WO2022271938A1 - Method of regulating gene expression - Google Patents
Method of regulating gene expression Download PDFInfo
- Publication number
- WO2022271938A1 WO2022271938A1 PCT/US2022/034706 US2022034706W WO2022271938A1 WO 2022271938 A1 WO2022271938 A1 WO 2022271938A1 US 2022034706 W US2022034706 W US 2022034706W WO 2022271938 A1 WO2022271938 A1 WO 2022271938A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- csf
- catheter
- pump
- ventricle
- patient
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 95
- 230000014509 gene expression Effects 0.000 title claims abstract description 13
- 230000001105 regulatory effect Effects 0.000 title claims description 10
- 239000012530 fluid Substances 0.000 claims abstract description 87
- 238000012230 antisense oligonucleotides Methods 0.000 claims abstract description 56
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 55
- 239000000074 antisense oligonucleotide Substances 0.000 claims abstract description 55
- 239000000463 material Substances 0.000 claims abstract description 55
- 230000008878 coupling Effects 0.000 claims abstract description 25
- 238000010168 coupling process Methods 0.000 claims abstract description 25
- 238000005859 coupling reaction Methods 0.000 claims abstract description 25
- 210000004556 brain Anatomy 0.000 claims abstract description 19
- 210000004705 lumbosacral region Anatomy 0.000 claims abstract description 19
- 230000008569 process Effects 0.000 claims description 44
- 230000001276 controlling effect Effects 0.000 claims description 11
- 238000001727 in vivo Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 238000011282 treatment Methods 0.000 abstract description 13
- 231100000419 toxicity Toxicity 0.000 abstract description 5
- 230000001988 toxicity Effects 0.000 abstract description 5
- 238000009826 distribution Methods 0.000 abstract description 3
- 210000005036 nerve Anatomy 0.000 abstract description 2
- 210000000578 peripheral nerve Anatomy 0.000 abstract description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 165
- 229940079593 drug Drugs 0.000 description 73
- 239000003814 drug Substances 0.000 description 73
- 238000007726 management method Methods 0.000 description 27
- 230000001225 therapeutic effect Effects 0.000 description 20
- 210000003484 anatomy Anatomy 0.000 description 16
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 11
- 238000012377 drug delivery Methods 0.000 description 11
- 230000006870 function Effects 0.000 description 11
- 229960000485 methotrexate Drugs 0.000 description 11
- 210000002330 subarachnoid space Anatomy 0.000 description 10
- 238000001802 infusion Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 241001494479 Pecora Species 0.000 description 7
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 230000002457 bidirectional effect Effects 0.000 description 5
- 230000008499 blood brain barrier function Effects 0.000 description 5
- 210000001218 blood-brain barrier Anatomy 0.000 description 5
- 238000004590 computer program Methods 0.000 description 5
- 230000029087 digestion Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 210000000278 spinal cord Anatomy 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 210000003722 extracellular fluid Anatomy 0.000 description 4
- 230000010355 oscillation Effects 0.000 description 4
- 230000000541 pulsatile effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 208000023105 Huntington disease Diseases 0.000 description 3
- 210000001015 abdomen Anatomy 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 210000003140 lateral ventricle Anatomy 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108020003215 DNA Probes Proteins 0.000 description 2
- 239000003298 DNA probe Substances 0.000 description 2
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 102100040347 TAR DNA-binding protein 43 Human genes 0.000 description 2
- 101710150875 TAR DNA-binding protein 43 Proteins 0.000 description 2
- 101150049278 US20 gene Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- -1 antibodies Proteins 0.000 description 2
- 238000013473 artificial intelligence Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000012539 chromatography resin Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 2
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920000344 molecularly imprinted polymer Polymers 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- POYODSZSSBWJPD-UHFFFAOYSA-N 2-methylprop-2-enoyloxy 2-methylprop-2-eneperoxoate Chemical compound CC(=C)C(=O)OOOC(=O)C(C)=C POYODSZSSBWJPD-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010040467 CRISPR-Associated Proteins Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101001072091 Homo sapiens ProSAAS Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 102100036366 ProSAAS Human genes 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229920003180 amino resin Polymers 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003172 anti-dna Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000003703 cisterna magna Anatomy 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 210000001808 exosome Anatomy 0.000 description 1
- 238000002060 fluorescence correlation spectroscopy Methods 0.000 description 1
- 210000004055 fourth ventricle Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000010801 machine learning Methods 0.000 description 1
- 238000007885 magnetic separation Methods 0.000 description 1
- 238000005404 magnetometry Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 238000012576 optical tweezer Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000010384 proximity ligation assay Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000004416 surface enhanced Raman spectroscopy Methods 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000000211 third ventricle Anatomy 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
- A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
- A61M27/006—Cerebrospinal drainage; Accessories therefor, e.g. valves
Definitions
- Illustrative embodiments generally relate to medical devices and methods and, more particularly, illustrative embodiments relate to devices and methods for managing subarachnoid fluid, such as cerebrospinal fluid ("CSF”), and/or drug delivery that may be used to treat neurodegenerative disorders.
- CSF cerebrospinal fluid
- a method of regulating gene expression of a patient couples a fluid channel between the lumbar region of the patient and the ventricle of the patient's brain.
- the fluid channel fluidly connects the lumbar region and the ventricle, and the fluid channel has an access port and a pump.
- the pump is energized to cause CSF to flow between the lumbar and ventricle of the patient.
- Antisense oligonucleotide material (ASO) is added to the access port before, during, and/or after energizing the pump.
- the method may further include de-energizing the pump to cause the CSF to flow under natural flow processes.
- the CSF may flow in one direction only between energizing and de-energizing the pump.
- the method may further de-energize the pump to cause the CSF to flow under natural flow processes.
- the CSF may flow in two or more directions between energizing and de-energizing the pump.
- the method may further reverse the direction of the pump output to cause the ASO to pass by the same point in the ventricle or lumbar regions in two directions.
- the fluid channel may further include a catheter having a lumen configured to transport ASO mixed with CSF of the patient.
- Adding antisense oligonucleotide material may include adding a bolus of antisense oligonucleotide material to the fluid channel through the access port.
- the method may further include controlling, via a controller, the pump output rate as a function of a parameter of the patient.
- the fluid channel may form a closed loop configured to circulate CSF and ASO mixture through the ventricle, the body chambers through which CSF flows, the lumbar, and fluid channel in one or two directions.
- the fluid channel may include a catheter.
- Coupling a fluid channel between the lumbar region of the patient and the ventricle may include locating a lumbar catheter in-vivo to the patient and extending from the patient's lumbar, locating a ventricle catheter in-vivo to the patient and extending from the patient's ventricle, mechanically coupling the catheter to the lumbar catheter, mechanically coupling the catheter to the ventricle catheter, and mechanically coupling the to the lumbar and ventricle catheters fluidly coupling the lumbar and ventricle of the patient via the fluid channel.
- a kit configured to assist with regulating gene expression includes an antisense oligonucleotide material (ASO) and a fluid management circuit.
