Graphic background shows icons depicting notebooks, DNA and liquid in beakers with the words #ScienceSaturday Takeover

#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research. From February 5 – April 16, 2022, a team of talented students from Columbia University’s M.A. in Biotechnology program is taking over the Rare Roundup section!

KIF1A-Related Research: From the Archives

The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and is Essential for Sensory Neuron Survival and Function

This week we’re discussing a 2016 paper that addresses some fundamental questions regarding KAND: How does knocking out a single copy of KIF1A impact cargo transport, and how do cargo deficits contribute to neurodegeneration?

To address these questions, the Hirokawa group knocked out one copy of the Kif1a gene in mice (Kif1a+/- mice), and isolated clusters of neurons from the Dorsal Root Ganglia (DRG). DRG neurons are responsible for transmitting touch, pain, and temperature signals from the skin to the brain. Notably, pain sensing neurons are known to express TrkA, a KIF1A cargo. Kif1a+/- mice lost pain sensitivity over their lifespan and had less TrkA-expressing neurons at older ages, an example of cell-specific progressive neurodegeneration. Neurons from Kif1a+/- mice were not able to transport TrkA effectively—cargo moved slower down the axon and sometimes reversed course entirely.

One massive undertaking in treating KAND is understanding which neurons are most affected by KIF1A dysfunction. This research provides insight into specific cells impacted by KIF1A loss that correlate with sensory neuropathy, a known KAND symptom. In addition, studies like this provide insight into the possible consequences of knocking out a mutant copy of KIF1A without increasing the expression of healthy KIF1A.

Rare Roundup

Welcome to the #ScienceSaturday Takeover portion of today’s post! Meet our guest bloggers from Columbia University, Aaron, Pragya, Keyue, Rakshitha, and Hazel, here.

Pathophysiology of neurodegenerative diseases: New approaches for investigation and recent advances

This article by Dr. Moretti discusses the common pathways through which neurodegeneration proceeds, including mitochondrial dysfunction, necrosis, downstream oxidative stress, and impaired lysosomal (autophagy) activity. The mitochondria produce energy in the form of ATP, which is responsible for maintaining the homeostasis of the brain and all living cells. If the brain lacks energy, cells start to malfunction and eventually die. The administration of excitotoxins or mitochondrial inhibitors found in neurodegenerative conditions enables the investigation of neurodegenerative disease mechanisms in animals by studying the correlation between oxidative stress and the development of neurodegenerative processes and behavioral alteration. Thus, researchers believe that investigating the role of mitochondria in different disorders may be the best strategy for neuroprotection. 

A critical obstacle that limits the use of some of these novel therapeutic approaches is the limited ability of many compounds to cross the blood-brain barrier. However, the recent use of nanotechnology and nanoparticle-based therapeutics seems promising to facilitate personalized medicine. “With further refinement of all these strategies, a cure for neurodegenerative conditions may finally be within our reach,” says Dr. Gil-Mohapel.

The impact of AI in rare diseases

The many advantages of AI usage are well known to us. This article explores a few of them while reminding us of more crucial factors before employing them in the rare community. While rare diseases need to advance and stay included in aspects of healthcare opportunities and the growing medical applications, it is also critical to consider the ethical, societal, and health implications of doing so. AI-based health care is an extensive and developing field and provides easy access to medical data through electronic health records. However, it has been a more challenging path to developing AI for rare diseases due to their heterogeneity and lack of consistent patient data.

Nevertheless, there have been positive advancements in using PET scan imaging as an AI tool since it allows for total body scanning and complex systems modeling to aid in creating virtual replicates of patients, known as digital twins. While the AI-rare community collaboration proves to be an impactful one, the ethical issues must be addressed to understand why advancement is more complex than it may seem. These include, but may not be limited to exclusion, stigmatization, discrimination by omission, and consent for revealing incidental findings by rare disease-aware artificial intelligence. Since the AI tool is potent and would provide clinicians with a support system in decision making, it is still under consideration for rare diseases. To eliminate fear in the rare community, it has been recommended that patient advocacy groups could be employed as a liaison between the needs of patients with RDs, physicians, and the AI development industry.

Moreover, the healthcare industry can take measures to protect patient privacy. For example, it was found that more patients find it acceptable to share their data anonymously for research purposes. This change may be a stepping stone towards developing a well-organized AI and research community for rare diseases, as policies that support patient privacy are of utmost importance and would subsequently bolster diagnosis.

The Burden of rare diseases: An economic evaluation

It is estimated that about 30 million people in the United States are affected by more than 7,000 rare diseases, half of them children. Most rare diseases have no specific treatment, including KAND, which means that patients with rare diseases and their families and society bear a substantial economic burden.

