Systems and methods for delivery of a therapeutic agent
View Patent ↗Methods and apparatus are provided for applying an fragment of a neurotoxin such as the active light chain (LC) of the botulinum toxin (BoNT), such as one of the serotype A, B, C, D, E, F or G botulinum toxins, via permeabilization of targeted cell membranes to enable translocation of the botulinum neurotoxin light chain (BoNT-LC) molecule across the targeted cell membrane to the cell cytosol where a therapeutic response is produced in a mammalian system. The methods and apparatus include use of catheter based delivery systems, non-invasive delivery systems, and transdermal delivery systems.
1. A method for treating a neuromuscular spasm in a targeted region of mammalian tissue, said method comprising:
delivering an active neurotoxin fragment consisting of a light chain of the neurotoxin throughout the targeted region; and
focusing energy on membranes of cells within the target region under conditions which cause a reversible poration in said cell membranes to permit entry of the active fragment into the cytosols of said cells, wherein cells within the targeted region which do not receive focused energy are not porated and do not receive active fragments into their cytosols.
2. A method as in claim 1 , wherein the active fragment consists of the botulinum light chain (BoNT-LC).
3. A method of claim 2 , wherein the active fragment comprises an amount of BoNT-LC therapeutically effective to inhibit a neurogenic pathway associated with the neuromuscular spasm.
4. A method of claim 3 , wherein the active fragment is BoNT-LC derived from at least one of the botulinum toxins A, B, C, D, E, F or G.
5. A method of claim 1 , wherein the neuromuscular spasm is associated with at least one condition selected from the group consisting of cervical dystonia, strabismus, blepharospasm, spasmodic dystonia, focal dystonia, writer's cramp, fibromyalgia, rhytides, glabellar lines, upper limb spasticity, Meige's syndrome and combination thereof.
6. A method of claim 1 , wherein delivering comprises advancing a catheter to said targeted region and releasing the active neurotoxin fragments from the catheter while applying energy from an applicator on the catheter.
7. A method of claim 6 , wherein delivering comprises aerosolizing the fragment from the catheter.
8. A method as in claim 6 , wherein delivering comprises injecting the fragment from a needle on the catheter.
9. A method as in claim 6 , wherein delivery comprises engaging one or more ports on the catheter against tissue and releasing the fragments from the port(s).
10. A method as in claim 9 , wherein engaging comprises inflating a balloon on the catheter to deflect the catheter.
11. A method of claim 1 , wherein the delivering is achieved using an inhaler.
12. A method of claim 1 , wherein the delivering is achieved transdermally
13. A method of claim 1 , wherein the energy applied to the targeted region is an electric pulse.
14. A method of claim 13 , wherein the electric pulse has a voltage between 1V and 500V.
15. A method of claim 13 , wherein the electric pulse comprises radiofrequency energy.
16. A method of claim 15 , wherein the radiofrequency energy is pulsed for durations between 5 microseconds to 100 milliseconds.
17. A method of claim 12 , wherein the electric pulse comprises a direct current pulse.
18. A method of claim 12 , wherein the electric pulse comprises an alternating current pulse.
19. A method of claim 1 , wherein the energy applied to the targeted region comprises ultrasonic energy.
20. A method of claim 19 , wherein the ultrasonic energy applied to the targeted region comprises focused ultrasound energy.
21. A method of claim 1 , wherein the energy applied to the targeted region comprises an x-ray beam.
22. A method of claim 1 , wherein the energy applied to the targeted region comprises microwave energy.
23. A method of claim 3 , wherein the neurogenic pathway is associated with and contributes to at least one symptom of pain.
24. A method of treating a respiratory ailment, comprising:
delivering a non-toxic therapeutically effective amount of a neurotoxin fragment consisting of BoNT-LC throughout a targeted region of the respiratory system; and
permeabilizing the membranes of some but not all cells within the region to allow entry of the BoNT-LC into the permeabilized cells only.
25. A method for treating a respiratory ailment in a patient, the method comprising:
delivering an active neurotoxin fragment consisting of a light chain of the neurotoxin throughout a targeted region of the respiratory system of the patient; and
focusing energy to some but not all cells in the targeted region under conditions which cause a reversible poration in the cell membranes which receive the energy to permit entry of the active fragment into cytosols of the cells which receive the energy but not to cells within the targeted region which do not receive the energy.
26. A method as in claim 25 , wherein the botulinum toxin fragment consists of the botulinum light chain (BoNT-LC).
27. A method as in claim 26 , wherein the active fragment comprises an amount of BoNT-LC therapeutically effective to inhibit a neurogenic pathway associated with the respiratory ailment.
28. A method as in claim 27 , wherein the active fragment is BoNT-LC derived from at least one of the botulinum toxins A, B, C, D, E, F or G.
29. A method of claim 25 , wherein delivering comprises advancing a catheter to the targeted region and releasing the BoNT-LC from the catheter.
30. A method of claim 29 , wherein releasing the BoNT-LC from the catheter further comprises aerosolizing the BoNT-LC from the catheter.
31. A method as in claim 29 , wherein delivering further comprises engaging one or more ports on the catheter against tissue and releasing the BoNT-LC from the port(s).
32. A method as in claim 31 , wherein engaging one or more ports on the catheter against tissue comprises inflating a balloon on the catheter to deflect the catheter.
33. A method of claim 25 , wherein applying energy to the target cells further comprises applying ultrasonic energy to the target cells.
34. A method of claim 33 , wherein applying ultrasonic energy to the target cells comprises applying focused ultrasound energy.
35. A method of claim 25 , wherein the respiratory ailment is selected from the group consisting of asthma, rhinitis, rhinorrea, chronic obstructive pulmonary disease, cystic fibrosis and combinations thereof.