Combination Treatment to Reduce Pathological Proteins in Neurodegenerative and Lysosomal Storage Diseases

NU 2021-206

INVENTORS
Joseph Mazzulli*
Iva Stojkovska

SHORT DESCRIPTION
A small molecule combination treatment to improve lysosomal function in neurodegenerative and lysosomal storage diseases

BACKGROUND
Many neurodegenerative disorders are characterized by a collapse in proteostasis, as shown by the accumulation of insoluble protein aggregates in the brain. Parkinson’s disease (PD) patients, in particular, display α-synuclein protein inclusions that contribute to cellular toxicity and pathogenesis, though the molecular mechanism of the inclusions is still not completely understood. Recently, Northwestern researchers found that in PD midbrain cultures, α-synuclein aggregates induced endoplasmic reticulum (ER) fragmentation and compromised ER protein folding, leading to aggregation and insolubility of the enzyme β-glucocerebrosidase (GCase), which is critical for trafficking and lysosomal function.

ABSTRACT

The inventors have found that simultaneous small molecule enhancement of ER proteostasis and trafficking improves Gcase solubility, ER morphology, and lysosomal function, all while reducing α-synuclein. This novel mix of small molecules employs repurposed ryanodine receptor (RyR) inhibitors to promote functional, soluble GCase folding in the ER with novel farnesyltransferase inhibitors (FTIs) to restore GCase trafficking and lysosomal activity in PD neurons. Utilizing this novel synergistic treatment strategy, the clearance of toxic storage material was dramatically enhanced in relevant iPSC-derived midbrain models that were developed to demonstrate α-syn accumulation and lysosomal dysfunction. Treatment strategies for neurodegeneration and storage diseases have formerly focused on single targets or pathways and resulted in minimal preclinical rescue effects and no clinical effect. As such, most patients with these disorders including those with PD only use treatments to manage symptoms. The identification of this synergistic strategy, therefore, will offer novel opportunities for the treatment of multiple neurodegenerative disorders that are characterized by protein inclusions like PD, Lewy body dementia (LBD), and Alzheimer’s disease (AD), as well as peripheral storage disorders where toxic materials accumulate.

APPLICATIONS

Treatment of proteinopathies that encompass age-related neurodegenerative disorders, including but not limited to PD, LBD, AD, amyotrophic lateral sclerosis, multiple system atrophy, Huntington’s disease, Prion disease, and progeria
Treatment of pediatric lysosomal storage disorders
Prevention of normal brain aging and cognitive decline

ADVANTAGES