Chiesi Global Rare Diseases selected 24 rare diseases associated with metabolism, neurology, congenital disorders, hematology and immunology as their research targets and conducted research and analysis on medical costs and social burden. These rare diseases involved 584,000 patients in the United States. After comparing the total cost burden of rare diseases with chronic mass-market diseases (including diabetes, cardiovascular disease, Alzheimer’s disease, arthritis, back pain, cancer, etc.), the researchers pointed out that the average economic burden PPPY (Per Person Per Year) of rare diseases was $266,000 (ranging from $121,000 to $334,000), about ten times the cost of mass-market conditions ($26,000 PPPY).

The researchers further analyzed and found the direct cost, indirect cost and mortality cost of the overall cost of the treatment decreased respectively from $118,000/day, $73,000/day, and $49,000/day without treatment to $63,000 /day, $40,000/day and $36,000/day.

Moreover, when no treatments were available, the range for productivity loss was approximately $33,000 to $61,000 for patients and $25,000 to $61,000 for caregivers, compared with approximately $3,000 to $22,000 for patients and $4,000 to $5,000 for caregivers when treatments were available. The overall burden of lack of treatment will be 21.2% higher than being treated. Researchers estimate that the social burden of all known rare diseases may be between $7.2 trillion and $8.6 trillion a year, while the total cost of 133 million mass-market patients with diseases is $3.4 trillion a year.

The results of this study can help policymakers better understand the benefits of investing in innovation and policy reform and encourage the government to introduce measures to stimulate neonatal disease screening, rare disease diagnosis, and drug development to obtain positive economic returns from the treatment of rare diseases.

FDA’s Accelerated Approval Pathway: A Rare Disease Perspective

This paper discussed the history, standard, problems and solutions of FDA’s accelerated approval pathway. But first, what is accelerated approval? Accelerated approval provides hope for patients with serious and life-threatening diseases for which there are no effective treatments. It still requires substantial evidence to meet FDA’s standard of safety and efficacy and it is simply different from traditional approval with regard to the type of data. For example, the endpoints could be surrogate endpoints that can be measured earlier than clinical endpoints like death. As surrogate endpoints may not be 100% correlated with the desired clinical benefits, it is a risky move. However, the process of drug approval is essentially a benefit-risk tradeoff. It is more than understandable that the more severe the disease and the more effective the treatment, the greater the acceptable risk. But still, ample evidence is required to prove the predictive ability of the surrogate endpoints, which will be further validated by real-world data in a long-term post-marketing confirmatory study. As you can imagine, accelerated approval is very critical to a rare disease like KAND, considering its degenerative nature, small and heterogeneous population, and limitations of prior clinical data. Most importantly, it brings us earlier access to new, safe and effective treatments, which might otherwise take a long time in the traditional fashion. 

How European reference networks help Ukrainian patients

​​This article by EURACTIV, a pan-European media network specializing in EU affairs, discusses some of the ways European Reference Networks (ERNs) are tackling the crisis unfolding for rare disease patients in Ukraine. ERNs are set in place to facilitate the sharing of knowledge and expertise within the EU-bloc and relevant partners. The ERNs rely on virtually connecting health care centers to deal with rare and low-prevalence diseases. With the Ukraine crisis unfolding, those suffering from rare diseases are especially vulnerable (as we discussed previously). A back-of-the-envelope calculation assuming that about 6% of the population suffers from rare diseases gives an estimate of about 2 million Ukrainian rare disease patients. Currently, these patients can be grouped into two groups: those who have left Ukraine and those who remain in the country. Patients that have left Ukraine are faced with a number of needs and challenges, including drug or dietary therapy, diagnostic needs and surgery. Patients who have been internally displaced may face similar challenges, but, currently, it is unknown how to reach these patients, let alone deliver therapy.

With these challenges in mind, ERNs are operating on two levels to assist rare disease patients where possible. On the first level, ERNs have established a “medical hub for rare diseases” where cases submitted are assessed on a case-by-case basis. If the hub is contacted, the network looks to solve the issue. The second level looks to help patients who need hospitalization, daily care, or especially specialized care. Here, ERNs provide medical guidance and recommendations on triage or transfer, providing a list of expert centers across the EU for treatment. Moreover, ERNs are offering this same help to Ukrainian hospitals that may not have the expertise to help specific rare disease patients.

As the war in Ukraine rages on, rare disease patients and communities are disproportionately affected by the conflict. Though significant challenges and problems remain, ERNs are contributing to providing care to vulnerable patients affected by the crisis. 

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