first and second lumens 144, 146 may be movable relative to one another. For example, as shown in Figure 4, the second lumen 146 may have an annular configuration with a distal outlet 149 sized to receive the first lumen 144 therethrough such that the first lumen 144 may be telescopic relative to the second lumen 146. An advantage of the movable lumens 144, 146 is that the catheter 104a can accommodate different patient-specific intrathecal lengths to position the first and second ports 142, 148 where desired.

[0047] 3-5, when a dual lumen catheter 104a is used, the second lumen 146 can have an associated atraumatic tip 150. For example, the second tip 150 can also have a tapered configuration (e.g., a frustoconical shape with a distal port and / or with the inner lumen 144 extending therethrough) or a curved configuration for atraumatic insertion.

[0048] For catheters 104a having lumens 144, 146 that are movable relative to one another, system 100 may have a valve 152 (FIG. 1) that allows the length of the first, or inner, lumen 144 to be adjusted within the intrathecal space relative to the second, or outer, lumen 146 while maintaining a fluid seal with the second, or outer, lumen 146. For example, valve 152 may be a Tuohy-Borst hemostatic valve that passes the first, or inner, lumen 144 into the second, or outer, lumen 146.

[0049] In some forms, one or both lumens 114, 146 may be lined with one or more suitable materials to mitigate adhesion of certain drugs or other fluids to be dispensed therethrough. For example, for lumens 114, 116 intended to dispense AAV, the lumens 114, 116 may be made of, include an inner layer of, or be lined with polytetrafluoroethylene (PTFE) to mitigate AAV adhesion. Other suitable compatible materials may alternatively be utilized.

[0050] In one example, the overall usable length of catheter 104a can be from 12 inches to 45 inches, with the inner lumen length adjustable from 0" to 6.3" (16 cm). In one example, the inner lumen can be 0.0155" to fit a 0.14 guidewire, or smaller for a 0.010 guidewire.

[0051] 6, the fluid delivery device 104 may also include an introducer needle 104b configured to guide the catheter 104a through the access location 112 and into the intrathecal space 114. The introducer needle 104b includes a lumen 160 through which the catheter 104a may be threaded to position the distal tip 140, 150 at a desired location within the intrathecal space 114. In some examples, the introducer needle 104b may be utilized to inject a first fluid and / or a second fluid. For example, a distal port 162 of the needle lumen 160 may be utilized to inject a flush fluid at the second location as described herein.

[0052] 7, the fluid delivery device 104 may be a lumbar puncture needle 104b configured to be inserted through the access location 112 into the intrathecal space 114. With this configuration, a clinician may position the port 162 to inject a first fluid and subsequently insert the needle 104b to inject a second fluid. In this example, the first and second locations may be within the same region of the intrathecal space.

[0053] In another example, as shown in Figures 8 and 9, the system 100 may include a plug-in port 105. The plug-in port 105 may be attached for access to any desired CNS location, including intraventricular (ICV) or intracisternal (ICM) from the lumbar, thoracic, cervical or intracranial. The plug-in port 105 may include a head portion 170 having one septum 170 or multiple septums 172, such as two, three or four, coupled thereto. The septum 172 is configured to prevent fluid flow through the port 105 from the CNS location while receiving a needle 104b therethrough for the introduction of a fluid, such as a therapeutic bolus or flush fluid as described herein. The plug-in port 105 may be subcutaneous and accessible through the patient's skin or may have a septum exposed through the patient's skin.

[0054] As shown, the plug-in port 105 may include an anchor portion 174 extending from a head portion 170 that allows the port 105 to be attached to a bone (such as a vertebra) of a patient. The head portion 170 may have a larger radial dimension than the anchor portion 174 such that the head portion 170 includes an outwardly protruding structure configured to abut a bone. For example, the head and anchor portions 170, 174 may be cylindrical as shown, and the anchor portion 174 may have a smaller diameter than the head portion. A bore or conduit 178 extends through the port 105 along its longitudinal length, with a first end adjacent the septum 172 and an opposite second end providing one or more fluid outlets 180 through the anchor portion 174. The fluid outlets 180 may be oriented to distribute fluid parallel to the longitudinal axis as shown, and / or may extend radially through the anchor portion 174.

[0055] In one form, the anchor portion 174 may be sized to be inserted through the bone such that its distal tip 176 is inserted into the desired CNS location, such as through the dura into the intrathecal space 114 or other CNS location. In another example, the port 105 may further include a flexible catheter or cannula 182 extending from the fluid outlet 180 and fluidly connected to the conduit 178. In this form, the catheter 182 may be inserted through the dura and threaded in a desired direction to direct fluid flow in a desired path within the intrathecal space 114 or other CNS location. In another example, the clinician may insert the entire needle 104b through the port 105 and use the needle 104b to directly access the intrathecal space 114 or other CNS location. With any of these configurations, a clinician inserts needle 104b through septum 172 to access conduit 178 and dispense a desired amount of fluid, such as a therapeutic bolus and / or flush fluid, which is then dispensed into the intrathecal space 114 or other CNS location. Port 105 allows the clinician to have repeatable and reliable access to the desired CNS location.

