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 .- 66 . (canceled)
67 . A fluid delivery system comprising:
a pump device including a first syringe configured to contain a therapeutic bolus, a second syringe configured to contain a flush fluid, and one or more drivers configured to cause the therapeutic bolus and the flush fluid to be expelled from the first and second syringes, respectively;
a fluid delivery device fluidly coupled to the plurality of syringes; and
a controller configured to:
control operation of the pump device to expel the therapeutic bolus from the first syringe and deliver the therapeutic bolus to the fluid delivery device for a first infusion into an intrathecal space of a patient in a first location; and
subsequently control operation of the pump device to expel the 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 infusion into the intrathecal space of the patient in a second location, the one or more flush flow rates based on at least one of patient anatomy or physiology.
68 . The fluid delivery system of claim 67 , wherein the first location is within a lumbar region up to a cistern magna region of the patient for infusion of the therapeutic bolus; and the second location is within a lumbar region up to a cisterna magna region of the patient for infusion of the flush fluid.
69 . The fluid delivery system of claim 68 , wherein the first location is within a thoracic region up to the cervical region; and the second location is within the lumbar region up to a cervical region
70 . The fluid delivery system of claim 67 , wherein the fluid delivery device comprises a catheter, the catheter including:
a first lumen with a first fluid port, the first lumen sized to position the first fluid port at the first location; and
a second lumen with a second fluid port, the second lumen sized to position the second fluid port at the second location.
71 . The fluid delivery system of claim 70 , wherein the first lumen is movably received within the second lumen.
72 . The fluid delivery system of claim 71 , further comprising a valve configured to allow a length of the first lumen to be adjusted relative to the second lumen while maintaining a fluid seal of the second lumen.
73 . The fluid delivery system of claim 67 , wherein the fluid delivery device comprises:
an introducer needle fluidly coupled to the plurality of syringes, the introducer needle comprising a lumen with a fluid port; and
a catheter fluidly coupled to the plurality of syringes and configured to be threaded through the lumen of the introducer needle, the catheter comprising a lumen with a fluid port, and
wherein the controller is configured to:
control operation of the pump device to expel the therapeutic bolus from the first syringe and deliver the therapeutic bolus to the catheter for the first infusion through the fluid port of the catheter into the intrathecal space of the patient in the first location; and
subsequently control operation of the pump device to expel the flush fluid from the second syringe and deliver flush fluid to the introducer needle at the one or more flush flow rates for the second infusion through the fluid port of the introducer needle into the intrathecal space of the patient in the second location.
74 . The fluid delivery system of claim 70 , wherein the catheter comprises an atraumatic tip.
75 . The fluid delivery system of claim 67 , wherein the second location is spaced caudally from the first location.
76 . The fluid delivery system of claim 67 , wherein the first location and the second location are in a same region of the intrathecal space.
77 . The fluid delivery system of claim 67 , wherein the fluid delivery device comprises a lumbar puncture needle fluidly coupled to the plurality of syringes, the lumbar puncture needle comprising a lumen with a fluid port; and wherein the controller is configured to:
control operation of the pump device to expel the therapeutic bolus from the first syringe and deliver the therapeutic bolus to the lumbar puncture needle for the first infusion through the fluid port of the lumbar puncture needle into the intrathecal space of the patient in the first location; and
subsequently control operation of the pump device to expel the flush fluid from the second syringe and deliver flush fluid to the lumbar puncture needle at the one or more flush flow rates for the second infusion through the fluid port of the lumbar puncture needle into the intrathecal space of the patient in the second location.
78 . The fluid delivery system of claim 67 , further comprising one or more plug-in ports, each having a septum and one or more fluid outlets, the plug-in ports configured to be implanted in the patient; and wherein the drug delivery member comprises a needle configured to pierce the septum of one of the plug-in ports to deliver fluid thereto, and the controller is configured to at least one of:
control operation of the pump device to expel the therapeutic bolus from the first syringe and deliver the therapeutic bolus to the needle for the first infusion through the one or more fluid outlets of the plug-in port into the intrathecal space of the patient in the first location; or
control operation of the pump device to expel the flush fluid from the second syringe and deliver flush fluid to the needle at the one or more flush flow rates for the second infusion through the one or more fluid outlets of the plug-in port into the intrathecal space of the patient in the second location.
79 . The fluid delivery system of claim 67 , wherein the controller is internal to the pump device.
80 . The fluid delivery system of claim 67 , further comprising a pressure sensor configured to measure cerebrospinal fluid (CSF) pressure of the patient; and wherein the controller is in communication with the pressure sensor and configured to 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 the one or more flush flow rates in response to determining that the CSF pressure exceeds a predetermined threshold; or
begin the second infusion in response to determining that the CSF pressure indicates an ascending or descending phase of a waveform.
81 . The fluid delivery system of claim 80 , wherein the pressure sensor is in line or coupled to the catheter along the length thereof to be positioned within the intrathecal space of the patient.
82 . The fluid delivery system of claim 67 , further comprising a display configured to provide a user interface.
83 . The fluid delivery system of claim 67 , 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.
84 . The fluid delivery system of claim 83 , 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.
85 . The fluid delivery system of claim 84 , 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.
86 . The fluid delivery system of claim 67 , 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.
87 . The fluid delivery system of claim 67 , 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.
88 . The fluid delivery system of claim 87 , 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.
89 . The fluid delivery system of claim 67 , wherein the target area is the brain, the spine or combinations thereof.
90 . The fluid delivery system of claim 67 , further comprising the flush fluid, the flush fluid comprising an artificial cerebrospinal fluid or anti-inflammatory fluid.
91 . The fluid delivery system of claim 67 , further comprising the therapeutic bolus, the therapeutic bolus comprising 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.
92 . The fluid delivery system of claim 67 , further comprising the therapeutic bolus and the flush fluid, at least one of the therapeutic bolus or the flush fluid comprising a contrast agent.
93 . The fluid delivery system of claim 67 , further comprising the therapeutic bolus, 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.
94 . The fluid delivery system of claim 93 , 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.
95 . The fluid delivery system of claim 93 , 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).
96 . The fluid delivery system of claim 67 , further comprising the therapeutic bolus, wherein the therapeutic bolus comprises adeno-associated virus (AAV) vector DNA sequences, recombinant AAV particles, or combinations thereof.
97 . The fluid delivery system of claim 96 , 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.
98 . The fluid delivery system of claim 67 , wherein the therapeutic bolus is infused according to a therapy platform comprising one of:
conventional gene replacement, x-reactivation, exon skipping, or promoter modulation.
99 .- 102 . (canceled)