Collection and Characterisation of Human Olfactory Ensheathing Cells

We aim to retrieve olfactory bulbs (OBs) from suitable human donors. We have defined two groups who will qualify:

Group 1 - Deceased Donors:

1A: Donors after brainstem death (DBDs) undergoing solid organ donation

1B: Donors after brainstem death (DBDs) considered unsuitable for solid organ donation

Group 2 - Living Donors:

Neurosurgical patients undergoing anterior cranial surgery in which the olfactory nerve (ON) is cut as part of the surgical procedure. The OB of the concomitant severed ON would be donated.

We aim to optimise OB collection and Olfactory Ensheathing Cell (OEC) culture and storage. We will study the effects of patient diagnosis, age, cause of death (if applicable), co-morbidities and warm ischaemic time on cell survival and regenerative function.

In future studies we aim to store OECs in a GMP facility and transplant OECs into patients with spinal cord injuries.

Study Overview

• Status: Recruiting
• Conditions: Spinal Cord Injury
• Intervention / Treatment: Procedure: Frontal Craniotomy and retrieval of OBs; Procedure: OB Retrieval During Anterior Cranial Surgery

Detailed Description

Spinal cord injury (SCI) is a devastating condition. To date there is no treatment to improve outcome. There is limited regenerative capacity of the central nervous system (CNS), such that damaged neurons and severed axons are not replaced.

A substantial body of evidence suggests that olfactory ensheathing cells (OECs) obtained from olfactory bulbs (OBs) facilitate neuronal regeneration in rodents and humans with SCI. Indeed, transplanting autologous OECs from an OB into the injury site improved neurological outcome in a patient with SCI.

Harvesting autologous OBs to culture OECs has several disadvantages:

1. If the OECs do not grow in vitro, the transplantation is abandoned;
2. The retrieval procedure exposes a paralysed patient to the risks of craniotomy;
3. Excising an OB can impair the sense of smell; and
4. The number of OECs obtained is limited to one OB.

Investigators will collect human OECs from suitable donors which we have defined as two groups. Group 1 patients will be brain dead donors identified by the neuro-intensive care team as potential candidates for solid organ donation. The OBs will be retrieved as near to death as possible. Group 2 patients will be living donors undergoing elective neurosurgery in which the olfactory nerve is sacrificed as part of that procedure.

There are two OBs located at the anterior skull base, responsible for transmitting the sensation of smell from the nose to the brain. Obtaining OECs requires a craniotomy (opening the skull) to remove the OBs.

PHASE 1 will be divided into 2 stages. In stage 1 we will culture OECs and characterise them in the central laboratory. We aim to determine how the yield of OECs and their regenerative properties are affected by freeze-thaw, time left at room temperature and time left at 40C before culture as well as patient age. Each harvested sample will be transferred to the lab for further processing. Processing includes but is not limited to histological fixation, sectioning and staining, cell culture and storage. Some OECs will be frozen in liquid nitrogen to determine whether they can indeed be stored. In stage 2 we will transfer OECs outside St. George's to a GMP facility (to be determined). In the GMP facility, the OECs will be processed and stored according to the optimised conditions we have determined.

In PHASE 2, the OECs will be transplanted into patients with SCI.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Marios Papadopoulos, FRCS (SN); Phone Number: 02087254179; Email: mpapadop@sgul.ac.uk
• Study Contact Backup: Name: Florence Hogg, MBChB; Email: fhogg@sgul.ac.uk

Study Locations

• United Kingdom
  • Tooting
    • London, Tooting, United Kingdom, SW17 0QT
      • Recruiting
      • St George's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Deceased brain dead donors and living patients undergoing anterior cranial surgery in which the ON may be sacrificed as routine part of the procedure.

Description

Inclusion criteria:

Group 1 - Deceased Donors 1A

1. Diagnosis of brainstem death, AND
2. Consent from next of kin (NoK) for organ donation
3. Consent from NoK for removal of olfactory bulbs (OBs)
4. Coroner's consent for removal of OBs (when needed).