[0056] In one example, the anchor portion 174 may have a screw or drill configuration, as shown in FIGURE 8, such that a clinician may rotate the port 105 during installation to screw the port 105 into the bone and secure the port 105 in place. In another example, rather than a screw anchor portion 174, the port 105 may be secured to the bone over a burr hole extending through the bone with a screw or other fastening member, and the anchor portion 174 may telescope from the head portion 170 through the burr hole to insert the tip portion 176 into the intrathecal space or other CNS location. For example, telescopic movement of the anchor portion 174 may be driven by the needle 104b.

[0057] As shown in FIGS. 1, 3 and 4, the pressure sensor 106 may be provided between the pump device 102 and the catheter 104, or may be embedded in or attached to the catheter 140a. For example, the pressure sensor 106 may be positioned along the usable length of the catheter 104a that will be disposed within the intrathecal space 114, thereby measuring the CSF pressure, for example, at the tip 140, 150. Using any configuration, the pressure sensor 106 may provide the CSF pressure data to the controller 108. The controller 108 may then monitor the pressure data to monitor for safety and maintain the intracranial pressure (ICP) within a desired therapeutic range (e.g., 5-15 mmHg) that may affect the CSF outflow pathway (e.g., nerve root sleeve, cribriform plate, olfactory nerve, internal ear canal, and arachnoid granulation a). For example, controlling intracranial pressure (ICP) within a desired therapeutic range may improve perfusion of a therapeutic bolus to brain / CNS tissue while also limiting leakage through undesired pathways, because ICP above a certain amount may increase leakage through outflow pathways and reduce penetration of the therapeutic bolus into the CNS tissue. Thus, the controller 108 may be configured to stop infusion of the first and / or second fluid or reduce the rate of infusion in response to determining that the CSF pressure data exceeds or falls below the therapeutic range. Additionally or alternatively, the controller 108 may be configured to monitor the CSF pressure data to identify a waveform and initiate infusion of the first and / or second fluid with the rising or falling phase of the waveform.

[0058] The pressure sensor 106 electronically communicates with the controller 108 using any known electronic communication method. For example, the controller 108 may be communicatively coupled to the sensor 106 using the hardware-implemented communication schemes detailed above, using one or more known wireless communication protocols, or using a combination thereof. Among others, communication between the controller 108 and the sensor 106 may be facilitated using the WirelessHART® protocol, the Ember protocol, the WiFi protocol, IEEE wireless standards, and the like. These communication protocols may employ protocol stack operations to receive, decode, route, code, and transmit wireless signals via an antenna to implement wireless communication between the controller 108 and the sensor 106.

[0059] Additionally, the pressure data may be stored in memory 132. The controller 108 may also be communicatively coupled to an external computing device that may, for example, compare the measured pressure data to a threshold pressure to determine whether the measured pressure data is within an acceptable threshold range. For example, the external computing device may be a desktop computer, a tablet, a mobile phone, a server, etc.

[0060] In some examples, the system 100 may include a display 154 (FIG. 1) to communicate information regarding the infusion of the first and second fluids to a clinician or other user. The display 154 may be utilized to dynamically show pressure data measured by the pressure sensor 106. The display 154 may also be a touch screen to facilitate interaction with the patient and clinician through a user interface ("UI"). Among other things, the UI may display the operational status of the pump device 102 (e.g., on, off, infuse, aspirate, infuse and aspirate, etc.) and may receive input from the patient and / or clinician. The UI may, for example, allow the clinician to start, stop, pause, or continue operation of the pump device 102. The UI may also allow the clinician to pre-program the pump device 102 prior to its use and may receive other input from the clinician, such as, for example, modifications to the infusion and aspirate profiles during operation of the pump device 102. The display 154 may be located on the housing 116 of the pump device 102, as desired, or may be a separate component.

[0061] 1, system 100 may include any components required to fluidly couple pump device 102 and its syringe 118 with lumens 144, 146 and optionally valve 152 of fluid delivery device 104. For example, system 100 may include tubing 156, connectors 158, such as Luer connectors, and strain relief jackets or members for various connections in system 100.

[0062] 10 and 11 show some of the algorithm steps for determining the location of therapeutic bolus delivery within the intrathecal space 114, the therapeutic bolus delivery target area and an injection protocol for a therapeutic bolus followed by flush fluid based on one or more input parameters. The input parameters can be one or more of the following: patient age, patient size, patient CSF volume, patient CSF dynamics, patient anatomical geography, optionally including nerve roots, patient physiological parameters such as heart rate, breathing or sleep, patient anatomical geography or disease, including disease stage or condition. One or more of the input parameters can be estimated according to corresponding patient group data to which the patient is matched or patient specific data obtained by imaging or other tests, including calculations performed on the imaging or tests. By one approach, the goal of the algorithmic injection is to obtain a predetermined percentage of the therapeutic bolus to a target area, such as the center of the brain, a specific area of ​​the brain (e.g., right hemisphere, left hemisphere, ventricular system, basal cistern and / or cerebellum), a specific area of ​​the spinal column, or a combination thereof. The flush fluid may be injected into the intrathecal space 114 a sufficient distance caudal to the therapeutic bolus delivery to ensure that the flush fluid pushes most or all of the therapeutic bolus rostrally. Alternatively, the flush fluid may be injected in the same region or location of the intrathecal space 114 as the therapeutic bolus.