- the fluid management circuit includes a pump, a catheter having an internal lumen, an access port configured to facilitate addition of ASO to the internal lumen of the catheter, and mechanical couplings configured to couple the catheter between and with at least two spaced apart internal catheters.
- the pump may be configured to selectively flow in either of two directions.
- the kit may further include a controller configured for controlling the pump output.
- a method of regulating gene expression of a patient includes providing fluid management system comprising a pump, a catheter, and an access port that is either part of the catheter or separate from the catheter.
- the method includes securing together the pump, catheter and access port to form a CSF fluid channel, coupling the catheter to an internal lumbar catheter extending from and embedded within the patient's the lumbar region, coupling another end of the catheter to an internal ventricle catheter extending from and embedded within the patient's the ventricle region, energizing the pump to cause CSF to flow in one or two opposite directions between the lumbar region and ventricle region of the patient; and adding antisense oligonucleotide material (ASO) to the catheter through the access port before, during, and/or after energizing the pump.
- ASO antisense oligonucleotide material
- the method may further include de-energizing the pump to cause the CSF to flow under natural flow processes.
- the CSF may flow in one direction only between energizing and de-energizing the pump.
- the method may further include de-energizing the pump to cause the CSF to flow under natural flow processes.
- the CSF may flow in two or more directions between energizing and de-energizing the pump.
- the method may further include reversing the direction of the pump output to cause the ASO to pass by the same point within the ventricle or lumbar region in two directions.
- the catheter may form a closed loop configured to circulate CSF and ASO mixture through the ventricle, the body chambers through which CSF flows, and the lumbar in one or two directions.
- Adding antisense oligonucleotide material may include adding a bolus of antisense oligonucleotide material to the catheter through the access port.
- Adding antisense oligonucleotide material may include adding a gradual flow of antisense oligonucleotide material to the catheter through the access port.
- the method may further include controlling, via a controller, the pump to oscillate CSF fluid flow.
- Illustrative embodiments of the invention are implemented as a computer program product having a computer usable medium with computer readable program code thereon.
- the computer readable code may be read and utilized by a computer system in accordance with conventional processes.
- Figure 1A schematically shows a cerebrospinal fluid circuit that may be used with illustrative embodiments of the invention.
- Figure 1 B schematically shows an external catheter configured in accordance with illustrative embodiments.
- Figure 1C shows a high level surgical flow process in accordance with illustrative embodiments of the invention.
- Figure 2 schematically shows a two pump circuit with drug fed into pump through separate fluid line in accordance with illustrative embodiments.
- Figure 3 schematically shows a two pump circuit with drug introduced directly into fluid line
- Figure 4A schematically shows a flow control valve circuit that may be used with illustrative embodiments.
- Figure 4B schematically shows a syringe pump dosing circuit with a drug introduced directly into the fluid line configured and usable with illustrative embodiments.
- Figure 5 schematically shows a two-pump circuit with a mixing chamber in accordance with illustrative embodiments.
- Figure 6 schematically shows a flow control valve with a mixing chamber in accordance with other embodiments.
- Figures 7 and 8 schematically show two different user interfaces in accordance with illustrative embodiments.
- Figure 9 shows a process of localizing drug delivery to a target area of the brain in accordance with illustrative embodiments.
- Figure 10 schematically shows directing flow from lumbar to ventricle in accordance with illustrative embodiments.
- Figure 11 schematically shows directing flow from ventricle to lumbar in accordance with illustrative embodiments.
- Figure 12 schematically shows directing flow from lumbar to ventricle with a pulsatile pattern in accordance with illustrative embodiments.
- Figures 13A and 13B schematically show bidirectional pump circuits that enable flow in two opposite directions ( Figure 13B between right and left ventricles in the brain) in accordance with illustrative embodiments.
- Figure 14 schematically shows another system interface in accordance with illustrative embodiments.
- Figure 15 shows a process of manually programming drug delivery in accordance with illustrative embodiments.
- Figures 16A, 16B, and 16C detail an example of illustrative embodiments of the invention.
- FIGS 17A, 17B, and 17C detail another example of illustrative embodiments of the invention.
- Figure 18 shows a method of regulating gene expression of a patient in accordance with illustrative embodiments.
- Illustrative embodiments regulate patient gene expression by controllably circulating antisense oligonucleotide material (ASO) through a closed fluid circuit formed between the patient's ventricle and lumbar regions.
- ASO antisense oligonucleotide material
- CSF/ASO fluid flow may be managed to localize treatment (e.g., providing deep brain distribution) while minimizing toxicity potentially caused by the ASO to certain nerves (e.g., the peripheral nerve). Details of various embodiments are discussed below.
- a system controllably applies a therapeutic material, such as a drug (e.g., methotrexate, a chemotherapy, small interfering RNA (siRNA), microRNA (miRNA), plasmid DNA, messenger RNA (mRNA), small activating RNA (saRNA), splicing-modulatory ASOs, and CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated protein, adenoviral vectors (AAV), and immunosuppressive drug) to a specific anatomical location within the subarachnoid space or other area.
- a drug e.g., methotrexate, a chemotherapy, small interfering RNA (siRNA), microRNA (miRNA), plasmid DNA, messenger RNA (mRNA), small activating RNA (saRNA), splicing-modulatory ASOs, and CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (C
- the therapeutic material which also may be referred to herein as a "drug,” may be applied in a single large volume as a bolus, or dosed gradually over a longer time.
- the system has a controller or control system that manages distribution of the therapeutic material within a CSF circuit through which cerebrospinal fluid (“CSF”) flows.
- the controller or “control system” manages pumps, valves, catheters, and/or other structure(s) to control fluid flow, flow direction, and frequencies of certain periodic flows of bodily fluids (e.g., CSF), to provide a more localized and efficient therapeutic application to a patient.
- Preferred embodiments enable the therapeutic material to penetrate the blood-brain barrier by either selecting appropriate CSF and therapeutic material flow rates, and/or controlling CSF flow to maintain a bolus of the therapeutic material within CSF at/near a desired location in the CSF circuit. Consequently, using various embodiments, medical practitioners can be more comfortable applying the appropriate application of the therapeutic in the patient, while reducing toxicity and, in some cases, reducing the need for larger volumes of the therapeutic. Details of illustrative embodiments are discussed below.
- CSF cerebrospinal fluid
- SAS subarachnoid space
- DPRs dipeptide repeat proteins
- TDP-43 have been implicated in neuronal death in the pathology of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), Alzheimer disease (AD), frontotemporal degeneration (FTD), Parkinson's disease (PD), Huntington's disease (HD), and progressive supranuclear palsy (PSP), to name just a few.
- ALS amyotrophic lateral sclerosis
- AD Alzheimer disease
- FTD frontotemporal degeneration
- PD Parkinson's disease
- HD Huntington's disease
- PSP progressive supranuclear palsy
- Techniques for removing DPRs and/or TDP-43 have included: shunting CSF from the CSF space, diluting the CSF (e.g., with an artificial fluid), administering a drug into the CSF, conditioning the CSF, and/or manipulating CSF flow.
