Cancer Research: Potential Key To Unlocking Alzheimer’s Disease Therapies
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Looking into Alzheimer’s disease
Alzheimer’s disease (AD) is a progressive neurological disorder that slowly destroys memory and thinking skills. The most common cause of dementia, the loss of thinking, remembering, reasoning and behavioral abilities, AD is ranked as the sixth leading cause of death in the United States.1 Symptoms first start appearing in older adults in their mid-60s, and it is estimated that more than 6 million Americans aged 65 and older have dementia caused by AD.2 The key pathology of Alzheimer’s disease is nerve cell loss and synaptic dysfunction. The popular biology of AD includes amyloid plaques and tau tangles throughout the brain.3 An important and yet unsolved question is how closely the presence of the pathologic plaques and tangles contribute to nerve cell death and synaptic dysfunction.
AD can be categorized into different stages: prodromal, mild, moderate or severe. Severe AD is characterized by very substantial changes in the brain; people with this stage of disease have trouble communicating and are almost entirely dependent on others for care.3 Currently, experts in AD understand the consequences of the progressive disease, but not why the disease progresses.
The number of AD cases is increasing each year because of the “double whammy” of longer life span and the baby boomer bulge. In the U.S., the number of individuals with the disease is expected to increase to more than 13 million by 2050; global trends are similar. Without means to delay, prevent or treat AD, the anticipated worldwide population of patients with AD may exceed 100 million by 2050.4
Treatment landscape and potential opportunities in Alzheimer’s disease
The goal of AD therapy is to delay or slow the deterioration of brain functions including behavioral symptoms and memory loss. Due to the complex nature of this neurological disease only a single target, cholinesterase inhibitors, has been approved for the treatment of cognitive symptoms of AD. Several therapies have been or will soon be approved to treat the behavioral symptoms such as depression, aggression or hallucination. Cholinesterase inhibitors aim to increase communication between the existing nerve cells to try to improve the symptoms of Alzheimer's. Their efficacy is transient. Identifying targets for treatment of AD is moving away from the traditional targets of amyloid and tau to more novel targets including neuroinflammation.4
Protein beta-amyloid plaques are the microscopic clumps in the brain that are a characteristic sign of AD. Current amyloid treatment strategies involve antibodies that mimic those produced by the immune system naturally to prevent amyloid clumping into plaques or help the body remove clumps that have already formed in the brain.5 This therapy is the furthest along despite decades of negative clinical trials.
Tau protein tangles cause a vital brain cell transport system to collapse, contributing to abnormalities in AD patients’ brains. Current tau treatment strategies include aggregation inhibitors and vaccines that are being studied in clinical trials. The inhibitors prevent the tau protein from destabilizing and tangling any further while the vaccine helps the immune system identify and target the pathological tau proteins, therefore slowing down neurodegeneration.6
Neuroinflammation has become an area of focus more recently within AD patients since chronic brain cell inflammation has been a consistent issue that researchers have attempted to tackle for decades. Historically, scientists thought neuroinflammation was the result of AD pathologies caused by plaques and tangles. Now, it is recognized that neuroinflammation precedes the appearance of plaques and tangles and may be a common cause of nerve cell death and synaptic dysfunction. The process of reducing neuroinflammation improves the ability of immune cells in the brain to eliminate harmful proteins that cause neuronal dysfunction and alleviate inflammatory processes that cause synaptic dysfunction and nerve cell death.7
Given the heterogeneity of the disease, a single therapy is unlikely to be effective in a majority of patients. The need for combination therapy to effectively treat AD will be guided biomarkers. Biomarkers will demonstrate the contribution of pathologies such as amyloid, tau and neuroinflammation to the disease. These biomarkers may help clinicians and scientists determine the cause of dementia in an individual patient to allow a personalized treatment regimen.4
Precision medicine: The relationship between cancer research and Alzheimer’s disease
In the search to discover new therapeutic approaches for AD, scientists are finding new inspiration where others may have never thought to look: cancer research trends.
Cancer death rates in the U.S. declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop ever recorded.8 Many experts credit advances in technology that allowed them to better understand the disease— referred to as the “omics cancer revolution”. Omics refers to biological sciences that end with “omics,” like genomics, transcriptomics, proteomics, or metabolomics. Better understanding of the biology of a disease has enabled better treatment targeting and potential outcomes for patients.
Applying lessons from the “omics cancer revolution” could drastically change the current treatment landscape for AD. In fact, seven recent papers from the National Institutes of Health highlighting advances in Alzheimer’s research all have one thing in common — omics.9
New imaging techniques for improved clinical strategy
New imaging techniques have also helped scientists’ clinical strategy around the world and led to improved treatment techniques for Alzheimer’s disease patients. Currently positron emission tomography (PET) and optical photothermal spectroscopy (O-PTIR) are two imaging techniques that experts have been using to get a better sense of what is going on in the brains of AD patients. These scans show the distribution of synaptic damage, a more specific disease pathology present at early stages of the disease.10
Structural imaging provides information about the shape, position or volume of brain tissue. Structural techniques including magnetic resonance imaging (MRI) using diffusion tensor imaging (DTI) show shrinkage in specific brain regions, identification of connectivity of the brain and pathology in white matter tracts as well as structural changes in gray matter from neurodegeneration, stroke or previous trauma. Functional MRI (fMRI) imagery reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen and identifying that those with Alzheimer's typically have reduced brain cell activity. This type of imagery along with PET scans offer a new strategy to stage the disease, monitor disease progression and assess the effectiveness of next-generation, disease-modifying treatments.11
As Alzheimer’s research continues to advance, biomarkers will play a crucial role along the path of the development of new therapies. They are key in supporting earlier more accurate diagnoses, monitoring the progression of the disease, and measuring patient responses to treatment. Scientists are now working to develop faster, less invasive and more widely accessible tests to measure these biomarkers in AD patients like a simple blood test or a widely available imaging scan(s), which could increase the potential to conduct AD testing on a much broader scale.12 In the future, these biomarker tests could also lead to physicians diagnosing patients before the onset of symptoms, which would accelerate care and prevent further deterioration of the brain.
By using a biomarker driven approach to inform its clinical strategy, common to today’s oncology trials, we at INmune Bio (INMB) hope to improve the chances of success in its Alzheimer’s studies. We believe that decreasing neuroinflammation may slow or stop the progression of the cognitive and psychiatric symptoms of Alzheimer’s patients and improve in the overall quality of life of the patient and their caregivers. The team is developing a second-generation selective Tumor Necrosis Factor (TNF) inhibitor that neutralizes soluble TNF (sTNF) without affecting trans-membrane TNF (tmTNF). This novel strategy appears to effectively reduce neuroinflammation and may improve cognition. The strategy has yielded positive results from an ongoing Phase I clinical trial in patients with Alzheimer’s that will allow INMB to launch a larger blinded, randomized, placebo-controlled Phase II study this year.13
While additional clinical trials are needed to fully appreciate the potential of this approach, it is worthwhile to continue investigating this path as a potential successful road to develop therapies for a complex, difficult-to-target neurodegenerative disease.
Looking toward other diseases and leveraging the insights from drug development efforts for additional indications has been a useful tool in the past and may prove highly important in the future, especially for people with Alzheimer’s disease.
About the author:
R.J. Tesi, M.D., is president and CEO of INmune Bio.
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