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Amyloidosis Speakers Bureau (ASB)

The content of medical education is appropriately clinically centered. The delivery of this content remains relatively unchanged over the decades – typically taught by medical professionals through lectures, PowerPoint presentations, and patient case studies. We posit that there is an essential missing component: the patient voice. During the didactic years, medical students rarely hear from patients about their symptoms, diagnostic journey, emotional management, support and resources, and relationship with the medical community. These insights can offer impactful and durable education that complements traditional didactics in developing future medical practitioners.

Why is this important? Lack of awareness in the healthcare field is among the most critical and urgent challenges facing the amyloidosis community today. Raising awareness to accelerate diagnosis, coupled with available FDA-approved treatments, leads to a significant improvement in patient lives. 

At the Amyloidosis Speakers Bureau, two years ago we set out to understand whether our patient educators were making an impact following a presentation to U.S. medical students. Would their narratives elevate the students’ understanding of this rare disease and influence their attitudes and behavioral intent regarding patients?

In short, our study findings indicated “yes.”   Click HERE to read the peer reviewed published study.

The paper finds that, in a study where medical students were randomly assigned to either listen to an amyloidosis patient’s story or to a control group, those who heard the patient’s diagnostic and treatment journey differed in attitudes and intent from those in the control group. Those who heard the patient’s story were significantly more likely to intend to improve their communication with patients, learn more about amyloidosis, and agree that listening to patients is a vital part of diagnosis. 

 

 

With great appreciation we thank Dr. Adebanke Adebayo, Dr. Katherine Rowan, and Dr. Vaishali Sanchorawala for their important contribution to this paper. We would also like to thank the many ASB patient educators who contributed to this study and continue to give their time to raise awareness to the medical community through sharing their personal journeys. We could not have done this study without any of these wonderful individuals!



CRISPR/Cas9 – ATTR Clinical Trial Update

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.” In this piece we provide a clinical trial update for transthyretin (TTR) amyloidosis using this technology.

 

CRISPR FIXES GENES INSIDE THE BODY (3)

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.”

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings.

 

APPLYING THE CRISPR TECHNOLOGY (3)

Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat.The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.”

Facts about Transthyretin (ATTR) Amyloidosis. Source: https://ir.intelliatx.com/

 

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

Intellia Therapeutics and Regeneron shared a press release recently announcing initial data from the cardiomyopathy arm of the ongoing Phase 1 trial of NTLA-2001, an investigational single-dose in vivo CRISPR-Cas9 therapy for the treatment of transthyretin (ATTR) amyloidosis.

According to that press release, the interim data include 12 adult patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 were administered intravenously, and the change from baseline in serum transthyretin (TTR) protein concentration was measured for each patient. The data revealed that treatment with NTLA-2001 led to rapid and deep reductions of up to 94 % in serum TTR by day 28. In February 2022, the companies reported clinical data that revealed rapid, deep and sustained responses in a cohort of 15 patients with hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

ATTR is a rare, progressive disease, in which a protein known as TTR becomes misfolded and accumulates as plaques in tissues throughout the body. This causes serious complications that mainly involve the heart and nerves, and most patients die 2-15 years after disease onset. NTLA-2001 was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTRgene in liver cells.

Read more about the available clinical data for NTLA-2001 in a previous CMN clinical trial update here.

BACKGROUND

Back in May, 2021 we wrote about the breakthrough gene-editing technology CRISPR being applied to hereditary transthyretin amyloidosis (hATTR), worthy of a background read for those unfamiliar with this science or those looking for a refresher.

BLOG – CRISPR/Cas9 – Editing the Code of Life

 

 

Sources:

  1. CRISPR Medicine News: Special Update: News from the Gene-Editing Clinical Trials
  2. CRISPR Medicine News: CRISPR Therapy for Transthyretin Amyloidosis Results in Rapid and Prolonged Responses
  3. NIH Director’s Blog
  4. BLOG – CRISPR/Cas9 – Editing the Code of Life

FDA Drug Approval Process

Drugs are the lifeblood of patient treatments, and the development of new drugs is critical. Overseen by the FDA (U.S. Food and Drug Administration), they define a drug as “any product that is intended for use in the diagnosis, cure mitigation, treatment, or prevention of disease; and that is intended to affect the structure or any function of the body.”

