FLUID DELIVERY SYSTEMS AND METHODS OF TREATMENT
The disclosed systems and methods are configurable central nervous system (CNS) delivery solutions for therapeutics, such as genetic medicines. The systems and methods first infuse a therapeutic bolus within intrathecal space and subsequently infuse a flush fluid to move the therapeutic bolus rostrally toward a target area and achieve a desired spread in the spine and/or brain. The second location can be at a location caudal to the delivery location of the therapeutic bolus.
1 .- 33 . (canceled)
34 . A method for fluid delivery to a target area in a central nervous system of a patient, the method comprising:
infusing a therapeutic bolus into an intrathecal space of a patient in a first location;
subsequently infusing a flush fluid into the intrathecal space of the patient in a second location at one or more flush flow rates;
wherein a volume of the flush fluid corresponds to a volume of cerebrospinal fluid (CSF) between the first location and the target area; and the second location is spaced caudally from the first location, such that infusion of the flush fluid moves the therapeutic bolus rostrally to the target area.
35 . The method of claim 34 , further comprising imaging the patient to determine the volume of the cerebrospinal fluid between the first location and the target area.
36 . The method of claim 34 , wherein the one or more flush flow rates are based on at least one of patient anatomy or physiology data.
37 . The method of claim 36 , wherein the one or more flow rates are calculated using:
estimated or measured steady-streaming fluid velocities of cerebrospinal fluid within the intrathecal space of the patient between the first location and the target area divided into one or more axial sections; and
estimated or measured axial cross-sectional areas of the one or more axial sections.
38 . The method of claim 37 , wherein the one or more flush flow rates are based on averages of the steady-streaming fluid velocities or maximum values of the steady-streaming fluid velocities in the one or more axial sections.
39 . The method of claim 38 , wherein the one or more flush flow rates are calculated using a predetermined percentage of the averages of the steady-streaming fluid velocities or the maximum values of the steady-streaming fluid velocities in the one or more axial sections.
40 . The method of claim 36 , wherein the at least one of patient anatomy or physiology data comprises data obtained from patient imaging and tests, and computations performed on the patient imaging and tests.
41 . The method of claim 36 , wherein the at least one of patient anatomy or physiology data comprises one or more of: patient age, patient sex, patient size, patient CSF volume, patient CSF dynamics, patient respiration data, patient sleep data, patient anatomical geography, heart rate, or disease.
42 . The method of claim 41 , wherein the steady-streaming fluid velocities are estimated by a central nervous system computational or in vitro model for the patient using the at least one of patient anatomy or physiology data as input.
43 . The method of claim 34 , wherein the target area is the brain, the spine or combinations thereof.
44 . The method of claim 34 , further comprising:
measuring CSF pressure of the patient with a pressure sensor; and
stopping the infusion 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 drops below a predetermined threshold.
45 . The method of claim 34 , further comprising:
measuring CSF pressure of the patient with a pressure sensor; and
beginning the infusion of the flush fluid in response to determining that the CSF pressure indicates an ascending or descending phase of a waveform.
46 . The method of claim 34 , wherein the second location is spaced caudally from the first location.
47 . The method of claim 34 , wherein the first location and the second location are in a same region of the intrathecal space.
48 . The method of claim 34 , further comprising:
creating an access opening into the intrathecal space of the patient in a lumbar region thereof; and
inserting a catheter through the access opening and threading the catheter rostrally within the intrathecal space, wherein infusion of the therapeutic bolus and the flush fluid is performed through the catheter.
49 . The method of claim 48 , wherein the catheter comprises a first lumen with a first fluid port and a second lumen with a second fluid port, the second fluid port spaced proximally of the first fluid port, and threading the catheter rostrally within the intrathecal space positions the first fluid port at the first location within a lumbar region up to a cisterna magna region for infusion of the therapeutic bolus and positions the second fluid port at the second location within the lumbar region up to the cisterna magna for infusion of the flush fluid.
