April 2022

PRE-CLINICAL DRUG STUDY SHOWS PROMISE IN PARKINSONIAN DISORDER

A new study in the Journal of Parkinson’s Disease describes a study evaluating the efficacy of ATH434 in genetically altered mice that develop manifestations of Multiple System Atrophy (MSA). The study was led by David I. Finkelstein, PhD, Head of Parkinson’s Disease Laboratory at the Florey Institute of Neuroscience and Mental Health and the University of Melbourne.

Multiple System Atrophy is a rare, neurodegenerative disease characterized by failure of the autonomic nervous system and impaired movement. The symptoms reflect the progressive loss of function and death of different types of nerve cells in the brain and spinal cord. It is a rapidly progressive disease and causes profound disability. MSA is a Parkinsonian disorder characterized by a variable combination of slowed movement and/or rigidity, autonomic instability that affects involuntary functions such as blood pressure maintenance and bladder control, and impaired balance and/or coordination that predisposes to falls. A pathological hallmark of MSA is the accumulation of the protein α-synuclein within glia, the support cells of the central nervous system, and neuron loss in multiple brain regions. MSA affects approximately15,000 individuals in the United States, and while some of the symptoms of MSA can be treated with medications, currently there are no drugs that are able to slow disease progression and there is no cure.

In this study, genetically altered, or transgenic, mice overexpress α–synuclein, develop glial cell inclusions, and manifest motor and non-motor aspects of MSA. Animals received ATH434 in food or a control diet for 4 months starting at 12 months of age. Western blot analysis was used to assess oligomeric and aggregated forms of α-synuclein levels in brain and stereology was used to quantitate the number of neurons and glial cell inclusions in the substantia nigra pars compacta.

The study demonstrated that in the studied brain region, ATH434 treatment reduced both the toxic oligomeric and aggregated forms of α–synuclein, a central nervous system protein important for normal function of nerve cells. At the same time, ATH434 treatment reduced the cardinal pathology of MSA (glial cell inclusions), reduced brain iron, preserved neurons, and improved motor performance. The publication concluded that ATH434 is a promising small molecule drug candidate that has potential for treating MSA. ATH434 has been granted Orphan designation for the treatment of MSA by the U.S. FDA and the European Commission.

Source: Finkelstein DI, Shukla JJ, Cherny, RA, et al. The compound ATH434 prevents alpha-synuclein toxicity in a murine model of Multiple System Atrophy. J Parkinson’s Dis. 2022;12(1):105-115.

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