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Approach to Therapy

Approach to Therapy

Alzheimer’s Disease & The Metabolic Approach to Therapy

Effective disease-modifying therapy is critically needed for the treatment of Alzheimer’s disease (AD), as the prevailing thinking over the last two decades has thus far not resulted in breakthrough solutions.  Despite extensive research and treatment with drugs that target symptoms, including acetylcholinesterase inhibitors and NMDA receptor antagonists the clinical course of Alzheimer’s disease has not been meaningfully slowed or stopped.

Inherent in AD are 2 major metabolic dysfunctions:  Aberrant glucose energy & lipid metabolism that lead to the pathological sequelae of plaques, tangles, fat deposits, oxidative stress and inflammation. These pathologies in turn perpetuate glucose energy and lipid metabolism dysfunctions in a massive positive feedback loop that lead to brain atrophy and death.

The rationale behind T3D-959 is to break this cycle by correcting these metabolic defects to effect potential disease remediation.

In addition to the aforementioned feedback loop, the Company’s novel neurometabolic approach to treating AD recognizes:

  1. Metabolism alterations precede structural change in AD (See FDG-PET image below).
    PET Scan
  2. Impaired glucose metabolism is inherent in neurodegeneration, found not just in AD, but in Huntington’s Disease and Parkinson’s Disease as well.
  3. Aberrant lipid metabolism was recognized by Alois Alzheimer 100y ago, observing fat deposits in the brain, identified last year as triglycerides. Also, the lipid trafficking ApoE as a factor in AD is well established.
  4. Abeta and Insulin have interwined molecular interactions with Abeta binding to insulin, the insulin receptor, insulin degrading enzyme and regulating IRS-1.
  5. Similarities in AD and Type 2 diabetes that both involve insulin resistance; including amyloid aggregation and cognitive impairment.

Congruence of The Metabolic Approach and Plaque Approach to AD Therapy

The metabolic hypothesis and beta amyloid plaque hypothesis of AD are not antithetical but congruent. Approaching disease therapy directed at ameliorating both metabolic dysfunctions and plaque accumulation is a potentially attractive avenue to effect potential disease remediation.


Alzheimer's disease

Alzheimer’s disease is [commonly understood to be] caused by the ‘starvation’ of the brain (caused by poor energy metabolism in the brain) and the ‘strangulation’ of the brain (caused by inflammation, tau tangles and beta amyloid plaques in the brain).

In pre-clinical animal studies, T3D Therapeutics’ new drug candidate, T3D-959, has shown evidence of a reversal of the diseased state in the brain by histopathology (microscopic tissue analysis).


Mild Cognitive Impairment

Mild Cognitive Impairment (MCI) is a condition resulting from impairment in the brain’s glucose metabolism. MCI comes before cognitive decline in Alzheimer’s disease patients, and is evident early in the course of Alzheimer’s disease. Our lead drug candidate T3D-959 is designed to improve neuro-metabolic dysfunction (the brain’s inability to efficiently create and metabolize, or utilize, energy), which we believe could dramatically affect molecular, biochemical and histopathological defects that cause cognitive impairment and motor dysfunction.

Other Neurodegenerative Diseases

Because T3D-959’s mechanism of action is designed to provide anti-inflammatory and anti-wasting effects, along with an ability to repair damaged nerve cells (remyelination), there is potential for T3D’s new drug candidate to address other neurodegenerative diseases, in addition to Alzheimer’s disease.

PPAR delta agonist compounds such as T3D-959 have recently been found to have strong neuroprotective effects that we believe make T3D-959 a candidate drug for development for potential treatment in a number of CNS diseases (e.g. Huntington’s disease, Parkinson’s disease) (refs.15,16).

Beyond Alzheimer’s disease, these other diseases present added life cycle management opportunities for T3D-959 and other structurally-related compounds within the Company’s exclusive license.