Research, ideas, and leadership for a more secure, peaceful world
Author
Luca Giani
Neurodegenerative diseases (NDD) such as Alzheimer’s, Parkinson’s, and ALS represent a global health crisis affecting more than nine million people in the United States alone. NDDs are caused by progressive loss of central nervous system neurons - currently, there is no cure to reverse this loss. The only approved therapies are palliative or mildly reduce some symptoms.
Each year the number of Americans suffering from neurodegenerative diseases increases, due to an aging population and better diagnostics. This places an enormous economic and emotional burden on these individuals, their families, and their caretakers. Although the number of Americans impacted continues to increase, the last decade has seen only a few new drugs approved for NDD treatment, compared to many more approved for other disease areas such as cancer. Why?
First, there is limited understanding of the causes, specific biology, and pathways of NDD. Second, government and private funding for NDD drug discovery has historically been lower, compared to other disease areas. Third, few policies have been implemented to coordinate across stakeholders, share research, and increase access to funding.
There may be some hope. The last decade has seen a dramatic increase in research approvals, and funding for drugs for certain diseases such as ALS. Other diseases, like Frontotemporal Dementia, are still lagging behind.
My goal is to understand how technology and policy can make these research networks more efficient, speed up drug discovery, and drive forward the creation of new treatments. While a Technology and Public Purpose Fellow, I'll be focusing on the following research areas:
This brief report will (a) give an introduction to NDDs, (b) describe why they can be considered a health crisis, and (c) outline the research plan for my fellowship.
Neurodegenerative diseases are characterized by progressive deterioration and loss of neurons and motor neurons in the brain and spinal cord. Although each neurodegenerative disorder is unique in its clinical presentation and underlying biology, they often have overlapping features.[1] While the exact cause of neuronal loss is different for each disease, it often comes with misfolded protein aggregates and other stress factors such as oxidative stress or brain inflammation. Unfortunately, there are no effective treatments for NDDs, which are ultimately fatal. Most treatments offer palliative relief from symptoms, and sometimes a slight increase in life expectancy or better daily functionality for a limited time.
The most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), Frontotemporal Dementia (FTD) and Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS).
AD is the most common form of dementia, affecting 6 million Americans, and accounting for roughly 60% of all NDDs. AD may present in younger individuals, but it is most common in the elderly, with incidence as high as 50% among people over 85 years of age[2]. Most commonly, AD patients are characterized by an insidious onset and gradual progression of memory loss in conjunction with the loss of other cognitive domains (often visuospatial or executive function), leading to a complete loss of functional independence.
The goal of medical management of AD is therefore aimed at improving patient symptoms and optimizing both caregiver and patient quality of life.
PD is the second most common neurodegenerative disorder, after AD. PD affects between 1.5-2 million Americans, with a prevalence of 0.3% for the general population, 1% for those over 60 and 3% for those over 80. The main symptom associated with PD is Bradykinesia, a condition that causes resting tremor, rigidity and postural instability. Other motor characteristics include limited expression of emotions in the face, as well as changes in vision, abnormally small handwriting and stooped posture. PD can also be associated with nonmotor symptoms such as dysfunction of the nerves regulating non-voluntary body functions, like heart rate, blood pressure, and sweating. Other symptoms include sleep disturbances, mood disorders, and cognitive disturbances. All of these factors can adversely impact the patient's quality of life.
MS is a progressively debilitating disease that affects the brain and spinal cord. In MS, the immune system attacks myelin, which covers nerve fibers. This causes communication problems between the brain and the rest of the body to be disrupted. The disease eventually leads to permanent nerve damage with loss of function.
People with severe disabilities may need to be treated. Some people may lose their ability to walk on their own or with assistance, while others may experience prolonged periods of remission that do not include any new symptoms. About 400,000 Americans suffer from MS.[3]
FTD is the umbrella name for a variety of heterogeneous clinical conditions that result from neurodegeneration primarily in the anterior and frontal temporal lobes and subcortical structures. FTD is characterized by early changes in emotion, behavior, language, and motor skills. About 60,000 Americans are estimated to suffer from some form of FTD.[4]
FTD is a common form of early-onset dementia in patients under 65, and is most commonly diagnosed in middle-aged people, with an average age at onset of 56. However, it can be detected in patients as young as the second decade of life[5], with 13% of cases occurring prior to age 50.
