DD-A279, a peptide-based molecule targeting LPS
The most recognized hypotheses on the pathogenic mechanisms of Alzheimer’s disease (AD) are the amyloid cascade hypothesis and the tau hyperphosphorylation hypothesis. However, the underlying causes and optimal treatment are still elusive. With the repeated failure of clinical trials based on the amyloid and tau hypothesis, these hypotheses have come under inspection. Among alternative hypotheses being investigated, the infectious hypothesis is one of the emerging hypotheses for AD.
The infectious hypothesis refers to that a pathogen such as virus and bacteria is the cause of AD, supported by evidence that some pathogens like herpesviruses, Chlamydia, and Porphyromonas gingivalis are found more commonly in AD patients. Despite the some obstacles the infectious hypothesis encounters, there are optimistic evidences for further research in this area.
Various bacteria are found in the AD brain, most of which are gram-negative bacteria. It has been reported that gram-negative bacteria cross the blood brain barrier (BBB) and influence AD pathology. In addition, gram-negative bacteria byproducts such as lipopolysaccharides (LPS) and capsular proteins can also penetrate the BBB and impact on AD pathology and neuroinflammation.
P. gingivalis, one of gram-negative bacteria causing periodontitis, has been linked to cognitive impairment. Its gingipains and lipopolysaccharides have been found in the AD brain. Atuzaginstat (formerly called COR388) is an inhibitor of proteases called ‘gingipains’ produced by P. gingivalis. Although the Phase 2/3 trial (GAIN) of Atuzaginstat in AD had failed to meet its co-primary endpoints (ADAS-Cog11 and ADCS-ADL), the prespecified subgroup analysis revealed that there was a statistically significant 57% slowing of decline in the ADAS-Cog11 within a subgroup who had the saliva P. gingivalis DNA and took the higher dose. As in the case of donanemab, the jury is still out.
A powerful endotoxin, LPS, among several gram-negative bacteria byproducts, exists in the blood of AD patients in high concentration, causes AD pathology, and induces cognitive dysfunction. LPS is being considered one of promising therapeutic targets for AD.
DanDi Bioscience, headquartered in Seoul, is a biotech pharmaceutical company that develops first-in-class new drugs with an innovative mechanism of action for infectious diseases. The company developed its novel, peptide-based ‘DD-A279’ effectively targeting LPS to treat AD, grounded on the infectious hypothesis. In pre-clinical studies, DD-A279 has evidenced the significant reduction in AD pathology and the attenuation of cognitive decline in AD animal models. Now, DanDi is almost ready for a global Phase 1 clinical trial.
Meanwhile, Dr. Minho Moon at Konyang University (in conjunction with DanDi Bioscience) has recently published a review paper titled “Gram-negative Bacteria and Their Lipopolysaccharides in Alzheimer’s Disease: Pathologic Roles and Therapeutic Implications.” in the journal ‘Translational Neurodegeneration’. This paper reviewed the roles and pathomechanisms of gram-negative bacteria along with their molecules, and the possibility of adopting those as novel therapeutic targets for AD.