- Recent breakthrough techniques for handling this problem include ameliorating the CSF, and treating a neurological disorder by removing or degrading a specific (toxic) protein.
- Amelioration involves systems and methods for ameliorating a fluid in the subarachnoid space (SAS) (e.g., a cerebrospinal fluid (CSF), an interstitial fluid (ISF), blood, and the like) of a mammalian subject, unless otherwise particularly distinguished (e.g., referred to as solely CSF).
- SAS subarachnoid space
- Representative systems may be completely or partially implanted within the body of the mammalian subject (discussed below).
- the systems and/or components thereof may also be completely or partially implanted within the SAS and exposed to the exterior via a port 16 (e.g., a medical valve that provides selective access to the interior system components).
- a port 16 e.g., a medical valve that provides selective access to the interior system components.
- Amelioration may include changing the physical parameters of the fluid, as well as digestion, removal, immobilization, reduction, and/or alteration, to become more acceptable and/or inactivation of certain entities, including: target molecules, proteins, agglomerations, viruses, bacteria, cells, couples, enzymes, antibodies, substances, and/or any combination thereof.
- amelioration may refer to removing toxic proteins from or conditioning one or more of the blood, interstitial fluid, or glymph contained therein, or other fluid, as well as the impact that this removal has on treating diseases or conditions that affect various bodily functions, (i.e., improving the clinical condition of the patient).
- amelioration may be performed by any one of: digestion, enzymatic digestion, filtration, size filtration, tangential flow filtering, countercurrent cascade ultrafiltration, centrifugation, separation, magnetic separation (including with nanoparticles and the like), electrophysical separation (performed by means of one or more of enzymes, antibodies, nanobodies, molecular imprinted polymers, ligand-receptor complexes, and other charge and/or bioaffinity interactions), photonic methods (including fluorescence-activated cell sorting (FACS), ultraviolet (UV) sterilization, and/or optical tweezers), photo-acoustical interactions, chemical treatments, thermal methods, and combinations thereof.
- various embodiments or implementations of the present invention may reduce levels of toxicity and, after reduced, facilitate maintaining the reduced levels over time.
- the extent of amelioration, as reflected by the concentration of the target biomolecules, may be detected through a variety of means. These include optical techniques (e.g., Raman, coherent Stokes, and anti-Stokes Raman spectroscopy; surface enhanced Raman spectroscopy; diamond nitrogen vacancy magnetometry; fluorescence correlation spectroscopy; dynamic light scattering; and the like) and use of nanostructures such as carbon nanotubes, enzyme linked immunosorbent assays, surface plasmon resonance, liquid chromatography, mass spectrometry, circular proximity ligation assays, and the like.
- optical techniques e.g., Raman, coherent Stokes, and anti-Stokes Raman spectroscopy; surface enhanced Raman spectroscopy; diamond nitrogen vacancy magnetometry; fluorescence correlation spectroscopy; dynamic light scattering; and the like
- nanostructures such as carbon nanotubes, enzyme linked immunosorbent assays, surface plasmon resonance, liquid chromatography, mass spectrometry, circular proximity ligation as
- Amelioration may include the use of a treatment system (e.g., UV radiation, IR radiation), as well as a substance, whose properties make it suitable for amelioration.
- Amelioration of CSF or ameliorated CSF - which terms may be used interchangeably herein - refers to a treated volume of CSF in which one or more target compounds have been partially, mostly, or entirely removed. It will be appreciated that the term removed, as used herein, can refer not only to spatially separating, as in taking away, but also effectively removing by sequestering, immobilizing, or transforming the molecule (e.g., by shape change, denaturing, digestion, isomerization, or post- translational modification) to make it less toxic, non-toxic or irrelevant.
- ameliorating agent generally refers to a material or process capable of ameliorating a fluid, including enzymes, antibodies, or antibody fragments, nucleic acids, receptors, anti-bacterial, anti-viral, anti-DNA/RNA, protein/amino acid, carbohydrate, enzymes, isomerases, compounds with high-low biospecific binding affinity, aptamers, exosomes, ultraviolet light, temperature change, electric field, molecular imprinted polymers, living cells, and the like. Additional details of amelioration are taught by PCT Application No. PCT/US20/27683, filed on April 10, 2020, the disclosure of which is incorporated herein, in its entirety, by reference. In a similar manner, details for further treatments are taught by PCT Application No. PCT/US 19/042880, filed July 22, 2019, the disclosure of which is incorporated herein, in its entirety, by reference.
- illustrative embodiments form a CSF circuit/channel (identified by reference number "10") that manages fluid flow in a closed loop.
- Figure 1A shows one embodiment of such a CSF circuit 10.
- internal catheters 12 positioned in-vivo/interior to the body fluidly couple together via the subarachnoid space.
- a first internal catheter 12 fluidly couples a prescribed region of the brain (e.g., the ventricle) to a first port 16, which itself is configured and positioned to be accessible by external components.
- a second catheter couples the lumbar region or the lower abdomen of the subarachnoid space with a second port 16 that, like the first port 16, also is configured to be positioned and accessible by external components.
- the first and second ports 16 may be those conventionally used for such purposes, such as a valved Luer-lock or removable needle.
- the first and second internal catheters 12 thus may be considered to form a fluid channel extending from the first port 16, to the ventricle, down the spine/subarachnoid space to the lumbar, and then to the second port 16.
- These internal components which may be referred to as "internal CSF circuit components," are typically surgically implanted by skilled professionals in a hospital setting.
- the CSF circuit 10 also has external components (referred to as "external CSF circuit components).
- the external CSF circuit components include at least two fluid conduits 14.
- the external CSF circuit components include a first external fluid conduit 14, that couples with the first port 16 for access to the ventricle.
- the other end of the first external conduit 14 is coupled with a management system 19, which includes one or more CSF pumps (all pumps are generically identified in the figures as reference number "18"), one or more user interface/displays 20, one or more drug pumps 18, and a control system/controller 22.
- the fluid external fluid conduit 14 may be implemented as a catheter and thus, that term may be used interchangeably with the term "conduit" and be identified by the same reference number 14.
- this management system 19 is supported by a conventional support structure (e.g., a hospital pole 24 in Figure 1A).
- a second external catheter 14 extends from that same CSF management system 19 and couples with the second port 16 and the management system 19.
- This management system 19 and external catheters 14 therefore form the exterior part of a closed CSF circuit 10 for circulating the CSF and therapeutic material.
- the CSF circuit 10 may have one or more components between the first and second ports 16 and the respective removable connections of the first and second external catheters 14.
- the first port 16 may have an adapter that couples with the first external catheter 14, or another catheter with a flow sensor may couple between such external catheter 14 and port 16.
- this still may be considered a removable connection, albeit an indirect fluid connection.
- the connection can be a direct connection or an indirect connection.