1B

1. Diagnosis of brainstem death, AND
2. Contraindications for solid organ donation
3. Consent from NoK for removal of OBs
4. Coroners consent for removal of OBs (when needed)

Group 2 - Living Donors

1. Patients having anterior cranial surgery in which the ON may be cut or removed as part of the procedure.
2. Consent from the operating surgeon to remove the OB of the corresponding ON in the event it is cut during the operation
3. Consent from the patient for removal of the OB of the corresponding ON in the event it is cut during the operation

Exclusion criteria:

1. Children (<18 years old)
2. Damage to anterior skull base including OBs
3. Meningitis

And applicable to group 2 only:

Patients unable to consent for surgery

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Other

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group 1A: Donors after brainstem death (DBDs) undergoing solid organ donation	Procedure: Frontal Craniotomy and retrieval of OBs; For Group 1A the craniotomy will occur during organ retrieval for transplantation under aseptic technique. For Group 1B it would occur as a separate surgical procedure prior to palliation under full asepsis.
Group 1B: Donors after brainstem death (DBDs) considered unsuitable for solid organ donation	Procedure: Frontal Craniotomy and retrieval of OBs; For Group 1A the craniotomy will occur during organ retrieval for transplantation under aseptic technique. For Group 1B it would occur as a separate surgical procedure prior to palliation under full asepsis.
Group 2: Neurosurgical patients undergoing anterior cranial surgery in which the olfactory nerve (ON) is cut as part of the surgical procedure. The OB of the concomitant severed ON would be donated.	Procedure: OB Retrieval During Anterior Cranial Surgery; Group 2: The patients routine anterior cranial surgery would proceed as planned without change to the surgical procedure. In the event that the ON had to be sacrificed for the purposes of surgery the OB of the concomitant nerve would be retrieved.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to culture olfactory ensheathing cells from human donors	Number of olfactory ensheathing cells cultured per olfactory bulb at days 10-15 in vitro.	10-15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of cause of death for Group 1 donors	Plot of cause of death vs. Number of olfactory ensheathing cells cultured per olfactory bulb at days 10-15 in vitro.	10-15 days
Effect of patient age	Plot of patient age vs. Number of olfactory ensheathing cells cultured per olfactory bulb at days 10-15 in vitro.	10-15 days
Effect of freeze/thaw cycles	Plot of number of freeze/thaw cycles vs. Number of olfactory ensheathing cells cultured at days 10-15 in vitro.	10-15 days
Effect of storage in liquid nitrogen	Plot of Number of olfactory ensheathing cells cultured at days 10-15 in vitro when cells are cultured fresh vs. after one week and one month storage in liquid nitrogen.	up to 1 month
Effect of time from extraction to culture at room temperature	Plot of time from extraction to culture vs. Number of olfactory ensheathing cells cultured.	1 month
Effect of time from extraction to culture at 4 deg C	Plot of time from extraction to culture at 4 deg C vs. Number of olfactory ensheathing cells cultured.	1 month

Collaborators and Investigators

• Sponsor: St George's, University of London
• Investigators: Principal Investigator: Marios Papadopoulos, FRCS (SN), St George's, University of London; Principal Investigator: Samira Saadoun, PhD, St George's, University of London

Publications and helpful links

General Publications

• Tabakow P, Jarmundowicz W, Czapiga B, Fortuna W, Miedzybrodzki R, Czyz M, Huber J, Szarek D, Okurowski S, Szewczyk P, Gorski A, Raisman G. Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury. Cell Transplant. 2013;22(9):1591-612. doi: 10.3727/096368912X663532.
• Miedzybrodzki R, Tabakow P, Fortuna W, Czapiga B, Jarmundowicz W. The olfactory bulb and olfactory mucosa obtained from human cadaver donors as a source of olfactory ensheathing cells. Glia. 2006 Nov 1;54(6):557-65. doi: 10.1002/glia.20395.
• Raisman G. Olfactory ensheathing cells and repair of brain and spinal cord injuries. Cloning Stem Cells. 2004;6(4):364-8. doi: 10.1089/clo.2004.6.364.
• Li Y, Decherchi P, Raisman G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing. J Neurosci. 2003 Feb 1;23(3):727-31. doi: 10.1523/JNEUROSCI.23-03-00727.2003.
• Keyvan-Fouladi N, Li Y, Raisman G. How do transplanted olfactory ensheathing cells restore function? Brain Res Brain Res Rev. 2002 Oct;40(1-3):325-7. doi: 10.1016/s0165-0173(02)00215-1.
• Raisman G. Olfactory ensheathing cells - another miracle cure for spinal cord injury? Nat Rev Neurosci. 2001 May;2(5):369-75. doi: 10.1038/35072576.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2018
• Primary Completion (Anticipated): June 1, 2021
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: April 26, 2016
• First Submitted That Met QC Criteria: August 12, 2016
• First Posted (Estimate): August 17, 2016

Study Record Updates

• Last Update Posted (Actual): May 4, 2018
• Last Update Submitted That Met QC Criteria: May 1, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Olfactory ensheathing cells
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Trauma, Nervous System; Spinal Cord Diseases; Spinal Cord Injuries
• Other Study ID Numbers: 16.0069

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Study Data/Documents

1. Individual Participant Data Set
   Information comments: The project documents will be available directly from the research team. Please e-mail Dr Florence Hogg fhogg@sgul.ac.uk