The FDA’s Center for Drug Evaluation and Research (CDER): “The center’s evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. CDER ensures that drugs, both brand-name and generic, are effective and their health benefits outweigh their known risks.”

There are several phases (comprising twelve steps) of the FDA drug development and approval process, depicted in a two-page graphic here, and described below.



PRE-CLINICAL RESEARCH

This is the drug sponsor’s discovery and screening phase, comprising two steps.

The Start. The sponsor develops a new drug compound and seeks to have it approved by the FDA for sale in the U.S.

Step 1: Animals Tested. The sponsor must test the new drug on animals for toxicity. Multiple species are used to gather basic information on the safety and efficacy of the compound being investigated/researched.

Step 2: IND Application. The sponsor submits an Investigational New Drug (IND) application to the FDA based on the results from initial testing that includes the drug’s composition and manufacturing, and develops a plan for testing the drug on humans (aka a clinical trial).

The FDA reviews the IND to assure that the proposed studies, generally referred to as clinical trials, do not place human subjects at unreasonable risk of harm. The FDA also verifies that there are adequate informed consent and human subject protection.

 

CLINICAL

This phase is all about the clinical trial, all of which must be approved by the FDA before they can begin. In an earlier blog – Clinical Trials 101 – we offer an expanded discussion along multiple facets regarding clinical trials which you may find informative.

According to the National Institutes of Health (NIH), clinical trials are research studies performed on people that are aimed at evaluating a medical, surgical, or behavioral intervention. Clinical trials are the primary way that researchers find out if a new treatment, like a new drug or medical device (e.g., a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still, others test ways to prevent a health problem before it begins. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.

Clinical trials are comprised of four phases to test a treatment, find appropriate dosages, and detect side effects. If following the completion of the first three phases, researchers find the drug or intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects. The fourth phase continues post-FDA approval. Overall, the duration of a clinical trial spans years.

Step 3: Phase I Trial. A Phase I trial tests an experimental treatment on a small group of often healthy people (20 to 80 in number) to judge its safety and side effects and to find the correct drug dosage.

Step 4: Phase 2 Trial. A Phase II trial uses more people (100 to 300 in number). While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase can last several years.

Step 5: Phase 3 Trial. A Phase III trial gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. If the FDA agrees that the trial results are positive, it will approve the experimental drug or device.

 

NDA (NEW DRUG APPLICATION) REVIEW

This phase covers the FDA’s New Drug Application (NDA) review.

Step 6: Review Meeting. The FDA meets with the sponsor prior to submission of the NDA.

Step 7: NDA Application. The sponsor formally asks the FDA to approve a drug for marketing in the United States by submitting an NDA. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured.

Steps 8-9: Application Reviewed. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. If the FDA files the NDA, the FDA Review Team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.

Step 10: Drug Labeling. The FDA reviews the drug’s professional labeling and assures appropriate information is communicated to health care professionals and consumers.

Step 11: Facility Inspection. The FDA inspects the facilities where the drug will be manufactured. 

Step 12: Drug Approval. The FDA reviews will approve the application or issue a response letter.

 

POST-MARKETING RISK ASSESSMENTS

Phase IV clinical trial for drugs or devices takes place after the FDA approves their use. A device or drug’s effectiveness and safety are monitored in large, diverse populations, where the sponsor is required to submit periodic safety updates to the FDA. Sometimes, the side effects of a drug may not become clear until more people have taken it over a longer period of time.

 

WHO REVIEWS NEW DRUG SUBMISSIONS?

A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists review the drug sponsor’s data and proposed labeling of drugs.

 

WHAT OTHER DRUG PRODUCTS ARE REGULATED BY THE FDA?

Drugs include more than just medicines. For example, fluoride toothpastes, antiperspirants (not deodorant), dandruff shampoos, and sunscreens are all considered drugs.