- the first and second external catheters 12 and 14 preferably are configured to have removable connections/couplings with the management system 19, as well as their respective ports 16.
- removable couplings may include a screw-on fit, an interference fit, a snap-fit, or other known removable couplings known in the art. Accordingly, a removable coupling or removable connection does not necessarily require that one forcibly break, cut, or otherwise permanently break the ports 16 for such a connection or disconnection. Some embodiments, however, may enable a disconnection form the first and/or second ports 16 via breaking or otherwise, but the first and/or second ports 16 should remain in-tact to receive another external catheter 14 (e.g., at the end of life of the removed external catheter 14).
- Figure 1 B schematically shows more details of the first and/or second external conduits/catheters 14.
- the system receives a drug reservoir 17 (e.g., a single-use syringe) configured to deliver a dose of therapeutic material (e.g., a drug) that fluidly couples with the catheter 14 via a check valve 28 and T-port 19 on the catheter 14.
- a drug reservoir 17 e.g., a single-use syringe
- a dose of therapeutic material e.g., a drug
- the catheter 14 is coupled with a mechanical pump 18 and also preferably includes a sample port 23 with flow diverters 25 for diverting flow toward or away from a sample port 23.
- the sample port 23 preferably has sample port flow sensors 23A to track samples.
- Some embodiments may be implemented as a simple catheter having a body forming a fluid-flow bore with removably couplable ends (or only one removably couplable end).
- Illustrative embodiments add intelligence to make one or both of these external catheters 14 "smart" catheters, effectively creating a more intelligent flow system.
- either one or both of the external catheters 14 can have a processor, ASIC, memory,
- EEPROM electrically erasable programmable read-only memory
- FPGAs field-programmable gate arrays
- RFID magnetic resonance sensing
- NFC magnetic resonance sensing
- the management system 19 may be configured to coordinate with an EEPROM 27 to control CSF fluid flow as a function of the therapeutic material infusion flow added to the CSF circuit 10 (discussed below) via the check valve 28 at the output of the drug reservoir 17.
- one embodiment of the external catheter 14 has the noted electrically erasable programmable read-only memory, EEPROM 27, (or other logic/electronics) that can be implemented to accomplish a variety of functions.
- the EEPROM 27 can ensure that the CSF circuit 10 and its operation is customized/individualized to a patient, a treatment type, a specific disease, and/or a therapeutic material.
- the control system 22 may be configured to control fluid flow as a function of the therapeutic material.
- the EEPROM 27 or other logic of the external catheter 14 can be configured to provide alerts, and/or produce or cause production of some indicia (e.g., a message, visual indication, audio indication, etc.) indicating that the external catheter 14 has reached an end of its lifecycle, or indicating how much of its lifecycle remains.
- some indicia e.g., a message, visual indication, audio indication, etc.
- an external surface of the catheter 14 may have a tag that turns red when the EEPROM 27 and/or other logic 27 determines that the external catheter 14 has reached its full lifetime use.
- the external catheter 14 may be considered to have a usage meter, implemented as some logic or EEPROM 27, configured to track use of the CSF fluid conduit 14 to help ensure it is not used beyond its rated lifetime.
- the logic or EEPROM 27 can register with the control system 22 to start use timers to reduce tampering or use beyond a lifetime.
- Some embodiments have a printable circuit board (PCB) equipped with a wireless interface (e.g., Bluetooth antenna) or a hardware connection configured to communicate the pump 18 and/or control system 22.
- the external catheter 14 can be configured to time out after a certain period, capture data, and communicate back and forth with the control system 22 or other off-catheter or on-catheter apparatus to share system specifications and parameters.
- the intelligent flow catheter 14 can be designed with proprietary connections such that design of knockoffs or cartridges 26 (discussed below) can be prevented to ensure safety and efficacy of the CSF circuit 10 and accompanying processes.
- the external catheter(s) 14 also may have a set of one or more flow sensors and/or a set of one or more pressure sensors. Both of those flow sensors are shown genehcally at reference number 29, and may be located upstream or downstream from their locations in Figure 1 B.
- the left sensor(s) 29 generically shown in Figure 1 B can be a flow sensor, pressure, or both a flow sensor and pressure.
- the right sensor(s) 29 genehcally shown in Figure 1 B are positioned between the ports 16 on the body and the remaining components as shown.
- the flow sensor(s) 29 may be configured to detect flow through the bore of the catheter body, while the pressure sensor(s) 29 may be configured to detect pressure within the bore of the body.
- the flow sensor(s) 29 may monitor flow rate of fluid through the conduit bore and/or total flow volume through the conduit bore.
- the catheter 14 preferably is configured to have different hardness values at different locations.
- illustrative embodiments may use a mechanical pump 18, as shown and noted above.
- the pump 18 may periodically urge a compressive force along that portion of the catheter 14 it contacts at its interface 18A with the catheter 14.
- the outlet of the pump 18 in this case may be the portion of the catheter 14 that is receiving the output of a neighboring compressed catheter portion (e.g., a portion that is adjacent to the compressed catheter portion(s).
- illustrative embodiments form the catheter 14 to have a specially configured hardness at that location (e.g., 25-35 Shore A). Diameter also is important for flow and thus, one skilled in the art should determine appropriate diameters as a function of performance and durometer/hardness.
- the catheter portion that contacts the pump 18 is softer than the remainder of the catheter 14, although both could have the same hardness. Accordingly, the catheter preferably has a variable hardness along its length and may even have a variable diameter.
- kits may include the internal and external catheters 12 and 14.
- Another exemplary kit may include just the internal catheters 12 and the ports 16 (e.g., for a hospital), while a second kit may have the external catheters 14 and/or a single-use syringe.
- Other exemplary kits may include the external catheters 14 and other components, such as the management system 19 and/or a CSF treatment cartridge 26. See below for various embodiments of the CSF circuit 10 and exterior components that also may be part of this kit.
- the kit may include a number of other or similar items.
- the kit may include an antisense oligonucleotide material (ASO) and a fluid management circuit with a pump, catheter, access port, and mechanical couplings.
- ASO antisense oligonucleotide material
- the access port may be integrated into the other components.
- the access port may be part of the catheter, or a separate component.
- the mechanical couplings may be integral with the catheter or separate.
- these pumps 18, valves (discussed below and all valves generally identified by reference number 28), internal and external catheters 14, and other components may be considered to form a fluid conduit/channel that directs CSF to the desired locations in the body.
- CSF fluid conduit/channel that directs CSF to the desired locations in the body.
- other compartments can be managed (e.g., the lateral ventricles, the lumbar thecal sac, the third ventricle, the fourth ventricle, and/or the cisterna magna).
- both lateral ventricles could be accessed with the kit.
- CSF may be circulated between the two lateral ventricles, or a drug could be delivered to both ventricles simultaneously.
- the CSF management system 19 generally manages fluid flow to target anatomy through the CSF circuit 10.