[0063] In one example, after the parameters are determined, the user may create a CNS model for the patient using one of the CNS models known in the art that uses the parameters as inputs to estimate CNS fluid dynamics for the patient and provide a steady state fluid velocity of the CNS in the intrathecal space 114. Using the steady state fluid velocity data from the CNS model as input, the CNS may be divided into one or more axial sections based on the level of accuracy desired for a particular infusion. For example, the length of the axial sections may range from the length from the therapeutic bolus delivery location to the target area to an axial section having a length of about 1 mm to about 750 mm in an adult. For each axial section, an algorithm or an average steady state fluid velocity USS may be calculated / utilized for each axial section based on data from the CNS model.

[0064] The average cross-sectional area A of each particular axial section CS Using the above, the algorithm calculates the mean steady flow rate Q for a particular axial section using the following equation: SS can be determined:

[0065]

number

[0066] The algorithm can then determine the flush flow rate at each time point during the algorithmic injection based on the flow displacement from the therapeutic delivery port location along the spinal column. For example, the total flow displacement (dx) at each time step (dt) = cross-sectional area (A CS ) divided by the steady flow rate (Q SS ).

[0067] As shown in FIG. 10, these equations can be reflected as follows:

[0068]

number

[0069] With this configuration, the algorithmic injection will determine the location of therapeutic bolus delivery within the intrathecal space 114 and the Q at each location within the intrathecal space 114 until the therapeutic bolus reaches the predefined target area. SS As the fluid advances through the CNS based on the flow rate, the flush flow rate can be dynamically controlled.

[0070] In an alternative form, the algorithm may be implemented by computing the maximum steady-state fluid velocity U specified by the CNS model for each axial section. M may be utilized. The maximum value indicates the absolute peak steady-state fluid velocity around the spinal cord at a particular axial section. The steady-state fluid velocity around the spinal cord is not uniform in any axial section. If the algorithmic injection imposes a flush volume that produces a velocity greater than the maximum caudal velocity for each axial section or the greatest maximum velocity for all axial sections, no portion of the treatment bolus will travel caudally down the spinal cord.

[0071] The average cross-sectional area A of each particular axial section CS Using this, the algorithm calculates the maximum flow rate Q for a particular axial section using the following equation: M can be determined:

[0072]

number

[0073] The algorithm can then determine the flush flow rate at each time point during the algorithmic injection based on the flow displacement from the therapeutic delivery port location along the spinal column. For example, the total flow displacement (dx) at each time step (dt) = cross-sectional area (A CS ) divided by the steady flow rate (Q M ).

[0074] As shown in FIG. 11, these equations can be reflected as follows:

[0075]

number

[0076] While algorithmic injection may utilize a flush flow rate determined by the above steps based on either an average steady state fluid rate or a maximum steady state fluid rate, algorithmic injection may alternatively operate at a predetermined percentage of the steady state fluid rate based on what percentage of the therapeutic bolus is desired to reach the target location and / or based on an ICP threshold, e.g., 100-105% of a selected value, 50% of a selected value, 70% of a selected value, etc. If the selected flush flow rate is lower than the maximum, some percentage of the therapeutic bolus may potentially travel caudally down the spinal column. In addition to or as an alternative to the therapeutic bolus rate, the desired flush volume may be maintained until a CSF pressure threshold is reached, and then the flush flow rate may be reduced to maintain the CSF pressure below, at, or within the threshold range.

[0077] With this configuration, the algorithmic injection can track the location of therapeutic bolus delivery within the intrathecal space 114 and the Q at each location within the intrathecal space 114 until the therapeutic bolus reaches a predetermined target region, such as the center of the brain. M The flush flow rate may be dynamically controlled as the bolus advances through the CNS based on the algorithm. The algorithmic infusion may be personalized, as desired, to ensure that a high percentage, e.g., 80-95%, of the therapeutic bolus is delivered to the brain (i.e., rostrally focused delivery) or a low percentage, e.g., 5-20%, of the therapeutic bolus is delivered to the brain, allowing the remaining percentage to spread in the spinal column and brain as the therapeutic bolus moves rostrally from the delivery site. In fact, spread of the therapeutic bolus may be limited to the entire spinal column by flowing the therapeutic bolus only up to a cervical location.

[0078] Additionally, the total amount of flush fluid injected, i.e., flush volume, can be determined based on the location of the therapeutic bolus delivery within the intrathecal space 114. The flush volume corresponds to the CSF volume between the location of the therapeutic bolus delivery and the target area. In some instances, the CSF volume can be estimated by a CNS computational model or an in vitro model, or determined by imaging of the patient. Furthermore, the total flush time can then be calculated by dividing the flush volume by a predetermined flush amount.