HD is a condition that affects approximately 60,000 Americans.[6] It is an inherited genetic neurodegenerative condition that causes involuntary movements, personality changes, and dementia. It is caused by excessive repeats of sequences in huntingtin genes.[7] HD is a rare disease, with an estimated worldwide prevalence of 2.7 cases per 100,000, with higher rates in Asia, North America and Europe. Median HD diagnosis is 40 years.
ALS affects about 20,000 Americans. ALS is a neurodegenerative disorder characterized by degeneration of the upper and lower motor neurons in the brain and spinal cord, causing respiratory paralysis and death. Approximately 10% of patients have a family history of ALS and are labeled familial ALS.
ALS is a fatal disease leading to severe disability and eventually death from ventilatory failure. It has a prevalence of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival.[8]
NDDs affect over 9 million Americans alone. This number is expected to increase to 21 million by 2050. These diseases are associated with a significant economic burden (>$900B), in addition to the emotional and social burdens on caregivers and patients.
It is becoming more urgent to find treatment options for neurodegenerative diseases. There is currently no cure, and the only options available are palliative care to reduce symptoms. If effective ways to decrease the progression and incidence of neurodegenerative diseases are not discovered, the increase in their frequency is likely to have devastating effects on families, individuals, and society.
Important research initiatives are underway, both in terms of exciting innovative therapies and basic science to understand the underlying causes of neurodegenerative diseases. But we need to do more and better. The burden of Alzheimer's disease would be reduced by 50% if dementia was detected five years earlier and lifestyle changes were implemented.[9] Policy makers should take inspiration from the success stories of previous initiatives to fight cancer and AIDS and support a coordinated program to combat neurological disorders. Brain and Cognitive Sciences researchers estimate that the understanding of neurodegenerative diseases is on average at least a decade behind that of cancer. In other words, we have a poor understanding of pathophysiology of NDDs including key molecular defects or pathways[10].
Patrizia Cavazzoni, Director of the FDA's Center for Drug Evaluation and Research, adds that - making things more complicated in drug discovery for NDDs - animal models are less translational compared to other disease areas (i.e. positive results observed in animals are not confirmed in humans). Furthermore, lack of prognostic and diagnostic biomarkers make the evaluation of drug response in clinical trials more complex[10].
Basic research is essential to uncover the molecular and physiological mechanisms that lead to neurodegenerative disorders. By continuing to expand on this research and sharing findings with one another, the scientific community could identify molecular targets to be used in novel therapeutic interventions[11], and it perhaps becomes essential to invest in diverse testing hypotheses to reach more successful drug discovery.
To sustain an effort against this neurological crisis, large-scale funding for basic research, and diversified therapeutic alternatives are paramount. Funding must come from the government, the investment community and industry, with the right incentives for each actor.
Given the rapid aging of our population and predicted rise in neurodegenerative diseases, now is the time to use technology and public policy to further understand the underlying causes of the disease and facilitate the creation of new effective therapeutic options.
Some examples of innovative therapies include Voyager Therapeutics’ vectorized antibodies that may effect long-term gene expression and disease correction for neurodegenerative diseases. Other monoclonal antibodies have proven successful at eliminating plaques of misfolded proteins inside and outside of neurons, but with some off-target or toxic effects.
On an opposite end of the spectrum, companies like Cognito Therapeutics are paving the way for non-invasive drug alternatives such as frequency optimized light- and sound-based therapeutical headsets that can improve memory and cognition. Other innovations by research groups utilize machine learning trained AI models to quickly test millions of combinations of known libraries of molecules to effect particular pathways that may lead to neurodegenerative diseases. And these are just a few of the innovative approaches being undertaken.