- that management system 19 has at least one pump 18 that directs flow of the CSF, and at least one pump 18 that directs flow of a therapeutic material (e.g., a drug) though the CSF circuit 10 to desired anatomy.
- a therapeutic material e.g., a drug
- Alternative embodiments may have more pumps 18 for these functions, or combine pumps 18 for these functions.
- the management system 19 also has a plurality of valves 28 to control flow, and the control system 22, as noted, is configured to control the pumps 18 to selectively apply the drug-carrying CSF to desired local anatomy.
- Figure 1A also shows a user interface 20 that enables a clinician to control drug and fluid parameters in the CSF circuit 10 (discussed below) via the control system 22.
- Some embodiments may use a monitoring process, such as real-time spectroscopy, to monitor drug concentrations in the CSF.
- a spectrophotometric sensor may be placed in the CSF circuit 10 to measure the localized concentration of a substance based on its absorption at various wavelengths.
- some embodiments may use a sensor constructed to measure a single wavelength or multiple wavelengths. The reading taken by the sensor may be relayed to the control system 22, where it would then be stored or processed for various purposes.
- This signal could be processed for a number of purposes, such as to trigger the control system 22 to alter the fluid flow, flow direction, and/or frequencies of certain periodic flows of bodily fluids (e.g., CSF) to provide a more localized and efficient therapeutic application to a patient in real-time. It will be appreciated that the signal could also be stored or displayed such that the changes to flow, direction or frequencies of period flows could be adjust manually.
- bodily fluids e.g., CSF
- FIG. 1C shows a high level surgical flow process that may incorporate the CSF circuit 10 of Figure 1A in accordance with illustrative embodiments of the invention. It should be noted that this process is substantially simplified from a longer process that normally would be used to complete the surgical flow. Accordingly, this process may have many additional steps that those skilled in the art likely would use. In addition, some of the steps may be performed in a different order than that shown, or at the same time. Those skilled in the art therefore can modify the process as appropriate. Moreover, as noted above and below, many of the materials, devices, and structures noted are but one of a wide variety of different materials and structures that may be used. Those skilled in the art can select the appropriate materials and structures depending upon the application and other constraints.
- step 100 The process begins at step 100 by setting up the internal catheters 12 inside the patient. To that end, step 100 accesses the ventricles and thecal sacs using standard catheters and techniques, thus providing access to the CSF. Step 102 then connects access catheters 12 to peritoneal catheters 12, which are tunneled subcutaneously to the lower abdomen. The tunneled catheters 12 then are connected at step 104 to the ports 16 implanted in the abdomen.
- step 106 may prime and connect the extracorporeal circulation set 14 to the subcutaneous access ports 16.
- this step uses an extracorporeal circulation set, such as one provided by Endear Therapies, Inc. of Newburyport, MA, and/or the external catheters 14 discussed above.
- step 110 which connects an infusion line or other external catheter 14 to the management system 19, and then sets the target flow rate and time.
- setup is complete and treatment may begin (step 112).
- the process then removes endogenous CSF from the ventricle.
- This CSF may then be passed through a digestion region (e.g., through a cartridge 26 having a specific digesting material), where certain target proteins in the CSF are digested.
- the cartridge 26 may have an inner plenum space 1830 of the cartridge 26 filled with a plurality of (e.g., porous, chromatography resin) beads that have been compression packed.
- a filter membrane may be disposed at the first end of the cartridge 26 and a second filter membrane may be disposed at the second end of the cartridge 26.
- the ameliorating agent may be decorated on the beads 1835.
- the cartridge 26 may be compression packed with a chromatography resin (e.g., agarose, epoxy methacrylate, amino resin, and the like) that has a protease covalently bonded (i.e. immobilized) to the three- dimensional resin matrix.
- the selected protease may be configured to degrade and/or removing target toxic biomolecules by way of proteolytic degradation.
- the resin may be a porous structure having a particle size commonly ranging between 75-300 micrometers and, depending on the specific grade, a pore size commonly ranging between 300-1800 A.
- the cartridge 26 has ameliorating agent that removes and/or substantially mitigates the presence of toxic proteins from the CSF.
- step 116 the treated CSF exits the digestion region and is returned via the CSF circuit 10 to the lumbar thecal sac.
- step 118 which stops the pump 18 when treatment is complete.
- the management system 19 then may be disconnected and the ports 16 flushed.
- the CSF circuit 10 is configured to improve the likelihood of the drug passing through the blood- brain barrier.
- the management system 19 enables the user or logic to independently set both the flow rate of CSF circulation (e.g., between .05 ml/min and 2.0 ml/min, such as 0.5 ml/min) and the dosing rate of the drug (e.g., between .01 ml/min to 2.0 ml/min, such as .02 ml/min).
- these rates are different, although they can be the same.
- the CSF circulation rate is controlled to be different from the natural CSF flow rate.
- the natural CSF flow rate is the rate of CSF flow without intervention by outside equipment, such as the pumps 18 and other CSF circuit components — even if it is within a range of typical non- interventionally controlled CSF flow rates.
- the non-natural CSF flow rate is the flow rate with such intervention.
- the CSF flow rate is simply changed from its truly natural flow rate — i.e., the rate at which the CSF flows without intervention.
- the CSF flow rate may be greater than the rate of drug infusion, while in other embodiments, the CSF flow rate is less than rate of the drug infusion rate. Other embodiments may set them to be equal.
- Those skilled in the art can select the appropriate flow rate based on a variety of factors, including the drug being delivered, the illness, patient profile, rated pressure of the CSF circuit 10, etc.
- the inventors recognized that varying the two rates in a coordinated manner enables more control of the drug dose as well as more control of the drug treatment time. Stated another way, these two independent flow rates enable setting of the dosing rate, which allows the user to optimize drug concentration. At the same time, having the ability to set the flow rate allows the user to control the rate of delivery (as opposed to relying upon natural CSF flow).
- the selected CSF flow rate may be constant or variable.
- the CSF flow rate may be set to a first rate for a first period of time, a second rate for a second period of time, and a third rate for a third period of time.
- various embodiments enable flow of the CSF within the CSF circuit 10 at two or more flow rates at two or more different times.
- the drug delivery rate may be constant or variable in a similar manner, but coordinated with the CSF flow rate to deliver preferred results.
- Figure 2 schematically shows a two pump CSF circuit 10 with the drug fed into the pump 18 through a separate fluid line/catheter 12/14 in accordance with illustrative embodiments.
- Figure 3 schematically shows a two pump CSF circuit 10 with drug introduced directly into fluid line.
- the CSF circuit 10 has two pumps 18, Pump 1 and Pump 2, to enable a user to set flow rate and dosing rate independently.
- Pump 1 may be programmed to control the rate of CSF circulation
- Pump 2 may be programmed to control the dosing rate of the drug to be delivered.
- Both pumps 18 could be programmed to achieve a desired delivery profile.
- Check valves 28 or other flow control devices prevent backflow into either pump 18.
