The Alzheimer’s Disease Project

Objective:

Crossing the Blood Brain Barrier with Targeted CLR-TargoSphere®-Encapsulated Paclitaxel and Curcumin for the Treatment of Early and Mid-Stage Alzheimer’s Disease

The Unresolved Problems:

Of all the neurodegenerative diseases for which targeted delivery to the brain may offer hope, Alzheimer’s disease remains the most important to address. It is the 6th leading cause of death in the US, and the only cause of death that cannot be prevented, cured, or reduced. The mortality in 2015 is estimated at 700,000 people in the US, with an estimated 5.3 million Americans of all ages suffering from dementia with approximately 200,000 people under the age of 65 (younger onset AD). Almost two thirds of Americans with AD are women (3.2 million women and 1.9 million men).

The number of Americans with AD and other dementias is expected to grow each year as the size and proportion of the population age 65 and older continues to increase. By 2025, the number of people age 65 and older with AD in the US is expected to reach 7.1 million (a 40% increase from 2015).

Alzheimer’s disease is one of the costliest chronic diseases of society. In addition to the incredible emotional toll and costs to families and caregivers, an estimated 17.9 billion hours of unpaid care, valued at $217.7 billion is given annually, with an additional $226 billion for total direct costs, with half of that borne by Medicare.

In 2050, the projected total private and government costs for Alzheimer’s disease in the US will rise to $1.1 trillion (The Alzheimer’s Association 2015).

Although the cognitive impairments, loss of executive functions, and progressive dementia seen in AD is believed to be associated with increased amyloid beta aggregation triggering the toxic events that lead to progressive neurodegeneration, no drug candidates targeting either the amyloid cascade or abnormal tau protein have yet produced a successful treatment.

Until now, a major limitation in the use of potentially effective therapeutic agents such as paclitaxel and curcumin for the treatment of AD has been the inability to cross Blood Brain Barrier (BBB). This problem can now be corrected with CLR-TargoSphere® delivery, which crosses the BBB.

THE SOLUTION:

Treatment of Alzheimer’s disease requires crossing the Blood Brain Barrier with therapeutic agents that will enable early targeting of amyloid beta, when pathology remains reversible, and also reversing or inhibiting the development of hyperphosphorylated neurofibrillary tangles of the abnormal protein tau (NFT).

Studies have repeatedly shown a strong correlation between abnormal tau (NFT) buildup and cognitive decline with impaired synaptic transmission between neural synapses early in AD, even before a significant amount of amyloid beta plaques have been deposited. Because of the mutual pathologic contributions of amyloid beta and tau, a treatment strategy targeting both factors is necessary in order to modify the progression and deterioration in AD.

Treatment with paclitaxel and curcumin has been shown in numerous in-vitro and in-vivo published studies to inhibit immunologic and inflammatory factors associated with the onset and progression of Alzheimer’s disease.

The CLR-TargoSphere® can deliver the encapsulated agents paclitaxel and curcumin to monocytes, and also preferentially to M-2 anti-inflammatory macrophages, which cross the BBB to reach perivascular spaces, activated microglia, and astrocytes.

THE STRATEGY:

  • Target the brain endothelial tissues, perivascular spaces, activated glial cells, and astrocytes with the microtubule-stabilizing compound paclitaxel to inhibit abnormal tau hyperphosphorylation and synaptic transmission pathology; and
  • Enhance uptake and ingestion of amyloid plaques by the brain’s glial cells and astrocytes with curcumin.

PROOF OF CONCEPT:

The CLR-TargoSphere® encapsulated compounds paclitaxel and curcumin are being targeted to the brain to cross the Blood Brain Barrier (BBB) in a preclinical transgenic mouse AD model.

