Targeting misfolded proteins

Proclara takes a novel approach to treating protein misfolding diseases, based on the fact that many toxic aggregates of misfolded proteins share a common characteristic – the amyloid protein fold – that represents a unique target for drug development.

Proclara scientists have developed a novel proprietary technology known as GAIM, or General Amyloid Interaction Motif, that simultaneously targets multiple misfolded proteins implicated in both neurodegenerative and progressive peripheral diseases, potentially creating a more robust response that could be suitable for patients at all stages of disease.

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Excerpt

Proteins called chaperones bind to damaged or defective proteins in cells of the body. The chaperones ferry their cargo to the cells’ lysosomes, which digest and recycle waste material. To successfully get their cargo into lysosomes, however, chaperones must first “dock” the material onto a protein receptor called LAMP2A that sprouts from the membranes of lysosomes. The more LAMP2A receptors on lysosomes, the greater the level of CMA activity possible.

The team developed a novel drug that shows potential for treating Alzheimer’s. The new drug, called CA, works by increasing the number of those LAMP2A receptors. “CA (experimental drug) restores LAMP2A to youthful levels (in mice), enabling CMA to get rid of tau and other defective proteins so they can’t form those toxic protein clumps,” said Cuervo.

Results of the AMBAR trial

transfusion bag set-up

Abstract

This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild‐to‐moderate Alzheimer’s disease (AD).

Methods

Three hundred forty‐seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6‐week period of weekly conventional PE followed by a 12‐month period of monthly low‐volume PE), and placebo (sham).

Results

PE‐treated patients performed significantly better than placebo for the co‐primary endpoints: change from baseline of Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS‐ADL; P = .03; 52% less decline) with a trend for Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS‐Cog; P = .06; 66% less decline) scores at month 14. Moderate‐AD patients (baseline Mini‐Mental State Examination [MMSE] 18‐21) scored better on ADCS‐ADL (P = .002) and ADAS‐Cog (P = .05), 61% less decline both. There were no changes in mild‐AD patients (MMSE 22‐26). PE‐treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR‐sb) (P = .002; 71% less decline) and Alzheimer’s Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC) (P < .0001; 100% less decline) scales.

Discussion

This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.

Alzheimer’s + telomeres

The key process is cellular aging. A lot of interventional trials aimed at downstream biomarkers have proven to be ineffective points of intervention. In contrast, we target the single most effective point, both clinically and financially.