[0079] Optionally, in another example, the method described herein can include injecting a volume of flush fluid into the patient's intrathecal space 114 after injection of the therapeutic bolus at one or more flush flow rates, the volume of flush fluid corresponding to the CSF volume between the location of therapeutic bolus delivery and the target area. Optionally, the method can include one or more of the examples described herein, including determining one or more flush flow rates based on at least one of the patient's anatomical or physiological data and utilizing system 100.

[0080] Returning to the system 100 described above, the algorithmic infusion may be delivered through one of the exemplary fluid delivery devices 104 using the pump device 102. For example, the first fluid port 142 of the first lumen 144 may be a therapy bolus delivery port, and the second fluid port 144 of the second lumen 146 may be a flush fluid delivery port 148. With this configuration, one syringe 118 of the pump device 102 may contain a drug 134, such as AAV, and be fluidly connected to the first lumen 144, and the other syringe 118 of the pump device 102 may contain a flush fluid 136, such as artificial CSF, and be fluidly connected to the second lumen 146. Alternatively, in an example using a catheter 104 having a single lumen 144, the catheter 104 can be withdrawn to position the first fluid port 142 at a second location for flush fluid delivery, and the syringe 118 can be sequentially connected to the first lumen 144.

[0081] For one particular algorithmic injection, the catheter 104 may be passed through a lumbar puncture access site 112 into the intrathecal space 114 to position a therapeutic delivery fluid port 142 from the lumbar to the cisternal region or from the thoracic to the cervical region, and flush fluid ports 142, 148 may be positioned in the lumbar to the cisternal region or in the lumbar to the cervical region.

[0082] Once the controller 108 has determined, received, or retrieved an algorithmic infusion, the processor 130 executes the infusion stored as computational logic 138 by executing computer readable instructions. For example, the algorithmic infusion may include instructions for the processor 130 to activate the driver 128 and inject fluids 134, 136 into the intrathecal space 114 at the therapeutic delivery location and the fluid delivery location. In such an example, the instructions may include a first instruction to expel a therapeutic bolus 134 from the first syringe 118. In response to these instructions, the driver 128 operates to drive the plunger rod 122 to move through the barrel 120 a desired amount according to the desired drug volume. Movement of the plunger rod 122 expels the therapeutic bolus 134 from the barrel 120 into the intrathecal space 114 at the therapeutic delivery location of the first fluid port 142 of the catheter 104. The commands may further include second commands to expel flush fluid 136 from the second syringe 118. In response to these commands, the driver 128 operates to drive the plunger rod 122 to move a desired amount through the barrel 120 according to a desired flush fluid volume. Movement of the plunger rod 122 expels the flush fluid 136 from the barrel 120 and into the intrathecal space 114 at the flush fluid delivery locations of the second fluid ports 142, 148 of the catheter 104.

[0083] Additionally, as the controller 108 operates the pump device 102 to deliver the therapeutic fluid 134 and the flush fluid 136 according to the algorithmic infusion, the controller 108 may also monitor the CSF pressure data received from the pressure sensor 106. In some cases, the controller 108 may then compare the measured pressure to a stored threshold pressure or range and determine whether the measured CSF pressure is greater than, less than, or equal to the stored threshold pressure. If the controller 108 determines that the measured pressure is greater than or less than the stored threshold pressure, then the controller 108 sends a stop or flush rate decrease signal to the processor 130, which causes the processor 130 to stop or control the first and / or second driver 128 to stop fluid flow from the pump device 102 or to decrease the amount of translation of the plunger rod 122 within the barrel 120, thereby decreasing the infusion flow rate.

[0084] In one example, the flush fluid 136 can be an artificial CSF or other anti-inflammatory fluid. It has been found that larger injection bolus volumes of saline can potentially result in inflammation in CNS tissue. The larger flush volumes of the methods provided herein utilizing artificial CSF or other anti-inflammatory fluids relative to previous flush methods can prevent or reduce inflammatory responses in patients.

[0085] In another example, a contrast agent, such as an imaging agent / tracer or radiological contrast agent, may be added to the treatment bolus to allow the clinician to visualize the spread of the treatment bolus during or after algorithmic injection, and / or to the flush fluid to allow the clinician to visualize the spread of the flush fluid during or after algorithmic injection. The contrast agent may be iohexol, iodixanol, ioversol, or barium sulfate, among others.

[0086] In another example, a volume of air may be injected along with the treatment bolus and / or flush fluid, either before or after. The air pockets resulting from the injection of air may be utilized in combination with spinal orientation and / or curvature positioning to impede and / or limit the biodistribution of the treatment bolus and / or flush fluid along the nerve axons.