 

CONCLUSION

FDA approval of a drug means that data on the drug’s effects have been reviewed by CDER, and the drug is determined to provide benefits that outweigh its known and potential risks for the intended population.

 

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SOURCE

National Institutes of Health

U.S. Food and Drug Administration

Drugs.com



Carpal Tunnel & Amyloidosis – An Update

The connection between carpal tunnel and amyloidosis is one that is already established. In fact, carpal tunnel syndrome is one of many potential symptoms of amyloidosis, but it is a symptom that tends to present early. It is not uncommon to hear patients started experiencing carpal tunnel five to ten years before they were diagnosed with amyloidosis.

TWO STUDIES

Clinicians are becoming aware of this connection and are starting to investigate the connection. Two studies have been published that investigate the connection between carpal tunnel and amyloidosis.

The first study from 2018 was a “prospective, cross-sectional, multidisciplinary study of consecutive men age ≥ 50 years and women ≥ 60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red.”3 Of the patients that were eligible for Congo red staining (n=98), a total of 10 came back positive for amyloidosis.3 That is a hit rate of just over 10%.

In a larger second study from 2022, a total of 185 patients underwent carpal tunnel release surgery, where 54 biopsies confirmed evidence of amyloidosis with Congo red staining.1 That is a hit rate of 29%.

The results of these studies are powerful and provide an opportunity to change the trajectory of diagnosing amyloidosis, particularly doing so much earlier. According to the Bureau of Labor and Statistics and the National Institute for Occupational Safety and Health, carpal tunnel release surgery is the second most common type of surgery, performed over 230,000 times every year.4

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

“Since carpal tunnel syndrome is often one of the earliest signs of underlying amyloidosis, those with undiagnosed disease could greatly benefit from tissue biopsies at the time of surgery. A positive biopsy result could initiate the road to disease stabilization and hopefully future cures, avoiding the all-too-often rapid decline of health before final recognition. Bringing the surgeon into the arena of amyloidosis diagnosis and care broadens the net for catching this disease early and prepares the surgeon as a team-player for future medical support.”

Charles Williams Sr., MD

Retired Orthopedic Surgeon

 

CONCLUSION

Screening for amyloidosis in carpal tunnel release surgery can be a low-cost method of detecting amyloidosis that should be considered.2

Most importantly, identifying and diagnosing amyloidosis early has the potential to significantly improve patient outcomes and substantially alter the course of disease.

Truly life changing.

P.S. Click here to read our previous post on Carpal Tunnel & Amyloidosis

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Resources:

  1. https://pubmed.ncbi.nlm.nih.gov/35469694/
  2. https://consultqd.clevelandclinic.org/cardiac-amyloidosis-look-to-the-wrist-for-an-early-diagnostic-clue/
  3. https://www.sciencedirect.com/science/article/pii/S0735109718381634?via%3Dihub
  4. https://www.orthoarlington.com/contents/patient-info/conditions-procedures/11-astounding-carpal-tunnel-statistics
  5. https://www.verywellhealth.com/open-surgery-or-endoscopic-carpal-tunnel-surgery-4083069
  6. https://mailchi.mp/ea0a0bb441eb/carpal-tunnel-amyloidosis

AI, Protein Folding & Amyloidosis

The Protein Folding Problem

Proteins are the building blocks of life. They are large complex molecules, made up of chains of amino acids, and what a protein does largely depends on its unique 3D structure. Figuring out what shapes proteins fold into is known as the “protein folding problem.”  For decades and decades, one of biology’s biggest challenges has been finding a solution for the “protein folding problem” and is explained in the linked video below.

AI, DeepMind and Google Find Answers

Founded in 2010, DeepMind researches and builds safe AI (Artificial Intelligence) systems that learn how to solve problems and advance scientific discovery for all. They joined forces with Google in 2014 to accelerate their work. They’re a team of scientists, engineers, machine learning experts and more, working together to advance the state of the art in AI.

In a major scientific breakthrough, DeepMind’s AI system AlphaFold has been recognized as a solution to this grandest of all biological problems – the “protein folding problem.”  Here is an excellent video explaining AlphaFold and the making of a scientific breakthrough.

