Dr. Michal Schwartz and colleagues (Rehovot, Israel)
founded Proneuron, a SCI-focused biotechnology company whose mission
is to develop immunological approaches that minimize post-injury
neurological damage. Inspired by Hippocrates’ ancient wisdom that “natural
us are the true healers of disease,” Schwartz uses the body’s inherent
healing mechanisms to develop therapeutic approaches that proactively
augment naturally occurring autoimmune processes.
Specifically, the investigators use activated
macrophages (a white blood cell) isolated from patient’s blood to reduce
neurological damage after acute SCI. Although healing immune cells are
scarce in the “immune-privileged” central nervous system, Schwartz and her
colleagues haves circumvented this limitation by incubating the patient’s
macrophage-containing blood with skin tissue. The isolated macrophages are
then surgically implanted into the spinal cord within 14 days of injury.
By mediating protective immune responses, these activated macrophages
theoretically promote functional recovery.
In 2005, Dr. Nachshon Knoller and Proneuron
colleagues reported the results of a preliminary phase I clinical trial
in which eight individuals with acute SCI were treated with such
skin-activated macrophages. Age ranged from 18 to 65 years (mean 27
years), seven of the eight subjects were men, and five had been injured
from traffic accidents. All had sustained ASIA-A-complete injuries
ranging from the C5 to T11 level within two weeks of treatment.
To prepare the activated macrophages, 200
milliliters of blood was collected, and a 10x3-centimeter strip of skin
was excised from the patient’s arm. Macrophages isolated from the blood
were incubated for one day with the skin tissue and then harvested.
After surgically exposing the injured cord through a laminectomy and
opening of protective membranes, four-million cells were injected into
the area right below (i.e., caudal) the injury-site lesion.
Functional improvement was measured over the course
of a year using ASIA assessment standards and various
electrophysiological measurements. Of the eight patients treated, three
improved from ASIA A to C (complete injury to partial motor and sensory
recovery). Electrophysiological measurements indicated restoration of
some nerve conductivity in most subjects during the follow-up period.
Although adverse events were observed during the study period, none were
attributed to the therapeutic intervention per se.
Proneuron initiated a much larger phase-II clinical
trial intending to recruit 61 patients at several treatment sites in
Israel and the USA. In 2006, Proneuron suspended the trial, stressing
that this action was not due to any safety or clinical issues.
In 2009, Dr. Daniel Lammertse (USA), one of
the trial’s study directors, reported the results obtained in subjects
recruited and evaluated before the study was stopped. Of the 50 subjects
recruited, efficacy data had been collected on 40. Approximately, 29% of
the macrophage-treated subjects improved from ASIA-A complete injuries
to ASIA-B incomplete injuries. In contrast, about 62% of the untreated
control subject made the same transition. In other words, the controls
did better. The investigators concluded: “The results do not support the
clinical use of autologous incubated macrophage therapy for complete
In a 2012 publication, Dr. Lammertse and
investigative-team colleagues confirmed these results. This article
reported that efficacy data now had been collected on 43 participants.
Seven treatment and 10 of control participants had improved from ASIA-A
to ASIA-B injuries. In addition, two treatment and two control
participants converted from ASIA-A to ASIA-C. The investigators
concluded: “Although these results do not support treatment of complete
SCI with autologous incubated macrophage therapy as specified in this
protocol, it is hoped that ongoing preclinical research will yield
improved methods of producing a therapeutic cell phenotype and less
invasive cell delivery.”