[0087] In another example, the patient may be positioned in a head-down tilt orientation, e.g., at an angle to the horizontal such that the patient's head is below the feet. In the head-down tilt orientation, the patient may be positioned at an angle of 0-90 degrees from a supine position. Utilizing this orientation, a buffer may be added to the therapeutic bolus to add properties to the therapeutic bolus that cause the bolus to move rostrally after injection. In one example, the buffer may be cold relative to the patient's CSF temperature, such that a relatively cooler therapeutic bolus with the buffer will drop within the CNS after injection. For example, the buffer may have a temperature in the range of 0-3.5° C. lower than body temperature, etc. In another example, the buffer may cause the therapeutic bolus to have a greater density than the patient's CSF, such that a relatively denser therapeutic bolus with the buffer will drop within the CSN after injection.

[0088] In another example, the patient may be positioned in a head-up tilt orientation, for example at an angle to the horizontal such that the patient's head is above the patient's feet. In the head-up tilt orientation, the patient may be positioned at an angle of 1 to 90 degrees upward from a supine position. It is understood that the craniospinal axis (CSA) is flexible when a person is standing or otherwise has a head-up tilt orientation, which causes the dural sac to stiffen and the cranial components to be relatively less rigid. Due to this relative flexibility and the closed fluid nature of the CNS, injected fluids have a strong tendency to migrate rostrally, given the prospect of expansion with the more flexible tissues that surround the brain when in the head-up tilt orientation.

[0089] The systems and methods described herein are suitable for administering to a subject any therapeutic bolus and / or flush fluid composition, such as a pharmaceutical composition having one or more therapeutic agents. Indeed, the devices of the present disclosure optionally have one or more doses of a therapeutic agent, such as a therapeutic agent suitable for treating (in whole or in part) a disease, infection, or injury of the central nervous system or spinal column. For example, the present disclosure provides a method for delivering therapeutic agents to a desired anatomical location (e.g., the intrathecal space) using the systems described herein to treat a variety of conditions, including Huntington's disease, spinal muscular atrophy (SMA), survival motor neuron (SMN) deficiency, pain, amyotrophic lateral sclerosis (ALS) (including superoxide dismutase 1 (SOD-1) associated ALS), multiple sclerosis (e.g., primary progressive multiple sclerosis), Angelman syndrome, Dravet syndrome, Alzheimer's disease and other tau protein-related diseases, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), epilepsy, pre-visualase seizures, migraine headaches, acute disseminated encephalomyelitis, acute myelitis, and chronic myelopathy. The present invention provides methods for treating alpha-synuclein-related diseases, including cluster seizures, meningitis (e.g., neoplastic meningitis), Parkinson's disease, cancer (e.g., central nervous system lymphoma, leptomeningeal tumor, or secondary malignant neoplasm (SMN)), inflammation, Sanfilippo A or B, Friedreich's ataxia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D), Cerebral Amyloid Angiopathy (CAA), Rett's syndrome and other x-linked CNS diseases, Duchenne muscular dystrophy, Friedreich's ataxia, Spinal Muscular Atrophy with Dyspnea (SMARD1), CLN8, or Amyloid Congophilic Angiopathy (ACA).

[0090] The multiple syringes 118 may contain various fluids within the barrel 120. For example, the fluids may have therapeutic agents such as nucleic acids, protein therapeutics, cell therapeutics, small molecules, viral vectors encoding therapeutic proteins, or combinations thereof.

[0091] Examples of protein therapeutics include antibody-based therapeutics such as antibodies, antibody fragments, or antibody-like protein products (e.g., scFv, bispecific antibodies, antibody mimetics, etc.) that contain the binding region of an antibody. Antibody-based therapeutics may target, for example, amyloid plaques, tau protein, cancer antigens, or abnormal alpha-synuclein. Examples of protein therapeutics also include, but are not limited to, hormones, enzymes (e.g., lysosomal enzymes such as alpha-L-iduronidase, N-acetylgalactosamine-4-sulfatase, or beta-glucuronidase), growth factors (e.g., fibroblast growth factor (FGF) or neurotrophins or neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), or nerve growth factor (NGF)), blood factors, bone morphogenetic proteins, interferons, interleukins, and thrombolytic drugs. Examples of cell-based therapies include, but are not limited to, stem cell therapeutics and immune cells (including modified immune cells such as CAR T cells). Suitable small molecule therapeutics include, but are not limited to, analgesics, ion channel blockers, antispasmodics, antibiotics or antivirals, anti-inflammatory drugs, anticoagulants, chemotherapeutics, antidepressants, antianxiety drugs, steroids, etc.In various embodiments, the therapeutic agent is baclofen, morphine, bupivacaine hydrochloride, clonidine hydrochloride, gabapentin, idursulfase, cytarabine, methotrexate, corticosteroids, edaravone conjugates, conotoxin, avomorphine, prednisolone succinate, carbidopa / levodopa, tetrabenazine, benzodiazepines such as diazepam and midazolam, alphaxalone or other derivatives, cyclophosphamide, idursulfase (Elaprase), The therapeutic options include cerebrospinal fluid (Trademark), iduronidase (Aldurazyme®), topotecan, busulfan, opumaveloxolone, epicatechin, methylprednisolone, frataxin substitutes, reservatol, nicontinamide, AT-10 (RNA that induces splicing regulation in mature amyloid precursor protein RNA), Celebril™, anti-A antibodies, elenbecestat, corticosteroids, or nusinersen (Spinraza®), or combinations thereof.