According to Professor Venki Ramakrishman, Nobel laureate and President of the Royal Society,

This computational work represents a stunning advance on the protein-folding problem, a 50-year-old grand challenge in biology.  It has occurred decades before many people in the field would have predicted. It will be exciting to see the many ways in which it will fundamentally change biological research.

 

Potential Impact for Amyloidosis

For diseases which originate with misfolded proteins, such as amyloidosis, “investigators have been doing this exercise by ‘brute force’ until now,” according to Dr. Angela Dispenzieri from the Mayo Clinic.  This AI research is likely to open a whole new world of insight and answers, from which new and more effective treatments can be developed.

Marina Ramirez-Alvarado, Ph.D., whose research laboratory at the Mayo Clinic studies misfolding and amyloid formation in light chain amyloidosis, had this to say.

The protein folding problem, one of the most important scientific questions of the 20th century is making headlines today with the artificial intelligence work from DeepMind. It is clear that DeepMind will provide important basic understanding of the folding process and will significantly benefit those amyloidosis diseases that involve secreted, folded proteins, such as light chain (AL), and Transthyretin (ATTR) amyloidosis.

Dr. Morie Gertz, a hematologist/oncologist from the Mayo Clinic who has decades of clinical experience with amyloidosis, weighs in on some of the possible outcomes from this ground-breaking research.

The ability to predict protein folding in three dimensions may result in the ability to predict which protein sequences are likely to form amyloid fibrils. In light chain amyloidosis this could allow for long-term monitoring of selected patients likely to develop amyloidosis. This would permit extremely early diagnosis long before symptoms developed. It would also allow for the exploration of why wild-type TTR amyloidosis forms amyloid fibrils in the heart in some patients but not in others.

 

However, it won’t answer all questions …

Dr. Vaishali Sanchorawala, director of Boston University’s Amyloidosis Center offers these words of perspective.

The “protein folding problem” that DeepMind’s AlphaFold is designed to solve is predicting the native, functional state of a protein from just its amino acid sequence. Amyloidosis, though, is caused by our bodies’ failure to solve that problem, resulting in misfolded and aggregated proteins. AlphaFold’s remarkable achievement can definitely help to better understand native structure of amyloidogenic light chain proteins. However, amyloid fibrils are different from the native states of their precursor proteins and therefore the adaptation of AlphaFold to study protein misfolding and aggregation, perhaps by predicting the structures of complex amyloid fibrils, might be better able to predict the effects of mutations that alter people’s risk of developing amyloidosis.

 

In closing …

AI is rapidly advancing the knowledge of protein misfolding, unlocking answers for amyloidosis which should lead to earlier diagnosis, improved treatment, and better patient survival.

 

 

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Sources:

Angela Dispenzieri, M.D.

Morie A. Gertz, M.D., M.A.C.P.

Vaishali Sanchorawala, M.D.

Marina Ramirez-Alvarado, Ph.D.

 

High Accuracy Protein Structure Prediction Using Deep Learning

John Jumper, Richard Evans, Alexander Pritzel, Tim Green, Michael Figurnov, Kathryn Tunyasuvunakool, Olaf Ronneberger, Russ Bates, Augustin Žídek, Alex Bridgland, Clemens Meyer, Simon A A Kohl, Anna Potapenko, Andrew J Ballard, Andrew Cowie, Bernardino Romera-Paredes, Stanislav Nikolov, Rishub Jain, Jonas Adler, Trevor Back, Stig Petersen, David Reiman, Martin Steinegger, Michalina Pacholska, David Silver, Oriol Vinyals, Andrew W Senior, Koray Kavukcuoglu, Pushmeet Kohli, Demis Hassabis.

 

In Fourteenth Critical Assessment of Techniques for Protein Structure Prediction (Abstract Book), 30 November – 4 December 2020. Retrieved from here.

 

 

Understanding the Term “Amyloid”

Amyloid is a term that is often misunderstood. It is actually a term that is broader in meaning than generally realized. It’s easy to think that ‘amyloid = amyloidosis,’ but it’s actually associated with many diseases outside of the world of amyloidosis.

