Blade Therapeutics, Inc. (Blade or the company), a biopharmaceutical company focused on developing cutting-edge treatments for debilitating fibrotic and neurodegenerative diseases, today announced peer-reviewed publication of preclinical study data supporting the neuroprotective effects of inhibiting dimeric calpains in spinocerebellar ataxia type-3 (SCA3). Also known as Machado Joseph Disease (MJD), SCA3/MJD is a rare, inherited (autosomal-dominant) neurological disorder.
“Blade is encouraged by these findings that further support the therapeutic hypothesis for targeting calpains in orphan genetic neurodegenerative diseases,” said Wendye Robbins, M.D., president and CEO of Blade. “We look forward to starting a planned phase 1 study evaluating our lead calpain inhibitor, BLD-2184, in the first half of 2022.”
The scientific article (Cells 2021, 10(10), 2592), titled “A Novel Calpain Inhibitor Compound Has Protective Effects on a Zebrafish Model of Spinocerebellar Ataxia Type 3,” was published in Cells, an international peer-reviewed journal of cell biology, molecular biology, and biophysics (click here). In the preclinical in vivo studies, a transgenic zebrafish model of SCA3/MJD was used to evaluate the prophylactic and therapeutic treatment effects of Blade’s proprietary small-molecule calpain inhibitor, BLD-2736. The untreated SCA3/MJD zebrafish accumulate mutant protein aggregates within their neurons, which leads to neurodegeneration and impaired movement as measured by their swimming ability. Treatment with the calpain inhibitor decreased the presence of insoluble protein aggregates and improved movement behavior (improved swimming) in a dose-dependent manner. The studies also demonstrated that treatment with BLD-2736 increased a key marker of autophagic activity, which is the natural mechanism by which misfolded and aggregated proteins within cells are cleared.
“We were excited to find that treating the SCA3/MJD zebrafish with BLD-2736 could improve swimming and reduce protein aggregates, even when the treatment was delayed until an age when protein aggregates were known to already be present,” said study author Dr. Angela S. Laird, senior lecturer and researcher at the Centre for Motor Neuron Disease Research and Macquarie Medical School at Macquarie University, Sydney, Australia.
Neuroscientists at Macquarie Medical School conducted the study, which was sponsored by Blade Therapeutics Pty Ltd, a wholly owned subsidiary of Blade Therapeutics, Inc. The team led by Dr. Laird pioneered the world’s first zebrafish model of SCA3/MJD and is a leader in researching potential treatments for the disease.
Blade’s lead candidate in neurodegeneration is BLD-2184, a small-molecule, CNS-penetrant calpain inhibitor. In preclinical studies, BLD-2184 increased autophagy in vitro in neuronal cells and significantly reduced neurotoxic mutant protein fragments and aggregates in an in vivo mouse model of SCA3/MJD. Pending completion of the investigational new drug (IND) application process and subsequent regulatory activation of the IND, Blade plans to start a phase 1 clinical study of BLD-2184 in the first half of 2022 in healthy volunteers. BLD-2184 is an investigational medicine that is not approved for commercial use by the FDA or any other regulatory authority.
Calpains’ Role in Neurodegeneration
Dimeric calpains (CAPNs 1, 2, 9) are calcium-activated cysteine proteases that regulate cellular function. Calpains are implicated as key mediators in the progression of number of neurodegenerative diseases. Notables are autosomal-dominant (genetic) neurodegenerative diseases caused by toxic protein aggregates due to expanded poly-Q repeats, such as SCA3/MJD and Huntington’s disease. In published reports, calpains have been shown to cleave these mutant poly-Q proteins, a necessary step leading to the formation of neurotoxic protein aggregates within neurons. Calpains are also known to be key regulators (inhibitors) of autophagy, the intracellular mechanism by which damaged, misfolded and aggregated proteins are normally cleared to maintain normal cellular function.
Spinocerebellar Ataxia Type-3
Spinocerebellar ataxia type-3 (SCA3), also known as Machado Joseph Disease (MJD), is an autosomal-dominant inherited disease. It results from a genetic mutation in the ATXN3 gene that causes the misfolding and aggregation of the mutant protein within neurons. This leads to impairment of nerve cells in the brain and nerve fibers carrying messages to and from the brain and progressive degeneration of the cerebellum (the coordination center of the brain) and related brain regions. SCA3/MJD patients display a slow neurodegeneration characterized by progressive impairment of movement and cognitive function, ultimately resulting in paralysis and death. Overall prevalence of this rare, incurable condition is estimated to be 1-2 in 100,000 people. Currently, there are no approved therapies to treat the underlying cause of SCA3/MJD.
Blade Therapeutics, Inc. is a biopharmaceutical company focused on developing cutting-edge treatments for debilitating, incurable fibrotic and neurodegenerative diseases that impact millions of people worldwide. The company has deep expertise in novel biological pathways – including autotaxin / LPA and calpain biology – that are foundational to cell- and tissue-damage responses resulting from protein deposition or aggregation associated with fibrotic and neurodegenerative diseases. Blade expects to advance a differentiated pipeline of oral, small-molecule therapies that include a non-competitive autotaxin inhibitor and inhibitors of dimeric calpains designed for potential treatment of lung, liver and cardiac fibrosis or neurodegenerative diseases. The company’s focused approach offers the potential to produce disease-modifying, life-saving therapies. Visit www.blademed.com for more information and follow Blade on LinkedIn.
Media Relations – Michael Blash
Investor Relations – Krishna Gorti, M.D.