- the drug may be fed into the pump 18 through a separate fluid line/catheter ( Figure 2) and input to mix with the patient's CSF in the internal catheter/tubing set 12 before being reintroduced to the body.
- the drug may also be pre-loaded into a cartridge 26 or other type of drug reservoir and connected directly into the fluid line/catheter 14 ( Figure 3).
- the CSF mixes with the drug as it flows through the cartridge 26 and tubing set 12/14.
- Figure 4A schematically shows another embodiment in which a flow control valve 28 is used in place of Pump 2.
- that flow control valve 28 preferably is programmed to control the dosing rate (i.e., the rate of adding the drug to the CSF circuit 10 carrying the CSF.
- FIG 5 schematically shows a two-pump circuit 10 with a mixing chamber 30 in accordance with illustrative embodiments.
- the noted mixing chamber 30 is added to both the two-pump circuit 10 ( Figure 5) and the flow control valve 28 circuit ( Figure 6).
- the mixing chamber 30 can contain a sensor that provides a readout of a drug's concentration in the CSF, or the management system 19 could simply be programmed to produce a specific drug concentration in the CSF.
- CSF delivery may be manually programmed on an interface/display 20 similar to Figures 7 and 8.
- Figures 7 and 8 schematically show two different user interfaces 20 in accordance with illustrative embodiments.
- the user may specify a drug concentration and the management system 19 responsively may adjust the dosing rate accordingly to achieve that concentration.
- the user can also input a maximum dosage. After this dosage was reached, the management system 19 would automatically stop treatment.
- Figure 8 shows one such interface 20 (e.g., a graphical user interface or a manual interface).
- the CSF flow rate may differ at different parts of the CSF circuit 10 — total CSF flow rate in the CSF circuit 10 is not necessarily homogenous.
- some parts of the CSF circuit 10 may be wider (e.g., certain human geographies) and thus, may be slower than the average CSF circuit flow rate, while other portions may be narrower, causing a nozzle effect and increasing the CSF flow rate at that point.
- the CSF flow rate can be controlled to provide a desired rate across the entire CSF circuit 10, even if that rate may deviate in local parts of the CSF circuit.
- Figure 9 shows another embodiment that localizes drug delivery at a target area of the brain using a bolus drug infusion.
- a dose of drug can be delivered in a short time period (e.g., 10 seconds, 20 seconds, 60 seconds), or over a longer period (i.e., gradual drug administration, as noted above).
- the shorter drug delivery is known in the art as a "bolus" drug delivery.
- Figure 9 alternates the flow direction of the pump 18.
- the pump 18 thus has programmable controls, via the control system 22, for flow rate and frequency of these alternations.
- the flow rate and frequency preferably are programmed to achieve a desired delivery profile.
- the process of Figure 9 is substantially simplified from a longer process that normally would be used to complete the localize drug delivery. Accordingly, this process may have many additional steps that those skilled in the art likely would use. In addition, some of the steps may be performed in a different order than that shown, or at the same time. Those skilled in the art therefore can modify the process as appropriate. Moreover, as noted above and below, many of the materials, devices, and structures noted are but one of a wide variety of different materials and structures that may be used. Those skilled in the art can select the appropriate materials and structures depending upon the application and other constraints. Accordingly, discussion of specific materials, devices, and structures is not intended to limit all embodiments.
- Figure 9 therefore delivers a drug intrathecally using positive displacement at a desired flow rate. It may incorporate the components discussed above, as well as principles discussed for other embodiments, such as that discussed above with regard to Figure 2.
- the process of Figure 9 begins at step 900 by adding the drug in a bolus dose to the CSF circuit 10, and/or administering a tag for imaging to the drug. In the latter example, its position can then be tracked using standard imaging techniques to determine when the drug has reached the target anatomy. Alternative embodiments add the drug to the CSF without administering a tag. Such steps may use other techniques to ensure the drug is localized at the desired target anatomy.
- Step 902 sets the desired flow rate, direction, timing, and other parameters for the CSF circuit 10 to accomplish the bolus application.
- specific computer program code on a tangible medium within the control system 22 may cooperate with other components of the CSF circuit 10 to control addition of the therapeutic material, localize the therapeutic material, or both.
- step 906 controls the pump 18 to maintain the drug at that target location.
- step 906 may control the pump(s) 18 to oscillate at a desired flow rate and frequency to contain the drug at that prescribed or desired anatomical location for a pre-set period of time.
- the pump 18, which can be programmable and/or have logic, can reverse CSF flow; specifically, the pump 18 can alternate quickly between pushing and pulling flow of the CSF so that the bolus of drug is localized to the target anatomy in the brain (or another target anatomy).
- the higher concentration of drug in a portion of the CSF can moved back and forth over the target region.
- Other embodiments can simply slow down the CSF flow rate to ensure a longer drug application to the target. Either way, these embodiments preferably "soak" the target with the drug, providing a higher quality drug administration.
- this embodiment still administers a desired amount of the drug to the target by this localizing technique, consequently minimizing toxicity and drug costs (step 908).
- “reaching" the target anatomy may be defined by the user or other entity within the control system 22.
- the portion of CSF in the CSF circuit 10 having the higher concentration of drug may be considered to have reached the target anatomy when some identifiable portion of it (e.g., the highest concentration, or an interior point within the spread of the drug in the CSF) may be within a prescribed distance upstream of the target, or a prescribed distance downstream of the target.
- Some embodiments may require the defined portion of CSF with the high drug concentration to actually be at or in contact with that target region.
- Other embodiments may consider the drug to have "reached” the target simply by calculating the time it should take to reach that area, using artificial intelligence/machine learning, and/or through empirical studies.
- Illustrative embodiments can be implemented in a number of different manners with catheters 12/14, pumps 18, valves 28, etc. similar to those discussed above (including the noted external catheters 14).
- Figures 10-14 show several exemplary implementations.
- the CSF circuit 10 has four pinch valves 28 on tubing (i.e., external catheters 14), enabling fluid oscillation between opposing flow directions.
- pinch valves 1 and 2 are opened while pinch valves 3 and 4 are closed.
- pinch valves 1 and 2 are closed while pinch valves 3 and 4 are opened.
- Controlling the pinch valves 28 in this manner enables flow direction oscillation.
- the frequency at which the pinch valves 28 switched between open and closed may be set by the user as could the flow rate of the pump 18 (e.g., via the control system 22).
- Alternative embodiments may pre-program such parameters into the management system 19.
- pinch valve 28 configuration may be used to create a pulsatile flow pattern.
- pinch valves 3 and 4 remain closed, while pinch valves 1 and 2 are pulsed (i.e., periodically switched between open and closed) at a frequency set by the user.
- the ability to set the frequency at which the pinch valves 28 open and close enables a range of pulsatile effects to be implemented. For example, rather than rapidly switching between open and closed pinch valves 28, the valves 28 can remain closed long enough to build up a set pressure in the fluid line. Shortly after opening the pinch valves 28, a bolus of the drug can be released as a result of the pressure build-up.
