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BRISBANE, Calif., March 11, 2024 (GLOBE NEWSWIRE) -- Nitrase Therapeutics, Inc., a biopharmaceutical company deploying its NITROME platform to build a pipeline of therapies targeting nitrases and their substrates, a new class of enzymes discovered in-house that are implicated in a broad variety of diseases, today announced an abstract titled “Unveiling of a Novel Therapeutic Antibody Targeting Nitrated Alpha Synuclein for the Treatment of Parkinson’s Disease” was featured in an oral presentation at the Alzheimer’s Disease and Parkinson’s Disease (AD/PD) Conference taking place in Lisbon, Portugal from March 5-9, 2024. The presentation outlined data with Nitrase’s first-in-class antibody targeting extracellular nitrated alpha-synuclein (α-synuclein) for the treatment of Parkinson’s disease (PD) and other synucleinopathies. Nitrase’s antibody demonstrated both high affinity and selectivity for nitrated synuclein, and it demonstrated the ability to significantly reduce PD progression in in vitro and in vivo PD models.
A hallmark of PD pathology is the presence of Lewy Bodies and Lewy Neurites, which have been found to include an accumulation of nitrated α-synuclein. The role of nitrated α-synuclein in the pathology of PD has been characterized in multiple preclinical studies, and the introduction of nitrated α-synuclein in PD models induced motor dysfunction and the death of dopaminergic neurons. It has been established in published studies that PD pathology spreads between brain regions along neural circuitry through extracellular aggregated α-synuclein.
“Nitrated synuclein is elevated in the cerebral spinal fluid of PD patients suggesting it could be the pathogenic species driving spread between brain regions,” said Irene Griswold-Prenner, Ph.D., chief executive officer of Nitrase Therapeutics. “The in vivo data we presented with our antibody demonstrates its ability to significantly delay the aggregation of α-synuclein; thereby inhibiting pathological spread of PD from one area of the brain to another. Additionally, our antibody demonstrated superiority in a preclinical efficacy evaluation against the parental antibody of prasinezumab, which targets non-nitrated α-synuclein. We are not aware of any other program targeting the nitrated form of α-synuclein, and we look forward to advancing our promising therapeutic antibody towards the clinic.”
Nitrated α-synuclein is different from normal/non-nitrated α-synuclein because protein nitration causes changes in protein structure, function and/or aggregation state; therefore, the nitrated form of α-synuclein is a distinct target for the treatment of PD. Several studies have suggested that the insolubility of synuclein may be a result of nitration, since nitrated α-synuclein accumulates in the insoluble fraction of homogenates from PD brains. These aggregates are nitrated, and this nitration strongly induces neurodegenerative disease in models. Secreted nitrated α-synuclein, and not non-nitrated α-synuclein, is elevated in the cerebral spinal fluid of PD patients, and Nitrase has found that neutralizing secreted nitrated α-synuclein decreases the spread of pathology in models of PD. Non-nitrated α-synuclein is highly expressed in the blood stream and has been shown to act as a peripheral sink in other clinical trials. Since nitrated α-synuclein is only present at low levels in the blood stream, more of Nitrase’s antibody is accessible to nitrated α-synuclein present in the brain. Each of these factors suggest that nitrated α-synuclein plays an important role in α-synuclein accumulation and aggregation and PD pathology.
In preclinical studies, humanized and affinity matured antibodies were characterized for in vitro binding affinity towards nitrated α-synuclein (SPR, ELISA), selectivity towards the modification over non-modified synuclein (ELISA), target engagement (ELISA), developability/stability (AC-SINS, DSF, SEC), and in vivo PK and efficacy in mouse models of PD (IHC, ELISA). In vitro data demonstrated that the antibody has a specific nitrated α-synuclein binding affinity of <2 nM without detectable binding to non-nitrated α-synuclein or another nitrated protein. In vivo pharmacokinetic data showed that the concentration of the antibody within murine brain tissue far surpassed the half-maximal inhibitory concentration (IC50). Importantly, in a preformed fibril (PFF) induced mouse model of Parkinson’s disease, Nitrase’s anti-nitrated-α-synuclein antibody reduced the spread of synuclein aggregates. When evaluated against prasinezumab’s murine parental antibody in this in vivo model, Nitrase’s antibody demonstrated a superior ability to reduce synuclein aggregate spread. In summary, these data support the potential of Nitrase’s antibody to bind strongly and selectively to its nitrated α-synuclein target and reach the brain tissue with therapeutic concentrations, producing the desired efficacy outcome of reducing PD progression.
Kalpana Merchant, Ph.D., an advisor at the Michael J. Fox Foundation as an expert in neurobiology of chronic neurodegenerative and psychiatric disorders, and the former chief scientific officer for tailored therapeutics-neuroscience at Eli Lilly, added “Currently, there is no effective intervention to slow, halt or reverse the progression of Parkinson’s disease. The evidence of the presence of nitrated α-synuclein in the cerebral spinal fluid of PD cases combined with the promising preclinical data indicate that Nitrase’s neutralizing antibody targeting nitrated α-synuclein has the potential to slow the progression of this devastating disease.”
About Nitrase Therapeutics, Inc.
Nitrase Therapeutics is a pioneering biopharmaceutical company deploying its unique NITROME platform to unlock the therapeutic potential of nitrases, a new class of enzymes that it discovered, to develop a pipeline of therapies against a broad range of diseases. The medicines that Nitrase Therapeutics is developing will target these enzymes and potentially help slow or halt the progression of numerous diseases in which nitrases and nitro-substrates play a role, including Parkinson’s, cancer, immunological and fibrotic diseases. Nitrase Therapeutics (under the former name Nitrome Biosciences) has been widely recognized and has won multiple awards including the prestigious Target Advancement grant from The Michael J. Fox Foundation for Parkinson's Research (MJFF). Nitrase Therapeutics is located in Brisbane, CA, and its investors include Sofinnova Partners, AbbVie Ventures, Dementia Discovery Fund, Bristol Myers Squibb, Mission Bay Capital and Alexandria Venture Investments. For more information, please visit the company’s website at www.nitrasetx.com.
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