STUDIES SUPPORTING THIS TREATMENT STRATEGY:

Treatment with paclitaxel and curcumin has been shown in numerous in-vitro and in-vivo published studies to inhibit immunologic and inflammatory factors associated with the onset and progression of Alzheimer’s disease:

  • Paclitaxel has been shown to delay the onset of experimental autoimmune encephalitis and reduce scarring and enable axon regeneration after spinal cord injury in experimental animals when injected directly into the spinal canal (3, 4).
  • Paclitaxel enhances migration of TAMs to tumor sites and diseased tissues, with increased differentiation to the M1 phenotype (2).
  • Paclitaxel has been shown to inhibit abnormal tau hyperphosphorylation (5).
  • Curcumin induces uptake and degradation of amyloid beta by macrophages (6).
  • Curcumin decreases astrocyte proliferation, improves myelogenesis, and increases activity and differentiation of oligodendrocytes (7).
  • Curcumin inhibits amyloid beta-induced expression of Egr-1 protein and Egr-1 DNA-binding activity, thereby reducing Central Nervous System (CNS) inflammation and chemotaxis of monocytes (8,9).
  • Curcumin inhibits the activity of AP-1, a transcription factor involved in the expression of amyloid, and decreases the low-density lipoprotein oxidation and free radical formation that cause deterioration of neurons, not only in AD, but also in other neurodegenerative disorders such as Huntington’s and Parkinson diseases (10,11).
  • Curcumin has been shown to increase phagocytosis of amyloid beta and clearing of plaques from Alzheimer patient’s cells ex-vivo (12).

TREATMENT GOALS FOR ALZHEIMER’S DISEASE:

  • Targeted delivery of paclitaxel and curcumin across the blood Brain Barrier (BBB) to the endothelium and perivascular spaces of the CNS, and intracellularly to activated glial cells and astrocytes, the phagocytic cells of the brain;
  • Reduce tau hyperphosphorylation with paclitaxel and inhibit development of neurofibrillary tangles;
  • Reduce amyloid beta plaque formation and aggregation with targeted delivery of curcumin;
  • Delay onset and/or progression of cerebral atrophy;
  • Delay or inhibit progression of cognitive impairments;
  • Improve emotional and behavioral parameters;
  • Improve physical dexterity;
  • Delay vasomotor and parasympathetic autonomic deterioration;
  • Increase healthy and functional life span.

References:

  1. Lanni, J., et al., P53-Independent apoptosis induced by paclitaxel through an independent mechanism. PNAS. 94(18): 9679-9683; 1997.
  2. Shi, Jin-Yuan, et al., Tumor-associated macrophage: Its role in cancer invasion and metastasis. J. of Cancer Molecules. 71(5): 1825-1835; 2011.
  3. Crume, K, et al., Delaying the onset of experimental autoimmune encephalomyelitis with the microtubule-stabilizing compounds, paclitaxel and Peloruside A. J of Leukocyte Bio.86:949-958; 2009.
  4. Hellal, F, et al., Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science. 331(6019): 928-31; 2011.
  5. Erez, H., et al., Rescue of tau-induced synaptic transmission pathology by paclitaxel. Front Cell Neurosci.8:34. doi: 10.3389/fncel.2014.00034; Feb 10, 2014.
  6. Zhang, L, et al. Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer’s disease patients. J Alzheimer’s Dis. 10:1-7; 2006.
  7. Ambegaokar SS., et al., Curcumin inhibits dose-dependently and time-dependently neuroglial proliferation and growth. Neuro Endocrinol Lett. 24:469-73; 2003.
  8. Giri, RK, et al., Curcumin, the active ingredient of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression of CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor. J Neurochem. 91:1199-210; 2004.
  9. Pendurthi, UR, et al., Suppression of transcription factor Egr-1 by curcumin. Thromb Res. 97:179-89; 2000.
  10. Cole, G.M., et al., Neuroprotective effects of curcumin. Adv Exp Med Biol. 2007; 595:197-212.
  11. Choi, D.K., et al., Inhibitors of Microglial Neurotoxicity: focus on Natural Products. Molecules. 2011; 16, 1021-1043; doi: 10.3390/molecules 16021021.
  12. Ono, K., et al., Curcumin has potent anti-amyloidogenic effects for Alzheimer’s β-amyloid fibrils in vitro. J of Neuroscience Research. 15 March 2004; 75:742–750. Doi: 1002/jnr.20025.
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