Jace Biomedical, Inc. (JBI) was established to develop novel proprietary compounds for the treatment of AD. JBI’s technology is unique in that it targets the acetylation machinery within the Endoplasmic Reticulum (ER) of a cell as a novel approach to restore proteostasis in the brain for the treatment of AD. JBI’s tool compound, JBI‑009, has demonstrated success in animal models of AD where it has been shown to increase clearance of toxic Aβ aggregates, decrease levels of BACE1, reduce levels of phosphorylated tau, reduce amyloid-β pathology, improve synaptic plasticity, and normalize the lifespan of treated animals by restoring the natural proteostatic process.
Age is the greatest risk factor in many neurodegenerative diseases, including AD. AD, and other protein folding disorders, are characterized by the improper folding and aggregation of specific cellular proteins. As a part of the cells natural quality control system, aberrantly folded proteins are selectively targeted for degradation to maintain protein homeostasis (proteostasis) and ensure proper biological functions. During the aging process, cells eventually lose ability to maintain proteostasis, which can lead to pathogenesis and is the basis for many neurodegenerative diseases.
Clinically, AD is characterized by progressive memory deficits, cognitive impairments and personality changes accompanied by diffuse structural abnormalities in the brain observed during autopsy, which include neurofibrillary tangles and amyloid plaques.
Neurofibrillary tangles (NFT) are intracellular protein aggregates of hyperphosphorylated tau (p-Tau). Tau is a microtubule-binding protein that, when hyperphosphorylated, starts to form insoluble tangles in nerve cells in the brain. This leads to catastrophic cellular dysfunction and eventual cell death. Tauopathies are a large class of neurodegenerative diseases characterized by the pathological accumulation of filamentous p-Tau and are a major target for drug discovery.
Amyloid plaques are formed by aggregates of misfolded amyloid-β peptide (Aβ), which is produced from sequential enzymatic cuts of the Amyloid Precursor Protein (APP). During aging, and in AD, APP is first cut by β secretase then by γ-secretase to generate Aβ peptides, some of which are toxic. β-secretase, also known as BACE1, is the rate-limiting enzyme in Aβ production. Once aggregates of Aβ start to accumulate, the pathological process begins. Both Aβ and BACE1 are leading drug targets for the pharmaceutical industry. Most investigational treatments aim to clear Aβ, (generally by specific monoclonal antibodies) or inhibit BACE1 to reduce production of Aβ peptides.
To date, no disease modifying therapeutic has been approved to treat AD.
The endoplasmic reticulum (ER) is the organelle where most membrane and secreted proteins (including APP and Aβ) of the cell are synthesized and processed. When these processes go awry, the aberrant proteins are misfolded and susceptible to forming toxic aggregates. The ER also has a “quality control” system to monitor the structural integrity of new proteins; proteins that fail quality control are disposed of either by the ubiquitin-proteasome system, which preferentially disposes of monomeric proteins, or autophagy, which preferentially degrades toxic protein aggregates.
Recently, it was discovered that ER-based acetylation plays a key role in the regulation of this quality control system. Reduced lysine acetylation of nascent proteins can control ER proteostasis through novel mechanisms. In models of AD, biochemical inhibition of lysine acetylation leads to two different, but intimately linked, events: (i) reduced levels of APP and BACE1 and (ii) increased disposal of protein (Aβ) aggregates.
In AD, BACE1 is transiently acetylated in the lumen of the ER by two acetyltransferases, ATase1 and ATase2. Increased levels of both of these enzymes have been found in the brains of AD patients. Inhibition of ER acetylation reduces BACE1 levels, and consequently, lowers APP processing and levels of Aβ. Clearance of Aβ aggregates by autophagy is stimulated by reduced acetylation of another ER-based protein ATG9A.
JBI is developing a novel class of small molecules to target acetylation in the endoplasmic reticulum (ER) as a means of restoring proteostasis in neurodegenerative diseases such as Alzheimer’s disease. We are developing proprietary products that are based on the success of our tool compound, JBI-009. This novel therapeutic approach reduces pathological levels of acetylation in the ER, which conveys two key therapeutic effects:
1. Increased clearance of toxic protein aggregates (A-β) through autophagy.
2. Decreased levels of BACE1, Aβ and phosphorylated tau.