[0092] Nucleic acid therapeutic agents include DNA or RNA, which may be single-stranded or double-stranded, and may be modified or unmodified.In particular, nucleic acid may be antisense oligonucleotide, ribozyme, miRNA, siRNA and shRNA, or may be nucleic acid encoding clustered regularly interspaced short palindromic repeats ("CRISPR") associated protein (CAS) system, or combinations thereof.CRISPR / CAS system is further described, for example, in US Patent Publication No. 2018 / 0223311.

[0093] Optionally, the nucleic acid is selected from the group consisting of APP, MAPT, SOD1, BACE1, CASP3, TGM2, TARDBP, ADRB1, CAMK2A, CBLN1, CDK5R1, GABRA1, MAPK10, NOS1, NPTX2, NRGN, NTS, PDCD2, PDE4D, PENK, SYT1, TTR, FUS, LRDD, CYBA, ATF3, CASP2, HRK, C1QBP, BNIP3, MAPK8, MAPK14, Rac1, G ... SK3B, P2RX7, TRPM2, PARG, CD38, STEAP4, BMP2, GJA1, TYROBP, CTGF, ANXA2, DUOX1, RTP801, RTP801L, NOX4, NOX1, NOX2(gp91pho, CY BB), NOX5, DUOX2, NOXO1, NOXO2(p47phox, NCF1), NOXA1, NOXA2(p67phox, NCF2), p53(TP53), HTRA2, KEAP1, SHC1, ZNHIT1, LGALS3, S ESN2, SOX9, ASPP1, CTSD, CAPNS1, FAS, FASLG, CAPN1, FADD, CASP1, CASP9, p75NTR, PARK2, HTT (with expanded repeats), NogoA, MAG, OMGP, NgR1, PDE4, BCAN, NCAN, PTPRZ1, TNC, NRP1, NRP2, PLXNA1, PLXNA2, PLXNB1, PLXNC1, TROY, LRRC1, ROCK1, LimK1, LimK2, CFL1, KCNC4 , KCNE3, NAT8L, FKBP1A, FKBP4, LRRK2, DYRK1A, AKAP13, UBE2K, WDR33, MYCBP2, SEPHS1, HMGB1, HMGB2, TRPM7, BECN1, THEM4, SLC4A7, MMP9, SLC11A2, ATXN3, ATXN1, ATXN7, PRNP, EFNB3, EPHA4, EFNA5, EPHA7 and EFNB2.

[0094] In some embodiments, the therapeutic agent is an oligonucleotide having at least one modified nucleotide, optionally having a modified nucleotide that reduces binding to cerebrospinal fluid (CSF) proteins. In various embodiments, the modified nucleotide comprises a substituent at the 2' position, such as a 2'-O-2-methoxyethyl ("2'-MOE") group, as shown below, where X is O or S.

[0095] [ka]

[0096] Oligonucleotides with 2'-MOE modifications can be rapidly distributed in central nervous system tissues, and oligonucleotides with such modifications can exhibit extended half-lives in the CSF and central nervous system tissues, which can result in less frequent dosing.

[0097] In some cases, modified nucleotides can include a 2',4'-constrained group, such as a constrained 2'-O-ethyl ("cEt") group. In various cases, the cEt group can have an S-stereochemistry ("S-cEt"), as shown below, where X is O or S.

[0098] [ka]

[0099] Nucleic acids modified with constrained ethyl groups, such as S-cEt, may exhibit improved thermal stability, better efficacy and better therapeutic profile.

[0100] In various embodiments, the nucleic acid is an antisense nucleic acid that reduces expression of HTT (e.g., HTT with expanded repeats). The sequence of HTT is known. See, e.g., GenBank Accession No. NM_002111. In some embodiments, the nucleic acid is an antisense nucleic acid that targets an mRNA encoding a Huntington protein (HTT), such as mutant HTT (e.g., HTT with expanded repeats). In various aspects, the nucleic acid has the nucleic acid sequence ctcagtaacattgacaccac. In various aspects, the nucleic acid is used in conjunction with a device in a method of treating Huntington's disease.

[0101] In various embodiments, the nucleic acid is a modified antisense oligonucleotide that targets survival motor neuron-2 (SMN2) mRNA, and optionally targets an intron downstream of exon 7 of the SMN2 transcript. The sequence of SMN2 is known. See, for example, GenBank Accession No. NM_022876. Optionally, the antisense oligonucleotide is modified such that the 2'-hydroxy group of the ribofuranosyl ring is replaced with a 2'-O-2-methoxyethyl group, and the phosphate bond is replaced with a phosphorothioate bond. In various embodiments, the nucleic acid is nusinersen, and is used in conjunction with a device in a method for treating spinal muscular atrophy (SMA).

