Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system
BACKGROUND: The intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood-brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys.
METHODS: There are three studies presented, in each of which cynomolgus monkeys were injected into the IT space with radioactive tracer molecules and/or ASO by lumbar puncture in either a low or high volume. The first study used the radioactive tracer 64Cu-DOTA and PET imaging to evaluate the effect of the convective forces. The second study combined the injection of the radioactive tracer 99mTc-DTPA and ASO, then used SPECT imaging and ex vivo tissue analysis of the effects of convective forces to bridge between the tracer and the ASO distributions. The third experiment evaluated the effects of different injection volumes on the distribution of an ASO. In the course of performing these studies we also measured the CSF volume in the subject monkeys by Magnetic Resonance Imaging.
RESULTS: It was consistently found that larger bolus dose volumes produced greater rostral distribution along the neuraxis. Thoracic percussive treatment also increased rostral distribution of low volume injections. There was little added benefit on distribution by combining the thoracic percussive treatment with the high-volume injection. The CSF volume of the monkeys was found to be 11.9 ± 1.6 cm3.
CONCLUSIONS: These results indicate that increasing convective forces after IT injection increases distribution of molecules up the neuraxis. In particular, the use of high IT injection volumes will be useful to increase rostral CNS distribution of therapeutic ASOs for CNS diseases in the clinic.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
|---|---|
| Enthalten in: |
Journal of translational medicine - 18(2020), 1 vom: 08. Aug., Seite 309 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sullivan, Jenna M [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antisense oligonucleotide |
|---|
| Anmerkungen: |
Date Completed 14.05.2021 Date Revised 14.05.2021 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1186/s12967-020-02461-2 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM313460027 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM313460027 | ||
| 003 | DE-627 | ||
| 005 | 20231225150622.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12967-020-02461-2 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1044.xml |
| 035 | |a (DE-627)NLM313460027 | ||
| 035 | |a (NLM)32771027 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sullivan, Jenna M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.05.2021 | ||
| 500 | |a Date Revised 14.05.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: The intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood-brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys | ||
| 520 | |a METHODS: There are three studies presented, in each of which cynomolgus monkeys were injected into the IT space with radioactive tracer molecules and/or ASO by lumbar puncture in either a low or high volume. The first study used the radioactive tracer 64Cu-DOTA and PET imaging to evaluate the effect of the convective forces. The second study combined the injection of the radioactive tracer 99mTc-DTPA and ASO, then used SPECT imaging and ex vivo tissue analysis of the effects of convective forces to bridge between the tracer and the ASO distributions. The third experiment evaluated the effects of different injection volumes on the distribution of an ASO. In the course of performing these studies we also measured the CSF volume in the subject monkeys by Magnetic Resonance Imaging | ||
| 520 | |a RESULTS: It was consistently found that larger bolus dose volumes produced greater rostral distribution along the neuraxis. Thoracic percussive treatment also increased rostral distribution of low volume injections. There was little added benefit on distribution by combining the thoracic percussive treatment with the high-volume injection. The CSF volume of the monkeys was found to be 11.9 ± 1.6 cm3 | ||
| 520 | |a CONCLUSIONS: These results indicate that increasing convective forces after IT injection increases distribution of molecules up the neuraxis. In particular, the use of high IT injection volumes will be useful to increase rostral CNS distribution of therapeutic ASOs for CNS diseases in the clinic | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Antisense oligonucleotide | |
| 650 | 4 | |a CT imaging | |
| 650 | 4 | |a Convective forces | |
| 650 | 4 | |a Intrathecal | |
| 650 | 4 | |a Lumbar puncture | |
| 650 | 4 | |a PET imaging | |
| 650 | 4 | |a SPECT imaging | |
| 650 | 7 | |a Oligonucleotides, Antisense |2 NLM | |
| 700 | 1 | |a Mazur, Curt |e verfasserin |4 aut | |
| 700 | 1 | |a Wolf, Daniel A |e verfasserin |4 aut | |
| 700 | 1 | |a Horky, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Currier, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzsimmons, Bethany |e verfasserin |4 aut | |
| 700 | 1 | |a Hesterman, Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a Pauplis, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Haller, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Powers, Berit |e verfasserin |4 aut | |
| 700 | 1 | |a Tayefeh, Leighla |e verfasserin |4 aut | |
| 700 | 1 | |a DeBrosse-Serra, Bea |e verfasserin |4 aut | |
| 700 | 1 | |a Hoppin, Jack |e verfasserin |4 aut | |
| 700 | 1 | |a Kordasiewicz, Holly |e verfasserin |4 aut | |
| 700 | 1 | |a Swayze, Eric E |e verfasserin |4 aut | |
| 700 | 1 | |a Verma, Ajay |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of translational medicine |d 2003 |g 18(2020), 1 vom: 08. Aug., Seite 309 |w (DE-627)NLM142679194 |x 1479-5876 |7 nnns |
| 773 | 1 | 8 | |g volume:18 |g year:2020 |g number:1 |g day:08 |g month:08 |g pages:309 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12967-020-02461-2 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 18 |j 2020 |e 1 |b 08 |c 08 |h 309 | ||