However, there is much research left behind. Many academics are unable to continue their research because of lengthy and bureaucratic grant cycles. Some potentially life-changing patents are sitting in university technology transfer offices. And several entrepreneurs or scientists are unable to attract enough capital to even test their research in early stages.
Furthermore, not all neurodegenerative diseases are made equal. At the most recent ALS TDI summit, I learned about the vibrant community around this disease and the effective drug discovery that is being conducted. Together with patient advocacy groups, never-ending pushes from NGOs such as I AM ALS, awareness campaigns such as the Ice Bucket Challenge, and laws like Accelerating Access to Critical Therapies for ALS Act, further funding has gone into research that has then translated into the approval of three therapies for ALS this year alone. Can we apply some of these learnings from ALS to other disease areas?
The solution to neurodegenerative diseases could lie in technology to speed development and funding, increased access to research and patents, and policy to provide incentives for investors, scientists, and businesspeople.
My team will start by mapping the parties involved, the funding sources and uses, and the legislation passed to better understand the possible causes of discrepancies in the development of neurodegenerative diseases. Then, we will explore possible ways to improve the process using tech and policy.
Of course, we need all the help that we can get: do not hesitate to reach out to discuss this and the potential contributions that you could bring (lgiani@hks.harvard.edu).
[1] Erkkinen MG, Kim MO, Geschwind MD. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2018 Apr 2;10(4):a033118. doi: 10.1101/cshperspect.a033118. PMID: 28716886; PMCID: PMC5880171.
[2] Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ, Hebert LE, Hennekens CH, Taylor JO. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA. 1989 Nov 10;262(18):2551-6. PMID: 2810583.
[3] GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol 2017;16:877–897.
[4] Knopman DS, Roberts RO. Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci. 2011 Nov;45(3):330-5. doi: 10.1007/s12031-011-9538-y. Epub 2011 May 17. PMID: 21584654; PMCID: PMC3208074.
[5] Dobson-Stone C, Hallupp M, Shahheydari H, Ragagnin AMG, Chatterton Z, Carew-Jones F, Shepherd CE, Stefen H, Paric E, Fath T, Thompson EM, Blumbergs P, Short CL, Field CD, Panegyres PK, Hecker J, Nicholson G, Shaw AD, Fullerton JM, Luty AA, Schofield PR, Brooks WS, Rajan N, Bennett MF, Bahlo M, Landers JE, Piguet O, Hodges JR, Halliday GM, Topp SD, Smith BN, Shaw CE, McCann E, Fifita JA, Williams KL, Atkin JD, Blair IP, Kwok JB. CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis. Brain. 2020 Mar 1;143(3):783-799. doi: 10.1093/brain/awaa039. PMID: 32185393; PMCID: PMC7089666.
[6] Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. Mov Disord. 2012 Aug;27(9):1083-91. doi: 10.1002/mds.25075. Epub 2012 Jun 12. PMID: 22692795.
[7] Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. Mov Disord. 2012 Aug;27(9):1083-91. doi: 10.1002/mds.25075. Epub 2012 Jun 12. PMID: 22692795.
[8] Oskarsson B, Gendron TF, Staff NP. Amyotrophic Lateral Sclerosis: An Update for 2018. Mayo Clin Proc. 2018 Nov;93(11):1617-1628. doi: 10.1016/j.mayocp.2018.04.007. Epub 2018 Jul 4. PMID: 30401437.
[10] Cavazzoni, P. (no date) The path forward: Advancing treatments and cures for neurodegenerative, U.S. Food and Drug Administration. Available at: https://www.fda.gov/news-events/congressional-testimony/path-forward-advancing-treatments-and-cures-neurodegenerative-diseases-07292021 (Accessed: November 21, 2022).
[11] Testimony on neuroscience research (no date) National Institute of Neurological Disorders and Stroke. U.S. Department of Health and Human Services. Available at: https://www.ninds.nih.gov/about-ninds/budget-legislation/testimony/testimony-neuroscience-research (Accessed: November 21, 2022)
Giani, Luca. “Combat Neurodegenerative Diseases Crisis with Technology and Public Policy.” November 21, 2022