- Flow direction oscillation and a pulsatile flow pattern could also be produced using a bidirectional pump 18 instead of using pinch valves 28 (e.g., Figure 13A and Figure 13B).
- the pump 18 can be programmed to switch flow directions at a frequency set by the user. While flowing in one direction, the pump 18 can be programmed to pulse by starting and stopping at a frequency also set by the user.
- Those skilled in the art may use other techniques to provide bidirectional flow.
- some embodiments may set the frequency, flow rate, and other parameters as a function of the requirements and structure of the anatomy and devices used in the treatment (e.g., in the CSF circuit 10).
- those requirements may include the diameter of the catheters in the CSF circuit 10, physical properties of the drug, the interaction of the drug at the localized region, the properties of the localized region, and other requirements and parameters relevant to the treatment.
- those skilled in the art may select appropriate parameters as a function of the requisite properties.
- FIG 14 schematically shows another system interface 20 configured in accordance with illustrative embodiments.
- the delivery profile can be controlled manually with an interface 20, such as the interface 20 shown in Figure 14, and/or a delivery profile loaded onto the management system 19.
- this interface 20 may be a fixed control panel, or a graphical user interface on a display device.
- Figure 15 shows a process of manually programming drug delivery of a bolus in accordance with illustrative embodiments.
- this process is substantially simplified from a longer process that normally would be used to complete the localize drug delivery. Accordingly, this process may have many additional steps that those skilled in the art likely would use. In addition, some of the steps may be performed in a different order than that shown, or at the same time. Those skilled in the art therefore can modify the process as appropriate.
- many of the materials, devices, and structures noted are but one of a wide variety of different materials and structures that may be used. Those skilled in the art can select the appropriate materials and structures depending upon the application and other constraints.
- the process begins at step 1500, which sets the flow direction.
- Three options include lumbar to ventricle (1502A), ventricle to lumbar (step 1502B), or oscillating between flow directions (step 1502C).
- the process sets the flow rate at steps 1504A or 1504B, and sets the frequency of the pulse (step 1506A) or oscillation frequency (step 1506B).
- Alternative embodiments can be programmed using artificial intelligence algorithms or other program logic.
- Example 1 Administration of Methotrexate to a sheep using illustrative embodiments
- FIG. 16A-16C An outline of the study is depicted by Figures 16A-16C.
- a sheep used for this experiment received the CSF circuit 10 of illustrative embodiments. Circulation was started at the same time that methotrexate was infused. Methotrexate was infused at a gradual rate of 2 mLs over 2 minutes and then recirculation from lumbar to ventricle was started at a rate of 0.2 mLs/min. Circulation continued after drug infusion was stopped for four more hours. At zero to three hours, the circulation rate was at 0.1 mL/min and from four to six hours, circulation was at 0.3 mL/min.
- the dose of methotrexate infused was 12 mg.
- Drug concentration was measured with LC/MS (liquid chromatography with the mass analysis capabilities of mass spectrometry) in the CSF, spinal cord, and multiple brain regions.
- Figure 16B schematically shows the results.
- CSF levels of methotrexate were analyzed over time. Drug levels were found to be very high in the lumbar region where the drug was infused and a decline over time was measured except for an increase at 5 hours and then a subsequent decline.
- CSF levels of methotrexate were very low in the ventricular samples initially, but with time, increased at 4 and 5 hours, before declining to a similar level as the lumbar samples.
- Figure 16C shows how samples from twelve regions of the brain were homogenized and analyzed for methotrexate levels and measured as ug/mL/g of tissue.
- the x-axis of this graph is drug levels. All areas of the brain and spinal cord had good levels of methotrexate. It will be appreciated that methotrexate that is administered typically subdural in the thigh typically does not cross the blood-brain barrier and would not be found in appreciable levels in brain and spinal cord as a result.
- Example 2 Administration of Antisense Oligonucleotide to a sheep using illustrative embodiments
- ASO antisense oligonucleotide
- FIGs 17A-C An outline of the study is depicted in Figures 17A-C.
- ASO was infused at a rate of 2 mLs over 2 min.
- the dose of ASO infused was 30 mg.
- the direction of the flow was lumbar to ventricle me for the entire 4h.
- FIG. 17B The assay for detection of the ASO is depicted in Figure 17B.
- Sandwich hybridization ELISA Enzyme-Linked-immuno-absorption-Assay quantification used to measure the concentration of CAG repeats in tissue, CSF, and blood samples.
- Probes comprised of a sequence complementary to the analyte. Capture DNA probe conjugated to biotin label and applied to a streptavidin- coated microtiter plate. Detection DNA probe with digoxigenin label was used. To detect digoxigenin label, anti-digoxigenin (anti-Dig) peroxidase (POD) is reacted with substrate TMB for the signal measurement by an absorption change with a plate reader.
- Figure 17 C schematically shows the results.
- Samples from seventeen regions of the brain were homogenized and analyzed for ASO levels and measured as ug/g of tissue.
- the x-axis of this graph is drug levels.
- Most areas of the brain and spinal cord had good levels of ASO. It will be appreciated that the ASO if administered orally, subdurally, or intravenously typically does not cross the blood-brain barrier and would not be found in appreciable levels in brain and spinal cord as a result.
- Figure 18 shows a method of regulating gene expression of a patient in accordance with illustrative embodiments. It should be noted that this process is substantially simplified from a longer process that normally would be used to regulate gene expression. Accordingly, the process may have additional steps that those skilled in the art likely would use. In addition, some of the steps may be performed in a different order than that shown, or at the same time. Those skilled in the art therefore can modify the process as appropriate. Moreover, as noted above and below, many of the materials and structures noted are but one of a wide variety of different materials and structures that may be used. Those skilled in the art can select the appropriate materials and structures depending upon the application and other constraints. Accordingly, discussion of specific materials and structures is not intended to limit all embodiments.
- the method begins with step 1810, which couples a fluid channel between the lumbar region of the patient and the ventricle of the patient's brain.
- a physician or other caregiver first may locate an in-vivo lumbar catheter extending from the patient's lumbar, and an in-vivo ventricle catheter extending from the patient's ventricle.
- the ventricle catheter may be mechanically coupled to the lumbar catheter via an intermediate catheter, such as those discussed above, to produce the fluid channel Accordingly, this fluid channel fluidly couples the lumbar and ventricle of the patient.
- the catheter has a lumen configured to transport ASO mixed with CSF of the patient, and an access port to receive an ASO or other therapeutic.
- Step 1820 energizes a pump 18 to cause CSF to flow between the lumbar and the ventricle of the patient.
- the physician or other caregiver adds antisense oligonucleotide material (ASO) to the access port.
- ASO antisense oligonucleotide material
- this step can be performed before, during, and/or after step 1802 — energizing the pump 18.
- the ASO may be added via a bolus to the fluid channel through the access port.
- the ASO may be added more gradually without a bolus as discussed above.