To make understanding the term amyloid a bit easier, let’s take a step back and talk briefly about proteins and their structure. An easy way to understand this process is by using an analogy to words and language. The fundamental building block of language is the alphabet and individual letters. Putting these letters together allows us to create words that have meaning, but words alone are not enough to fully communicate what we are trying to say. We must have sentences to convey our ideas. 

The same goes for proteins. The way they are able to function properly is through folding. In the graphic below, you see the progression of protein folding. It starts with an amino acid (i.e., letters), which are put together to create a string of amino acids, also known as the protein’s primary structure. This string of amino acids is then organized into an alpha helix or a pleated sheet (i.e., words) to create the protein’s secondary structure. Finally, the helix or sheet is folded into what is known as the tertiary structure (i.e., sentences). This is an essential biological step that allows proteins to carry out their natural process.

So with that rudimentary analogy, let’s bring it back to amyloid. The word amyloid simply refers to a protein folding pattern, meaning when proteins fold, they fold into an amyloid orientation. Instead of being folded into their proper orientation (i.e., tertiary structure), they are misfolded into an amyloid pattern. 

To date, scientists have discovered 37 human proteins that are capable of forming amyloid, and each of these proteins is associated with a disease it can lead to.

In the world of amyloidosis, two common forms are ATTR and AL amyloidosis. These diseases are classified by the precursor proteins that form amyloid. In the case of ATTR amyloidosis, TTR (transthyretin protein) is the amyloid-forming culprit. In AL amyloidosis, immunoglobulin (also known as antibodies) light chain fragments form amyloid. 

But as mentioned earlier, amyloid can lead to diseases other than amyloidosis. Probably one of the most well known is Alzheimer’s disease. Alzheimer’s is associated with the amyloid precursor protein that forms from the β amyloid peptide. Other well-known diseases, such as Parkinson’s and Huntington’s disease, are also associated with amyloid. In Parkinson’s disease, the α-synuclein protein forms amyloid, whereas, in Huntington’s disease, Huntingtin exon 1 forms amyloid. Each is a distinct disease, but commonly involves the folding of an associated protein into amyloid. Even a specific type of prostate cancer results when Proteins S100A8/A9 form amyloid.

 

It’s a term I never entirely understood, so I hope this short article clears a few things up!

 

 

References:
https://en.wikipedia.org/wiki/Amyloid
https://www.ptglab.com/news/blog/the-complexity-of-proteins/

The History of Congo Red

“Congo red is the essential histologic stain for demonstrating the presence of amyloidosis in fixed tissues. To the best of my knowledge, nothing has been written about why the stain is named ‘Congo.’ ” according to Dr. David P. Steensma.

So how did this stain get its name? Where did it come from, and does it have a connection to the African Congo? The history is fascinating and below, with Dr. Steensma’s permission, we adapt his story of the history of Congo red.

Congo red didn’t start its life as a histological stain nor was it initially named “Congo.” Like Prussian Blue, it was developed to dye clothes. In 1857, William H. Perkin in the UK created the first synthetic aniline dye, a purple color he called mauvine, later known as “mauve.”

 

Until that time, mostly natural dyes had been used to dye fabrics. After Perkin’s discovery, there was a race to create synthetic colors – mostly in Germany, mostly aniline dyes. This is the chemical structure of Congo red; aniline is a phenyl group attached to an amino group.

 

A major problem with older fabric dyes is that they wash out easily. To stop fading, another chemical, a mordant, is needed. Companies in the late 19th century were keen to find dyes that didn’t require a mordant, to save time and money. (A company in Connecticut sells this one.)

 

In 1883, a young German chemist, Paul Böttinger created a new bright-red dye that stained fibres without needing a mordant. He brought it to the attention of his bosses at The Friedrich Bayer Company but they weren’t interested. Reportedly they were looking for a purple, not red.

