- Scientists develop novel "complement
inhibitor" therapy that reduces brain tissue inflammation and nerve cell
damage following stroke with better recovery of neurological deficits.
- Currently tissue plasminogen activator (tPA),
a so-called 'clot buster' drug, is the only pharmacological stroke
intervention available has certain limitations.
- Ischemic stroke due to clot is one of the major causes of mortality
and morbidity worldwide, especially in the elderly.
New stroke therapy developed that locally inhibits complement around stroke area minimizing tissue injury
but does not affect functioning of complement in other areas of the
body. This novel therapy has been created by a team of investigators at the
Medical University of South Carolina (MUSC) and successfully tested in a
preclinical model. Their findings of the study appear in an article published
online in the journal Science Translational
Aim of New Complement Inhibitor
The team believe that the inhibition of complement will limit neuronal damage to
the core area of stroke while preventing the extension of damage to the adjacent
increasing the area of brain involved.
an ischemic core where the greatest oxygen deprivation occurs during an
ischemic stroke. Neurons in that area are irreparably damaged and die. But
damaged neurons outside the stroke core can be salvaged," explains
principal investigator and senior author Stephen Tomlinson, Ph.D., professor
and vice chair for research and faculty development in MUSC's Department of
Microbiology & Immunology.
‘Novel complement inhibitor B4Crry seems to be safe and more effective in reducing brain damage and neurological deficits following stroke.’
"Unfortunately, complement becomes
activated and signals that these damaged neurons should be cleared from the
brain before they get a chance to recover."
Analyzing Effect of Complement in Stroke
study team did a series of experiments to outline the role of complement in
stroke since it contributes to neuro-degenerative as well as neuro-regenerative processes.
During these tests, they found that microglial
phagocytosis (ingestion by microglia) of neurons
, a previously described
phenomenon also occurs after stroke.
were seeing neuronal material inside the microglial cells and, at first, we
thought it must be some sort of artifact. It was a surprise," says Alawieh
"So, we repeated the experiment several times to be sure that phagocytosis
of live neurons was really what was happening. We didn't previously know that
occurred in the perilesional area after stroke."
- The team found that live but stressed neurons around the stroke
area display danger-associated molecular patterns (DAMPs; also called
neoepitopes) that stimulate complement
C3d deposition on the outer cell membrane. The C3d marks the neuron
for rapid elimination by
- This 'quick response' mechanism
helps explain the rapid loss of neurons observed in the perilesional area.
- Even more importantly, this
mechanism also promotes a
pro-inflammatory environment that drives significant chronic
inflammation and tissue damage after the stroke.
Why Brain Tissue Adjacent to
Stroke Area Becomes Damaged
The cells injured and destroyed by
stroke release harmful chemicals into the adjacent area and these neurons
temporarily go into a "shut-down mode" as a protective response. The patient's
immune system including complement mistakenly recognizes these non-functioning
cells as damaged cells that have to be cleared and thus these normal cells are
also eliminated (increasing the area of injury).
in stroke, complement becomes
pathological and inappropriately marks live
neurons for elimination.
Testing Complement Inhibitor Therapy in Preclinical Model - Study
- To inhibit the above processes, the
team created a novel therapeutic agent to inhibit complement activation
locally in areas where nerve cells express DAMPs (or neoepitopes).
- They joined an antibody fragment
that recognizes a post-ischemic neoepitope (the vehicle) to a complement
inhibitor dubbed B4Crry- and tested it in a murine stroke model.
- They B4Crry was found to bind to
(oxygen-deprived) cells and inhibit complement activation but did not bind to normally oxygenated
- The B4Crry had a short circulatory
half-life but a prolonged (35-hour) tissue half-life, ensuring that complement
inhibition would be limited to affected brain tissue and not affect systemic serum complement
- Animals treated with B4Crry showed
reduced C3d deposition in the post-stroke brain, lesser neurological deficits and a lesser infarct volume 24 hours
post-stroke in comparison to control animals.
- Over a 15-day recovery period,
B4Crry-treated animals had fewer
neurological deficits and
smaller lesions as well as better recovery of
initial deficits compared to control animals.
- Overall, the B4Crry-treated group
showed quicker learning curves, better learned memory retention, and a
four-fold increase in cortical and hippocampal neuroblasts compared to
- Importantly, B4Crry was found to be
effective in male, female, adult and aged animals, and effects were present over a 30-day
period and in animals treated
as late as 24 hours post-stroke.
Potential Merits of the Novel B4Crry Agent
- B4Crry shows a longer treatment window than for tissue plasminogen activator
(tPA), a so-called 'clot buster' drug, currently the only pharmacological
- Also, unlike tPA, B4Crry, could in theory be administered to persons
who are at risk for bleeding, a finding that needs to be validated in
human clinical trials.
- B4Crry, did not increase infection risk, since systemic complement
inhibition is known to increase risk of infections following stroke, thus
offering a critical advantage.
inhibitor is specifically targeted to the site of injury in the brain so it can
be administered at a dose that does not impact systemic complement
activity," explains Tomlinson. "That way we don't affect the
patient's complement system immune mechanism and don't increase the risk for
infections such as pneumonia
The perilesional area is a therapeutic target for stroke treatments because
that's where neurons can be still salvaged. Complement is deposited and
microglia attack neurons that could otherwise recover their function. We found
that B4Crry prevented microglial phagocytosis of these live neurons."
Scope of Study and Future Plans
team has already investigated the role of this approach in other conditions, such as cardiovascular
plan to further study complement inhibition treatment in Traumatic Brain Injury
(TBI) to understand how
complement-dependent mechanisms impact the prognosis of TBI
have demonstrated that the B4 epitope is expressed on other damaged human
tissues as well and plan to take forward B4Crry therapy in clinical trials with
human patients in the near future.
- Ali Alawieh, E. Farris Langley and Stephen Tomlinson, "Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice", Science Translational Medicine (2018) DOI: 10.1126/scitranslmed.aao6459