Parkinson’s potential

MANF protein proves capable of protecting dopaminergic neurons, staving off motor dysfunction

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NEW YORK—July saw MANF Therapeutics Inc., a wholly owned subsidiary of Amarantus Bioscience Holdings Inc., share news of a recent study focused on the therapeutic protein mesencephalic astrocyte-derived neurotrophic factor (MANF) that the company specializes in advancing. The article in question, “MANF protects dopamine neurons and locomotion defects from a human alpha-synuclein induced Parkinson’s disease model in C. elegans by regulating ER stress and autophagy pathways,” was published in Experimental Neurobiology and authored by researchers from Tongji University School of Medicine and Tongji University’s School of Life Science and Technology.
 
MANF is a naturally produced protein that helps to reduce or prevent apoptosis caused by injury or disease, through the unfolded protein response. Dr. John Commissiong, chief scientific officer of MANF Therapeutics, discovered the protein thanks to PhenoGuard, Amarantus’ proprietary discovery engine. MANF Therapeutics retains the rights to composition of matter patents and patent applications for its protein namesake, in addition to owning or having licenses to method of use patents and patent applications covering its use in ophthalmology, neurology and diabetes.
 
As explained by the Parkinson’s Foundation, Parkinson’s disease (PD) is a neurodegenerative disorder that affects predominately dopamine-producing (dopaminergic) neurons in a specific area of the brain called substantia nigra,” which is found in the midbrain and plays a role in movement. While the exact cause is unknown, it is known that Lewy bodies, deposits of misfolded alpha-synuclein, build up in the brain and dopaminergic neurons begin to die. This leads to common physical symptoms such as tremor, slow or stiff movement and issues with balance and gait, as well as issues such as mood disorders, cognitive impairment and autonomic dysfunction (malfunction of the autonomic nervous system, which regulates the function of the heart, bladder, intestines, sweat glands and blood vessels). The Parkinson’s Foundation estimates that some one million individuals in the United States are dealing with this neurodegenerative disease, and approximately 10 million face this disease globally.
 
In the recent paper, the abstract noted that MANF demonstrated “protective effects on neurotoxin-based models of Parkinson’s disease (PD). It still remains unclear whether MANF can rescue dopaminergic (DA) neurons in an alpha-synuclein model.” An alpha-synuclein model is generally considered a more accurate recreation of how Parkinson’s disease progresses in humans. This study used such a model, and overexpressed MANF “specifically in DA neurons by using an alpha-synuclein Caenorhabditis elegans (C. elegans) model” (a roundworm).
 
The results were encouraging:
 
“Our results showed MANF alleviated progressive neuronal degeneration and prevented locomotion defects. Indeed, MANF can protect cilia of DA neurons at an early stage, suggested that MANF participated in the whole process of neuronal degeneration,” the authors wrote in the abstract. “Furthermore, we found MANF facilitated the removal of misfolded alpha-synuclein proteins and rescued the function of damaged DA neurons. By using RNAi approach, we inhibited ER stress and autophagy related genes and effects of MANF were decreased, which demonstrated ER stress and autophagy pathways were involved in the MANF-mediated neuroprotection.”
 
In previous work, MANF has been shown to be capable of regenerating dopaminergic neurons “by restoring morphological and chemical imbalances in neurotoxin-based animal models of Parkinson’s disease,” as reported in an Amarantus press release. According to Commissiong, the nature of this regeneration is only partly known. “MANF robustly up-regulates GRP78 via a series of molecular events beginning with the transcription factor ATF6," he explains. "GRP78 suppresses the unfolded protein response that is associated with increased cell death. GRP78 also inhibits the proapoptotic caspase-3 enzyme. These actions of MANF translate into protection of the dopaminergic cell body in the substantia nigra, and proliferation of dopaminergic terminals in the striatum.”
 
Both gene therapy and convection enhanced delivery have proven to be viable methods of administering treatments in Parkinson’s models. Commissiong notes that “They are both efficient delivery methods, and the one used would depend on the experiment. MANF is 158-amino acids, and unlikely to cross the blood-brain barrier—the cutoff is around 40-amino acids.”
 
With a method of delivering MANF that bypasses the issue of the blood-brain barrier and a proven ability to positively affect neurons damaged in Parkinson’s disease, it’s little wonder that MANF intends to return to IND-enabling development efforts for the protein this year.
 
“In the immediate future, we will complete the remaining protocols needed to secure Investigational New Drug status for MANF, including manufacture of clinical-grade cGMP protein, toxicology and PK/PD,” Commissiong tells DDNews. “This will be followed by a series of clinical trials, ending with a new drug application (NDA) to the FDA, and finally treatment of patients, if all goes well and the NDA is approved. Therapeutic MANF will be delivered to the substantia nigra and/or putamen using the most modern methods of drug delivery. This standard of care will likely last about five years. It will be replaced by a new approach to treatment that will remain MANF-based, but is currently proprietary and in an early stage of development.”


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