[0102] Optionally, the nucleic acid encodes a beneficial protein, e.g., to replace a missing or defective protein, or encodes a cytotoxic protein to achieve a therapeutic effect, such as cancer cell death. Any of the protein-based therapeutics described herein may be delivered to a subject via delivery of a nucleic acid encoding the protein under conditions allowing for expression in vivo. For example, in various embodiments, the nucleic acid encodes a neurotrophic factor, such as, but not limited to, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 / 5 (NT-4 / 5), neurotrophin-6 (NT-6), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor family (e.g., FGFs 1-15), leukemia inhibitory factor (LIF), certain members of the insulin-like growth factor family (e.g., IGF-1), neurturin, persephin, bone morphogenetic proteins (BMPs), immunophilins, members of the transforming growth factor (TGF) family of growth factors, neuregulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor family (e.g., VEGF165), follistatin, or Hifl, or combinations thereof.

[0103] Optionally, the fluid has a gene expression (e.g., viral) vector. Examples of viral vectors include, for example, herpes simplex virus (HSV) vectors, adenovirus (Ad) vectors, parvovirus-based vectors (e.g., adeno-associated virus vectors), chimeric Ad-AAV vectors, and retroviral vectors (including lentivirus vectors, HIV vectors). In some embodiments, the viral vector is an AAV vector and all serotypes. In some examples, the therapeutic agent may include an AAV vector DNA sequence, a recombinant AAV particle, or a combination thereof. In a further example, the AAV vector DNA sequence may target the mRNA encoding the MECP2 gene and / or the AAV-containing miRNA sponge sequence that interferes with miRNA106a and Xist on the silent X chromosome, thereby slightly unfolding the chromosome and allowing re-expression of silent, healthy genes. In some examples, the gene expression vector may be injected according to a therapeutic platform, which may be one of conventional gene replacement, x-reactivation, exon skipping, or promoter modulation.

[0104] Alternatively or additionally, the fluid disposed within barrel 120 may be a diagnostic agent. The fluid may be a contrast medium, such as an imaging agent or radiological contrast agent. Among other things, the contrast medium may be gadolinium, iohexol, iodixanol, ioversol, or barium sulfate. The contrast agent may be added into the treatment bolus and / or flush fluid for real-time visualization and feedback control of flush amount and volume to achieve a desired distribution within the CSF. EXAMPLES

[0105] 12 and 13 show drug mass distribution plots for exemplary therapeutic bolus injections to show the contrast between lumbar puncture and procedures utilizing algorithmic injection according to the present disclosure.

[0106] In the lumbar puncture control shown in Figure 12, a sham therapeutic bolus was injected using a lumbar puncture technique in the lumbar region of the spine. The drug mass distribution plot for this procedure shows the distribution of the therapeutic bolus after 3300 seconds. As explained by the key, the brain exhibits a cross-sectional drug mass of approximately 0.0001, the cervical region has a range of cross-sectional drug masses from 0.0001 to 0.01, the thoracic region has a range of cross-sectional drug masses from 0.01 to above 1, and the lumbar region has a cross-sectional drug mass of greater than 1.

[0107] In the algorithmic injection example shown in FIG. 13, a sham therapeutic bolus was injected in the thoracic region of the spine and flush fluid was injected in the lumbar region of the spine. The drug mass distribution plot for this procedure also shows the distribution of the therapeutic bolus after 3300 seconds. As explained by the key, the brain and parts of the cervical region of the spine contain cross-sectional drug masses above 0.1, and many regions are greater than 1. Furthermore, the thoracic region has a range of cross-sectional drug masses from 1 to less than 0.01, while the lumbar region has a cross-sectional drug mass less than 0.01, and the tail is less than 0.001.

[0108] Thus, contrasting Figures 12 and 13, utilizing algorithmic injection as described herein greatly and unexpectedly increases the cross-sectional drug mass in a target region, such as the brain or other desired target region as shown, by over 1,000,000 percent. These dramatic results indicate that a therapeutic bolus can be precisely targeted to a specific region in the central nervous system. Advantageously, this targeting approach can reduce the size of the bolus and / or the number of injections, among other benefits.

[0109] It will be appreciated that elements in the figures are illustrated for simplicity and clarity and are not necessarily drawn to scale. For example, the dimensions and / or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help improve understanding of the various embodiments of the present invention. Also, common but well-understood elements that are useful or necessary in commercially feasible embodiments are often not depicted to facilitate a less obstructed view of these various embodiments. The same reference numerals will be used to describe similar or similar parts. While several examples are disclosed herein, any feature from any example may be combined with or substituted for other features from other examples. Additionally, while several examples are disclosed herein, changes may be made to the disclosed examples without departing from the scope of the claims.

[0110] Those skilled in the art will recognize that a wide range of modifications, variations and combinations may be made to the above-described embodiments without departing from the scope of the present invention, and that such modifications, variations and combinations should be considered as falling within the scope of the innovative concept.