- the fluid channel forms a closed loop configured to circulate CSF and ASO mixture through the ventricle, the body chambers through which CSF flows, the lumbar, and fluid channel in one or two directions.
- a controller 20/22 or other apparatus may manage the pump 18 to cause the ASO/CF mixture to flow at prescribed, non-natural rates in one direction or in two different directions.
- some embodiments may oscillate the mixture so that a prescribed region of the brain receives a more concentrated/focused dose of the ASO.
- illustrative embodiments enable a clinician to more effectively treat various diseases by targeting drug delivery via CSF in the subarachnoid space.
- Various embodiments of the invention may be implemented at least in part in any conventional computer programming language.
- some embodiments may be implemented in a procedural programming language (e.g., "C"), or in an object oriented programming language (e.g., "C"
- C ++ C ++
- Other embodiments of the invention may be implemented as a pre configured, stand-along hardware element and/or as preprogrammed hardware elements (e.g., application specific integrated circuits, FPGAs, and digital signal processors), or other related components.
- preprogrammed hardware elements e.g., application specific integrated circuits, FPGAs, and digital signal processors
- the disclosed apparatus and methods may be implemented as a computer program product for use with a computer system.
- Such implementation may include a series of computer instructions fixed either on a tangible, non-transitory medium, such as a computer readable medium (e.g., a diskette, CD-ROM, ROM, or fixed disk).
- a computer readable medium e.g., a diskette, CD-ROM, ROM, or fixed disk.
- the series of computer instructions can embody all or part of the functionality previously described herein with respect to the system.
- Such computer instructions can be written in a number of programming languages for use with many computer architectures or operating systems.
- such instructions may be stored in any memory device, such as semiconductor, magnetic, optical or other memory devices, and may be transmitted using any communications technology, such as optical, infrared, microwave, or other transmission technologies.
- such a computer program product may be distributed as a removable medium with accompanying printed or electronic documentation (e.g., shrink wrapped software), preloaded with a computer system (e.g., on system ROM or fixed disk), or distributed from a server or electronic bulletin board over the network (e.g., the Internet or World Wide Web).
- a computer system e.g., on system ROM or fixed disk
- a server or electronic bulletin board over the network
- some embodiments may be implemented in a software-as-a- service model ("SAAS") or cloud computing model.
- SAAS software-as-a- service model
- some embodiments of the invention may be implemented as a combination of both software (e.g., a computer program product) and hardware. Still other embodiments of the invention are implemented as entirely hardware, or entirely software.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2022297513A AU2022297513A1 (en) | 2021-06-23 | 2022-06-23 | Method of regulating gene expression |
CA3225436A CA3225436A1 (en) | 2021-06-23 | 2022-06-23 | Method of regulating gene expression |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163214239P | 2021-06-23 | 2021-06-23 | |
US63/214,239 | 2021-06-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2022271938A1 true WO2022271938A1 (en) | 2022-12-29 |
WO2022271938A9 WO2022271938A9 (en) | 2023-12-07 |
Family
ID=84544860
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2022/034706 WO2022271938A1 (en) | 2021-06-23 | 2022-06-23 | Method of regulating gene expression |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU2022297513A1 (en) |
CA (1) | CA3225436A1 (en) |
WO (1) | WO2022271938A1 (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999013886A1 (en) * | 1997-09-17 | 1999-03-25 | East Carolina University | Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications |
US20020004580A1 (en) * | 1997-08-12 | 2002-01-10 | Fueyo Joanna Lynn | ftsZ |
US20030060436A1 (en) * | 1998-11-05 | 2003-03-27 | Clifford Kent Weber Esq. | Treatment of parkinson's disease with oligonucleotides |
US20190009014A1 (en) * | 2015-12-28 | 2019-01-10 | Cognos Therapeutics Inc. | An Apparatus and Method for Cerebral Microdialysis to Treat Neurological Disease, Including Alzheimer's, Parkinson's or Multiple Sclerosis |
US20190085336A1 (en) * | 2016-02-04 | 2019-03-21 | Zhenglun Zhu | Treatment and diagnosis of inflammatory disorders |
US20210023293A1 (en) * | 2019-04-11 | 2021-01-28 | Enclear Therapies, Inc. | Methods of Amelioration of Cerebrospinal Fluid and Devices and Systems Therefor |
-
2022
- 2022-06-23 WO PCT/US2022/034706 patent/WO2022271938A1/en active Application Filing
- 2022-06-23 CA CA3225436A patent/CA3225436A1/en active Pending
- 2022-06-23 AU AU2022297513A patent/AU2022297513A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020004580A1 (en) * | 1997-08-12 | 2002-01-10 | Fueyo Joanna Lynn | ftsZ |
WO1999013886A1 (en) * | 1997-09-17 | 1999-03-25 | East Carolina University | Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications |
US20030060436A1 (en) * | 1998-11-05 | 2003-03-27 | Clifford Kent Weber Esq. | Treatment of parkinson's disease with oligonucleotides |
US20190009014A1 (en) * | 2015-12-28 | 2019-01-10 | Cognos Therapeutics Inc. | An Apparatus and Method for Cerebral Microdialysis to Treat Neurological Disease, Including Alzheimer's, Parkinson's or Multiple Sclerosis |
US20190085336A1 (en) * | 2016-02-04 | 2019-03-21 | Zhenglun Zhu | Treatment and diagnosis of inflammatory disorders |
US20210023293A1 (en) * | 2019-04-11 | 2021-01-28 | Enclear Therapies, Inc. | Methods of Amelioration of Cerebrospinal Fluid and Devices and Systems Therefor |
Also Published As
Publication number | Publication date |
---|---|
CA3225436A1 (en) | 2022-12-29 |
WO2022271938A9 (en) | 2023-12-07 |
AU2022297513A1 (en) | 2024-01-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11577060B2 (en) | Systems and methods for the conditioning of cerebrospinal fluid | |
US10695545B2 (en) | Systems and methods for the conditioning of cerebrospinal fluid | |
EP2133108B1 (en) | Pulsatile flux drug delivery | |
US11278657B2 (en) | Methods of amelioration of cerebrospinal fluid and devices and systems therefor | |
US20220313890A1 (en) | Method of regulating gene expression | |
AU2021357810A1 (en) | System and method for controlling csf flow and managing intracranial pressure | |
US20220096745A1 (en) | Subarachnoid fluid conduit system and kit | |
WO2022271938A1 (en) | Method of regulating gene expression | |
CN116471981A (en) | Subarachnoid fluid management methods and systems | |
US20220355015A1 (en) | Csf diagnostics platform | |
US20230321412A1 (en) | System and method for managing cancer cells in csf | |
AU2022315184A1 (en) | Csf diagnostics platform | |
US20230355118A1 (en) | System and method for monitoring physiological parameters based on cerebrospinal fluid pressures taken at two or more locations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22829302 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: AU2022297513 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 3225436 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2022297513 Country of ref document: AU Date of ref document: 20220623 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022829302 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022829302 Country of ref document: EP Effective date: 20240123 |