 

So Böttinger left Bayer and patented the chemical on his own. He offered it to several other companies, but they weren’t interested. Finally, a small Berlin-based dye manufacturing company called Agfa (Aktiengesellschaft für Anilinfabrikation), founded in 1867, bought it.

 

Congo red was a huge commercial success for Agfa – so much so that many other aniline dye companies went out of business. Bayer, the company that rejected Böttinger, only survived by creating their own Congo red … Agfa then sued them. (Clever sticker is from a Medium blog post.)

 

It became a classic case in patent law.  The “non-obvious” clause in patent world comes from Congo red.  Agfa and Bayer decided the lawsuit was becoming too expensive so they settled, agreed to co-market Congo red & share the profits. (This image is from http://chm.bris.ac.uk/motm/congo-red/congo-redh.htm…)

 

The lawsuits & lost sales had almost bankrupted Bayer. But now, with money from Congo red sales, Bayer was able to hire new chemists. In 1898 Bayer marketed heroin (!), and in 1899 they marketed a new drug you’ve probably heard of: aspirin. Heroin and aspirin saved the company.

 

In 1925 Bayer and Agfa and four other chemical companies merged to form IG Farben (Farben = colors/dyes in German). IG Farben made helpful chemicals like dyes and medicines, but also some terrible chemicals, like the infamous Zyklon B. As a result, they were dissolved after World War II.

 

The month Congo red was patented in 1885, there was a big event going on in Berlin: the Berlin West Africa Conference. In simple terms, the European powers were dividing colonial Africa. Otto von Bismarck, chancellor of the newly unified Germany, presided over the conference.

 

Britain & France already had established colonies; Italy controlled parts of East Africa, Portugal controlled Mozambique & Angola.  The Congo basin was a sticking point everyone was talking about. Some “genius” marketer at Bayer thought: what better name to give our new vivid dye?

 

Other dyes created at about the same time were Sudan Black, Sudan Red, Coomassie Blue, and Bismarck Brown – notice a theme? Africa = exotic and colorful in the late 19th century European mind. Incidentally, Sudan Black is also still used for histology, and Coomassie Blue in SDS-PAGE.

 

The real-world Congo was in the end given to the Belgian king, Leopold, as his private fiefdom. It became the site of some of the worst atrocities in human history, immortalized in Joseph Conrad’s book “Heart of Darkness”.

 

Anyway, Congo red, like many other aniline dyes, immediately started being used for histology. But it wasn’t particularly useful until 1922 when a young German pathologist, Hans Herman Bennhold, discovered it binds to amyloid. In 1929, Paul Divry, a Belgian neuropathologist studying degenerative changes in aging brains, first noted the characteristic green birefringence of amyloid substance when stained with Congo red and viewed under polarized light.  (This image is from Lai et al 2007 Kidney Int’l.)

 

 

General Principle of the Stain

According to Bitesize Bio,

Amyloid is similar in structure to cellulose, therefore it behaves similarly in its chemical reactions. It is a linear molecule, which allows azo and amine groups of the dye to form hydrogen bonds with similar hydroxyl radicals of the amyloid.

When examined in haematoxylin and eosin-stained sections of tissue, amyloid appears as an amorphous, glassy, eosinophilic material. Since this can be confused with some other materials, Congo red staining is needed to identify it.

When examined using regular bright-field microscopy, Congo red-stained amyloid appears pale orange-red. However, the bright field appearance alone is not diagnostic for amyloid, because small deposits may be difficult to see. Congo red-stained tissue sections must therefore be examined under polarised light allowing the characteristic ‘apple green’ birefringence to be seen which is diagnostic for the presence of amyloid.

 

Conclusion

Dr. Steensma writes “Congo red began its life as an extremely valuable textile dye – a dye of such importance that it not only revolutionized the textile industry but also resulted in a patent challenge that changed intellectual property law.” Decades later, the Congo red histologic stain is the gold standard today for the demonstration of amyloid in tissue sections.

Imagine that.

 

 

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Many thanks to Dr. Steensma for his permission to share this interesting story.

