Treatment of Severe Adult Traumatic Brain Injury Using Bone Marrow Mononuclear Cells

Traumatic brain injury (TBI) contributes to 50% of all trauma deaths. The mortality rate for
adults following severe TBI (Glasgow Coma Scale < 9) is estimated to be 33%. There is
currently no therapy to reverse the primary injury associated with TBI. Over the past 10
years there has been a growing body of literature supporting the use of various progenitor
cell types to treat acute neurological injuries such as TBI and stroke. Neural stem cells
(adult and embryonic), mesenchymal stromal and multipotent adult progenitor cells, and bone
marrow mononuclear cells (from which MSC and MAPCs are derived) have all shown efficacy in
pre-clinical models of TBI/stroke through various mechanisms; however, few groups believe
that true neural replacement and integration are the putative mechanisms involved in the
observed efficacy. More likely is that the progenitor cell populations are modifying the
regional response to injury (inflammatory/reparative vs. regenerative), resulting in
improved functional outcomes. Our primary hypothesis is that bone marrow mononuclear cell
(BMMNC) autologous transplantation after TBI is safe (harvest and infusion related toxicity)
after TBI. Our secondary hypothesis is that functional outcomes measures will improve after
BMMNC infusion, (3) BMMNC infusion will reduce BBB permeability, (4) BMMNC is
neuroprotective and preserves grey matter and white matter volumes after TBI.

Patients, ages18 to 55 years old, admitted to Memorial Hermann Hospital Trauma Center with
Glasgow Coma Scores (GCS) of 5 to 8 will be screened. Those patients meeting
inclusion/exclusion criteria (or their Legal Authorized Representative [LAR]) will be
offered consent to participate. This is a dose-escalation study consisting of 4 cohorts
including a control group (5 subjects/cohort). The first five subjects will not undergo the
bone marrow harvest procedure; though they will be followed and treated the same as the
other study participants and complete all follow-up procedures. Subjects 6-10 will receive
the lowest dose target of 6X106 mononuclear cells/kilogram body weight. Subjects 11-15 will
receive 9x106 mononuclear cells/kilogram body weight, and lastly Subjects 16-20 will receive
12X106 mononuclear cells/kilogram body weight. The study is NOT powered to detect functional
measures of efficacy. However, estimates can be made regarding potential treatment effect
sizes to allow rational power analyses for the follow-on Phase II study. This study should
determine if bone marrow harvest, BMMNC separation, and reinfusion is safe in adults with
acute, severe TBI.

Inclusion Criteria:

- Between 18 and 55 years of age on the day of injury;

- Hospital admission Glasgow Coma Score between 5 and 8;

- Initial injury occurring less than 24 hours prior to consent;

- Ability to speak English.

Exclusion Criteria:

- Known history of:

1. brain injury,

2. psychiatric disorder,

3. neurological impairment and/or deficit

4. seizure disorder requiring anti-convulsant therapy

5. recently treated infection

6. renal disease or altered renal function

7. hepatic disease or altered liver function

8. cancer

9. substance abuse of positive urine drug screen at admission

10. immunosuppression

11. HIV

- Obliteration of perimesencephalic cistern on initial head CT suggesting prolonged
hypoxic ischemic insult

- Initial hospital ICP > 40mm Hg

- Hemodynamic instability at the time of consent defined as ongoing fluid resuscitation
and/or requirement for inotropic support to maintain MAP at or above normals for age
- does not include CPP based inotropic support

- Uncorrected coagulopathy at the time of bone marrow harvest defined as INR >1.6, PTT
>36 sec, PLT < 100,000, Fibrinogen < 100g/dL

- Unstable pelvic fractures defined as requiring operative fixation to manage

- Pulmonary contusions defined as a chest x-ray with non-anatomic opacification and/or
PaO2:FIO2 ratio < 250 associated with the mechanism or injury

- Greater than AAST Grade I solid or hollow visceral injury of the abdomen and/or
pelvis as diagnosed by CT or other imaging

- Spinal cord injury as diagnosed by CT or MR imaging or clinical findings

- Persistent hypoxia defined as SaO2 < 94% for > 30 minutes occurring at any time from
hospital admission to time of consent

- Weight > 300 lbs

- Any contraindication to MRI (including being too large to fit into the MRI)

- Positive urine pregnancy test

- Participation in a concurrent intervention study

- Unwillingness to return for follow-up visits