50 . The method of claim 49 , wherein threading the catheter rostrally within the intrathecal space positions the first fluid port at the first location within a thoracic region up to the cervical region of the intrathecal space for infusion of the therapeutic bolus and positions the second fluid port at the second location within the lumbar region up to the cervical region of the intrathecal space for infusion of the flush fluid.
51 . The method of claim 49 , wherein threading the catheter rostrally within the intrathecal spaced comprises moving the first lumen relative to the second lumen within the intrathecal space.
52 . The method of claim 48 , wherein the catheter comprises a single lumen with a distal fluid port, and threading the catheter rostrally within the intrathecal space comprises:
positioning the distal fluid port at the first location within a lumbar region up to a cisterna magna region for infusion of the therapeutic bolus; and
withdrawing the catheter to position the distal fluid port at the second location within the lumbar region up to the cisterna magna for infusion of the flush fluid.
53 . The method of claim 52 , wherein threading the catheter rostrally within the intrathecal space comprises:
positioning the distal fluid port at the first location within a thoracic region up to a cervical region for infusion of the therapeutic bolus; and
withdrawing the catheter to position the distal fluid port at the second location within the lumbar region for infusion of the flush fluid.
54 . The method of claim 34 , further comprising:
creating an access opening into the intrathecal space of the patient in a lumbar region thereof with an introducer needle; and
inserting a catheter through the access opening and threading the catheter rostrally within the intrathecal space, wherein infusion of the therapeutic bolus is performed through the introducer needle and the infusion of the flush fluid is performed through the catheter.
55 . The method of claim 34 , further comprising creating an access opening into the intrathecal space of the patient in a lumbar region thereof with a lumbar puncture needle, wherein infusion of the therapeutic bolus and the flush fluid is performed through the lumbar puncture needle in the lumbar region.
56 . The method of claim 34 , further comprising piercing a septum of a plug-in port implanted in the patient with a needle, and wherein infusion of at least one of the therapeutic bolus or the flush fluid is performed through the plug-in port.
57 . The method of claim 34 , wherein infusing the flush fluid comprises infusing an artificial cerebrospinal fluid or anti-inflammatory fluid into the intrathecal space of a patient in the second location at the one or more flush flow rates.
58 . The method of claim 34 , further comprising positioning the patient in a head up tilt orientation prior to infusing the therapeutic bolus and infusing the flush fluid.
59 . The method of claim 34 , further comprising:
positioning the patient in a head down tilt orientation prior to infusing the therapeutic bolus and infusing the flush fluid; and
wherein the therapeutic bolus comprises a buffer, the buffer being at least one of: colder than a temperature of cerebrospinal fluid of the patient; or more dense than the cerebrospinal fluid of the patient.
60 . The method of claim 34 , wherein at least one of the therapeutic bolus or the flush fluid comprises a contrast agent.
61 . The method of claim 34 , wherein the therapeutic 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.
62 . The method of claim 61 , wherein therapeutic bolus comprises the nucleic acid selected from the group consisting of an antisense oligonucleotide, a ribozyme, an miRNA, an siRNA, and shRNA, or a nucleic acid encoding a clustered regularly interspaced short palindromic repeats (CRISPR) associated protein (Cas) system, or a combination thereof.
63 . The method of claim 62 , wherein the therapeutic bolus comprises an antisense oligonucleotide that targets mRNA encoding Huntington protein (HTT) or an antisense oligonucleotide that targets mRNA encoding survival motor neuron-2 (SMN2).
64 . The method of claim 34 , wherein the therapeutic bolus comprises adeno-associated virus (AAV) vector DNA sequences, recombinant AAV particles, or combinations thereof.
65 . The method of claim 64 , wherein the AAV vector RNA sequences encode miRNA sponge sequences that interfere with miRNA106a and Xist on the silent X-chromosome thereby slightly unfolding the chromosome and allowing re-expression of the silent healthy gene.
66 . The method of claim 34 , wherein the therapeutic bolus is infused according to a therapy platform comprising one of: conventional gene replacement, x-reactivation, exon skipping, or promoter modulation.
67 .- 102 . (canceled)