Reference:

“Congo” Red by David P. Steensma, MD; Archives of Pathology & Laboratory Medicine, 2001

 

 

 

 

Amyloidosis By The Numbers

 

As a member of the amyloidosis community, we consistently engage in conversations with patients across a variety of forums. One constant among these patients is a desire for more knowledge. We want to learn about symptoms, treatments, and how we are all impacted by this disease. To get some answers, Mackenzie’s Mission created a series of online questions. We heard from 575 respondents. Here are their answers.  Disclaimer: we are simply reporting the data as submitted.

 

In response to what is your current age today, the range was between 20 and 89, with 92.6% falling between the age of 40 and 79, and 83% falling between the age of 50 and 79.

 

 

In response to what was your age at time of diagnosis, the range was between 10 and 89, with 91% falling between the age of 40 and 79, and 63.8% falling between the age of 50 and 69.

 

 

The gender of respondents was somewhat balanced, with 54.5% female and 45.5% male.

 

 

The respondents currently live in 25 countries/areas around the globe, with 82.09% from the United States.

 

 

The types of amyloidosis were also diverse, including Primary/AL, hATTR, ATTRwt, Localized, and Secondary/AA.  About 3% of the respondents were types outside of these, or unknown.

 

When asked about the number of organs affected, the majority at 56.5% had two or more, followed by 36.7% with one organ involved. A small 6.8% had no organ involvement.

 

Next, we asked the respondents for specifics as to which organs had been affected by the disease. The heart and kidney were the most common, with the GI Tract and Nervous System coming in similarly at third and fourth. Fewer respondents listed problems with the liver, lungs, spleen and larynx. In addition, there was a surprisingly long list of other involvements filled in, each receiving just one tally.

 

The next four questions focused on the specialty of doctors that patients had visited, and the time to diagnosis.  We first asked how many doctors each respondent saw before getting a diagnosis. It is interesting to see how evenly it is spread across the selections.

 

We then wanted to know where their journey began. What was the specialty of the first doctor the respondent visited?  It was not a surprise that the majority of responses, at 53.9%, named their PCP/Internal Medicine as their first stop.

 

The next question was to determine what type of doctor made the amyloidosis diagnosis. The data seems to indicate that while PCP/Internal Medicine was the first point of inquiry at 53.9%, they arrived at a diagnosis only 1.9% of the time. Thus, referrals to specialists were key to getting a diagnosis, with nephrologists, hematologists/oncologists, and cardiologists the front runners at an aggregate of 72.9%. Having said that, per the earlier chart, it took many specialists to arrive at the answer.

 

Next, we wanted to know how long it took to get a diagnosis. We were surprised to learn that 50% of respondents said they received a diagnosis within the first six months, especially given the number of doctors visited to arrive at the diagnosis.

 

We then asked respondents to list all symptoms they experienced. The dominant symptoms were fatigue and shortness of breath – 64.2% and 53.7% respectively. The “Other” category came in strong at 22.4%, with an extremely long and diverse list of additional symptoms (too many to mention here). It does seem appropriate to observe that the diversity of symptoms reflects the complexity of this disease.

 

We wanted to better understand how long patients experienced symptoms before they sought medical attention (this is of course with the benefit of 20/20 hindsight). Some 37.6% of respondents sought treatment early, waiting six months or less. However, nearly half — approximately 46% — experienced symptoms anywhere from six months to three years before their first doctors visit.

 

We asked respondents the types of treatments they had undergone since diagnosis. A significant 77.8% had various types of drug therapy and 37% received a stem cell transplant. A number of the patients having a stem cell transplant also had drug therapies, so these responses are not exclusive of one another.

 

For those who underwent a stem cell transplant, we wanted to understand whether the procedure was done as an inpatient, an outpatient, or as a combination. The majority at 68.5%, for a variety of reasons, were inpatient.

 

Our next category of questions focused on clinical trials.  Of our 575 respondents, roughly one-quarter have participated in a clinical trial.

 

We asked those who participated in a clinical trial which one they were in. You can see below the distribution for the ATTR trials. We did ask a separate question regarding the AL-focused trials, however the data proved to be questionable and thus it was excluded from this recap.