Claims

1. A system for fluid delivery to a target region in a patient's central nervous system, the system comprising: a fluid delivery device; a pump device containing a therapeutic bolus and a flush fluid; and a controller operably coupled to the fluid delivery device and the pump device, the controller configured to: inject the therapeutic bolus into the intrathecal space of the patient at a first location; and subsequently operate the pump device to inject the flush fluid into the intrathecal space of the patient at a second location at one or more flush flow rates, the one or more flush flow rates being based on at least one of the patient's anatomical data or physiological data, the system.

2. The one or more flush flow rates are: the estimated or measured steady fluid velocity of cerebrospinal fluid within the intrathecal space of the patient between the first location, which is divided into one or more axial sections, and the target region; and calculated using the estimated or measured axial cross-sectional area of the one or more axial sections, The system according to claim 1.

3. The system according to claim 2, wherein the one or more flush flow rates are based on an average of the steady fluid velocities or a maximum value of the steady fluid velocities in the one or more axial sections.

4. The system according to claim 3, wherein the one or more flush flow rates are calculated using a predetermined percentage of the average of the steady fluid velocities or the maximum value of the steady fluid velocities in the one or more axial sections.

5. The system according to claim 1, wherein at least one of the patient's anatomical data or physiological data comprises data obtained from patient imaging and testing and calculations performed on the patient imaging and testing.

6. The system according to claim 1, wherein at least one of the patient's anatomical data or physiological data comprises one or more of the patient's age, gender, size, cerebrospinal fluid (CSF) volume, CSF dynamics, respiratory data, sleep data, anatomical geography, heart rate or disease.

7. The system according to claim 6, wherein the one or more steady fluid velocities are estimated by a central nervous system computational model or an in vivo model for the patient using at least one of the anatomical data or physiological data of the patient as input.

8. The system according to any one of claims 1 to 7, wherein the volume of the flush fluid corresponds to the volume of cerebrospinal fluid between the first location and the target region.

9. The system further comprising a pressure sensor configured to measure the cerebrospinal fluid (CSF) pressure of a patient; and the controller: stopping the injection of the flush fluid or reducing the one or more flush flow rates in response to determining that the CSF pressure exceeds a predetermined threshold or falls below a predetermined threshold; or starting the injection of the flush fluid in response to determining that the CSF pressure exhibits a rising or falling phase of a waveform configured to operate the pump device to perform at least one of the above. The system according to any one of claims 1 to 7.

10. The controller further: measures the CSF pressure of the patient using a pressure sensor; and is configured to start the injection of the flush fluid in response to determining that the CSF pressure exhibits a rising or falling phase of a waveform. The system according to any one of claims 1 to 7.

11. The fluid delivery device has a catheter, the catheter includes a first lumen having a first fluid port and a second lumen having a second fluid port, and the second fluid port is sufficiently spaced proximally from the first fluid port to position the first fluid port at a first location within the lumbar region to a cistern region for injection of the treatment bolus, and to position the second fluid port at the second location within the lumbar region to the cistern for injection of the flush fluid. The system according to any one of claims 1 to 7.

12. The fluid delivery device has a catheter, the catheter includes a single lumen having a distal fluid port. The system according to any one of claims 1 to 7. **Claim 13**: The system according to any one of claims 1 to 7, wherein the fluid delivery device has a guide needle; and has a catheter configured to be inserted through the guide needle, and the controller is configured to operate the pump device to inject the therapeutic bolus through the guide needle and to inject the flush fluid through the catheter. **Claim 14**: The system according to any one of claims 1 to 7, wherein the fluid delivery device has a lumbar puncture needle. **Claim 15**: The system according to any one of claims 1 to 7, wherein the fluid delivery device has a plug-in port, the plug-in port is configured to be implanted in the patient, and includes a septum configured to be punctured with a needle. **Claim 16** **Claim 17**: The system according to any one of claims 1 to 7, wherein the flush fluid has artificial cerebrospinal fluid or an anti-inflammatory fluid. **Claim 18**: The system according to any one of claims 1 to 7, wherein the therapeutic bolus has a buffer, and the buffer is at least one of colder than the temperature of the patient's cerebrospinal fluid or denser than the patient's cerebrospinal fluid. **Claim 19** **Claim 20**: The system according to any one of claims 1 to 7, wherein at least one of the therapeutic bolus or the flush fluid has a contrast agent, and the controller is configured to adjust the one or more flush flow rates based on real-time feedback from the contrast agent. **Claim 21** **Claim 22**: The system according to any one of claims 1 to 7, wherein the therapeutic bolus has a nucleic acid, a protein therapeutic, a cell therapy, a small molecule therapeutic, a viral vector encoding a therapeutic protein, an adeno-associated virus (AAV) vector DNA sequence, a recombinant AAV particle, or a combination thereof. **Claim 23**: The system according to any one of claims 1 to 7, wherein the controller is configured to operate the pump device to inject the therapeutic bolus according to a treatment platform, and the treatment platform has one of conventional gene replacement, x-reactivation, exon skipping, or promoter regulation.

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