Advancing therapeutics
for the prevention of Alzheimer's.

Using a novel approach for identification of disease modifier genes, ModGene has discovered a set of targets for control of beta-amyloid production in the periphery and has identified a series of compounds that successfully address these targets to reduce production of beta-amyloid by the liver.

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The Team

ModGene Pharma’s executive team combines world-class expertise in neurodegenerative disease research together with experience in the commercialization of technology platforms for drug discovery and development.

ModGene's Approach

ModGene Pharma will focus on bringing to market candidate therapeutics aimed at Alzheimer's disease prevention in early-stage patients and at-risk populations.

This shift from running clinical trials with patients after disease onset to those in earlier, pre-symptomatic stages allows preventive strategies to be tested. The scientific rationale for this therapeutic strategy is becoming increasingly clear. ModGene’s determination that the site of increased production of beta amyloid resides in the liver, not brain, immediately suggests that a preventive strategy is warranted.

Results from clinical trials and long-term research studies have shown that individuals who will develop the disease show significantly increased beta amyloid concentrations in the blood compared to normal individuals, for up to 10 years preceding disease onset.

A Call for Preventive Strategies to Stop Alzheimer's

In the 13 July, 2017 issue of Nature, McDade and Bateman1 review the demographic and economic factors indicating that Alzheimer’s Disease (AD), already a near-trillion dollar health issue, represents a medical problem whose costs are destined to increase greatly as populations enjoy increasing life expectancies. The authors survey the evidence from clinical experience and animal models and conclude that AD should be confronted before pathology has appeared via a ‘statin’-type approach. In particular, they cite studies with genetically engineered mouse models of amyloid-β deposition which demonstrate that treatments that lower amyloid-β production are most effective when administered before the plaques have developed and rare human mutations which lower amyloid-β production that are protective in the Icelandic population, reducing dementia incidence by 80%.

In studies correlating RNA expression in various tissues with mouse disease modifier genes, we demonstrated that the level of expression of the Presenilin2 gene by the liver determines the accumulation of pathogenic concentrations of AD-initiating amyloid-β within the brain2. The anti-leukemia therapeutic imatinib (trade name Gleevec), which does not cross the blood-brain barrier, reduced liver production of amyloid-β and lowered its accumulation in the brain below pathogenic levels. The peripheral amyloid-β origin concept has been confirmed in mouse studies which show that hippocampal amyloid-β accumulation accompanied by cognitive deficits initiated by endotoxin-induced peripheral inflammation was eliminated by imatinib administration3 as was tau hyperphosphorylation4, and that imatinib administration to amyloid plaque-bearing APP transgenic mice led to plaque reduction and cognitive improvement5. Furthermore, it was shown6 that intraperitoneal injection of beta-amyloid aggregates lead to brain amyloidosis, demonstrating directly that peripheral amyloid-β can enter the brain to initiate disease.

In humans, longitudinal studies have shown unequivocally that plasma amyloid-β levels are consistently higher in individuals destined to develop Alzheimer’s as compared to healthy controls both in autosomal dominant carriers (APP, PSEN1 and PSEN2)7,8 and in Down syndrome patients9,10. The elevation of plasma amyloid-β (specifically Aβ-42) in mutation carriers was shown to be stable for decades preceding age of onset8, suggesting a prolonged period of progressive accumulation that can be halted by drugs lowering its production in the periphery.

The imatinib-related compound, imatinib para-diaminomethylbenzene trihydrochloride, is more than three-fold more potent in inhibiting amyloid-β production than imatinib and exhibits only 1/16th of the activity of imatinib in the inhibition of Abl kinase (the imatinib target in leukemia), resulting in a selectivity ratio of nearly 60 for the AD indication11. These studies suggest that prophylactic reduction of amyloid-β at the site of its production in the livers of aging humans before plaque deposition begins has the potential to lower the incidence AD and point to the identites of drugs that can accomplish that goal. Patents11,12 have issued on the dual discoveries that pathogenic amyloid-β has a primary source in peripheral tissues outside of the brain (particularly the liver) and that the FDA-approved anti-leukemia drug imatinib is effective in reducing amyloid accumulation in the brain, even though it does not cross the blood-brain barrier, and on the discoveries of compounds that are more potent and selective for the Alzheimer’s indication. As pointed out by McDade and Bateman, the regulatory environment and lack of funding for prevention trials by venture capital and pharmaceutical companies held back progress in pursuing alternative therapeutic approaches. With the improved regulatory environment and acceptance of preventive clinical trials aimed at preclinical AD, ModGene Pharma has a clear path forward . We have identified a statin-type approach that utilizes a safe, approved drug that could be tested in Phase I/II studies relatively soon. The patent portfolio has been assigned to ModGene Pharma, LLC, which is seeking investors and pharmaceutical partners to run clinical trials that would allow development of AD-preventing medications.

1. McDade, E. & Bateman, R. J. Nature 547, 153-155 (2017).

2. Sutcliffe, J. G. et al. Neurosci Res 89, 808-814 (2011).

3. Weintraub, M. K. et al. Brain Behav Immun 33 24-28 (2013).

4. Gardner, L. E. et al. Neuroscience 331 72-77 (2016).

5. Cancino, G. I. et al. Brain 131 2425-2442 (2008).

6. Eisele, Y. S. et al. J Neurosci 34 10264-10273 (2014).

7. Bateman, R. J. et al. N Engl J Med 367 795-804 (2012).

8. Fagan, A. M. et al. Sci Transl Med 6 226ra30 (2014).

9. Zigman, W. B. & Lott, I.T. Mental Retard Dev Disabilities Res Rev 13 237–246 (2007).

10. Head, E. et al. J Alzheimer’s Disease 23 399-409 (2011).

11. Sutcliffe, J. G. & Hilbush, B.S. US Patent No. 9,707,231 (2017).

12. Sutcliffe, J. G. et al. European Patent No. 2365804 (2015).


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