MANF protein may ease TBI symptoms

MANF Therapeutics restarts IND-enabling work in light of new results

Rachel Flehinger
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NEW YORK—MANF Therapeutics Inc., a subsidiary of Amarantus Bioscience Holdings named after the promising protein integral to its primary research and indication, has announced the publication of a new article promising significant results in the treatment of traumatic brain injury (TBI). The study, entitled “MANF prevents traumatic brain injury in rats by inhibiting inflammatory activation and protecting Blood Brain Barrier,” was published in World Neurosurgery by researchers at Anhui Medical University and the University of Science & Technology of China Hefei. The results suggest that MANF may provide noteworthy protection against long-term neurological effects of TBI.
MANF refers to a naturally occurring protein in the human body—mesencephalic-astrocyte-derived neurotrophic factor. MANF is considered a highly promising regenerative candidate, showing positive outcomes on a number of orphan diseases including retinitis pigmentosa, Parkinson’s diseases, diabetes and Wolfram’s syndrome. MANF Therapeutics is currently looking at its potential for treatment of Alzheimer’s disease, myocardial infarction and antibiotic-induced ototoxicity (being toxic to the ear, namely the inner ear) in addition to the traumatic brain injury findings recently reported.
Research shows that MANF seems to work through the unfolded protein response to reduce or prevent cell death following trauma or injury. According the company’s press release, “MANF provides neuroprotective effect against acute brain injury after TBI, via attenuating BBB disruption and intracranial neuroinflammation, while the inhibition of NF-B signaling pathway could be a potential mechanism.” In other words, after a brain injury, heightened amounts of the MANF protein lessened the egregious effects of impact on the blood-brain-barrier (BBB), and thus lowered the risks of cerebral edema and inflammation.
Scientists found that in immediate aftermath of traumatic brain injury in rats, the body naturally flooded the brain with endogenous MANF. By adding a high dose of recombinant human MANF, the impact of TBI was dramatically reduced. Specifically, MRI’s conducted after the injury and following a high dose of exogenously produced MANF indicated a lower brain-water-content measurement. Likewise, the testing showed an increase in their modified Garcia score, which measures six indices of sensorimotor deficits, while also alleviating the blood-brain barrier permeability—a finding of particular interest to the scientists.
“The fact that MANF acts to restore the blood-brain barrier is highly consequential in terms of restoring one of the body’s crucial protective mechanisms. Further studies are required to understand how this mechanism would affect drug development,” asserts Gerald Commissiong, CEO of MANF Therapeutics.
MANF was initially identified by parent company Amarantus’ own platform, the PhenoGuard protein discovery engine. In 2017, Amarantus formed MANF Therapeutics as a wholly owned subsidiary to continue preclinical development of MANF, initially for the treatment of ophthalmological disorders. Amarantus entered into a manufacturing agreement with Catalent Pharma Solutions for clinical-grade production of MANF, with Catalent providing all cell line engineering, process development and clinical Good Manufacturing Practices (cGMP) biomanufacturing activities. Through that partnership, MANF Therapeutics had the tools for the rapid development of a high-performance cell line expressing the MANF protein, thus enabling them to scale up for cGMP production.
The MANF protein has proven to be effective in managing other diseases attributed to inflammatory response, and had begun Investigational New Drug (IND)-enabling  development to utilize MANF for ophthalmological conditions, including RAO and retinitis pigmentosa, back in 2016. It has already been granted orphan drug designations from the FDA for these conditions and has shown promise as a potential treatment for glaucoma, Parkinson’s, Alzheimer’s, diabetes and cardiovascular issues such as stroke and myocardial infarction. The results regarding its use in treating TBI, however, suggest a potential new indication, and has prompted the company to restart the IND preparations. Amarantus has retained regulatory expertise to identify the fastest path to human proof-of-concept data by evaluating well-respected regulatory pathways available worldwide and is targeting the initiation of first-in-man clinical studies for MANF in 2019.
“These findings mean we will re-initiate cGMP manufacturing for MANF,” states Commissiong. “This news is important because it speaks to MANF’s broad potential to protect brain cells from injury, and outlines key mechanisms into MANF’s biological function. Amarantus is developing the therapeutic protein MANF for various indications of the central nervous system, primarily ophthalmology and Parkinson’s. We may expand that list of indications over time as resources become available.”

Rachel Flehinger

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