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Madera's Approach to Alzheimer's Therapeutics: Upregulation of Functional ApoE via Small Molecules


Therapeutic Enhancement of Phagocytic Clearance of Beta Amyloid

 


 

Madera’s strategy is to focus on the identification and development of orally-available small molecule compounds that penetrate the brain to enhance the clearance of and interrupt the neuroinflammatory- cycle. Our strategy is supported by evidence of the central role plays in the early Alzheimer’s disease state.  (Please see our page on Alzheimer’s and Beta Amyloid.)  

ApoE, though its three isoforms (E2, E3, and E4), modulates neuroinflammation via several mechanisms (1).   Multiple studies have confirmed that ApoE4 is the most significant AD-genetic risk factor significantly increasing the risk for both early-onset AD (EOAD) and late-onset AD (LOAD) (2). CSF and plasma levels of ApoE in ApoE4 carriers are diminished vs non-carriers and is likely the result of decreased stability of ApoE4. Supporting the hypothesis that reduced ApoE levels in ApoE4 carriers and in AD patients leads to accumulation of is a recent study by Shinohara et al, that links diminished ApoE levels with accumulation in a region specific manner in the human brain (1C). ApoE may also function to attenuate the inflammatory process through a receptor-mediated, -independent mechanism (3).   In this context,Tai et al. report that ApoE suppression of both LPS and oligomeric -induced TNFalpha secretion in vitro (4).

In addition, small molecules that increase the expression of ApoE and the cholesterol transporter ABCA1 result in decreased and amyloid plaque levels and improved cognition.  For example, treatment of AD transgenic mice with non-clinical experimental LXR agonist compounds increases both ApoE protein and ABCA1 mRNA. These treatments resulted in lower levels of Aβ and amyloid plaques and increased cognitive ability in the animals (5,6). However, these experimental LXR agonist compounds displayed significant cardiovascular risks and never reached human testing.

Recent work with bexarotene - an RXR agonist and FDA-approved cancer drug - in mouse models of AD demonstrated an increase in ApoE levels leading to diminution in Aβ levels resulting in improved cognition and behavior (7). Clinically, bexarotene has cardiovascular side effects similar to LXR agonist compounds and also causes hypothyroidism.


Madera's goal, therefore, is to identify compounds that raise ApoE and ABCA1 levels in the brain while lacking the serious cardiovascular and other risks seen with the LXR/RXR.  Madera has already identified novel chemical matter - chemically distinct from known LXR and RXR compounds - that increases both ApoE protein and ABCA1 mRNA in a human brain astrocyte cell line and do not activate LXR. These chemical assets are the focus of research activity to identify new clinical agents for the treatment of AD. Furthermore, our lead compound MAD8100 has excellent bioavailability and enters the brain providing continuous exposure at therapeutic levels from a once-a-day oral dose.

 

References

(1) a) Heneka, M. T. et al, Lancet Neurol 2015; 14: 388-405.  b) Heneka, M. T. et al, Nat. Immun. 2015; 16(3): 229-236.  c) Kanekiyo T. et al, Neuron 2014; 81(4); 740-754.

(2) Verghese P. B. et al, Lancet Neurol 2011; 10: 241-252.

(3) a) Jansen, W. J. et al, JAMA 2015; 313(19): 1924-1938.  b) Ossenkoppele, R. JAMA 2015; 313(19): 1939-1949.

(4) Tai, L. M. et al, J. Neurochem. 2015; 133: 465-488.

(5) Jiang Q. et al. Neuron. 2008; 58: 681. 

(6) Fitz N. F. et al. J. Neurosci. 2010; 30: 6862.

(7) Cramer PE et al. Science 2012 335: 1503-1506.