 

The next question was aimed at the 77% who indicated they did not participate in a clinical trial, seeking to understand why not.  Striking was the number of respondents who declined, for whatever reason, to answer.

 

In the next question we asked respondents to provide some insight into how they rated their ability to tolerate treatment, whatever that may be. It was spread out, perhaps due to a wide range of treatments.

 

We then asked patients to assess their quality of life before and after treatment. For those that responded, the majority indicated at least a moderate improvement.

 

 

In our next-to-last question we asked the current state of their disease.

 

The final question was open-ended, where we asked respondents to complete the following sentence: “With hindsight, I would have appreciated knowing about …”  We received a massive number of responses, and in our desire to give everyone their full and unedited voice, we invite you to read through the many heartfelt and authentic voices (listed in the order received).   “With hindsight, I would have appreciated knowing about …”

 

 

CLOSING THOUGHTS

 

The responses we got from this study reinforce the complexity and diversity of amyloidosis. To each member of this community who stepped forward to answer the questions, we thank you. Gathering information, spreading awareness, and pushing for change leads us on the path to earlier diagnosis and an increase in life-saving research.

 

One repeating point people mentioned in the last question was a need for more information for doctors and members of the medical community, and for patients and caregivers who are dealing with this disease. If we continue to reach out to doctors, they will recognize the symptoms of amyloidosis and will think to test for it, leading to earlier diagnosis. If we continue to provide patients and caregivers with the most up to date information on treatments, resources, and where they can go for support, we can help arm those who are newly diagnosed. In this way, the sharing of information can be one of our most valuable tools.

 

Fight on, amyloidosis warriors. Fight on.

 

DOCTORS of Amyloidosis

Twelve of the most notable experts in the fight against this disease share, in their own unedited words, their views on the state of the disease. They voice what patients and the medical community need to do to push forward, and what lies ahead in the pipeline of potential treatment.

This unparalleled collection of messages from leading experts is a priceless read to understand the disease both today, and tomorrow.

We thank them for their words, and the passion and care they bring to their patients, in the fight against amyloidosis.

Thank you for taking the time to watch and read their stories.

Mackenzie

P.S. You can view the video, or for those preferring a larger font for easier reading, we have provided a transcript for download as well.

DOCTORS of Amyloidosis transcript (download)

 

 

 

 

Clinical Trials 101

Clinical research is simply medical research involving people. There are two types, clinical studies (aka observational studies) and clinical trials. In this blog, we explore clinical trials and the basics of what you need to know.

 

WHAT ARE CLINICAL TRIALS?

According to the National Institutes of Health (NIH), clinical trials are research studies performed on people that are aimed at evaluating a medical, surgical, or behavioral intervention. Clinical trials are the primary way that researchers find out if a new treatment, like a new drug or medical device (e.g., a pacemaker) is safe and effective in people. Often a clinical trial is used to learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still, others test ways to prevent a health problem before it begins. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.

 

WHY CLINICAL TRIALS ARE IMPORTANT

Clinical trials permit researchers to test the safety and effectiveness of new therapies. They also allow for a rigorous evaluation through patient participation. Bottom line: it is only after the extensive evaluation and testing from a clinical trial that the FDA will approve the widespread use of any new therapy.

According to Dr. Morie A. Gertz at the Mayo Clinic:

Advancing the medical care for all patients requires participation in clinical trials. Only through clinical trials can we further improve the available therapy options for current and all future patients. Clinical trials seek to answer questions about the natural history and biology of the disease as well as important questions regarding outcomes was all available new therapies. All current treatments received by our amyloid community were derived through others participation in clinical trials. Clinical trials are not only an opportunity to get the cutting edge therapy but is a way to “pay it forward“ for future generations of Patients.

 

WHAT ARE THE PHASES OF CLINICAL TRIALS?

All clinical trials must be approved by the U.S. Food and Drug Administration (FDA) before they can begin. Prior to that decision, scientists perform laboratory tests and studies in animals to test a potential therapy’s safety and efficacy. Assuming favorable outcomes, the FDA then gives approval for a clinical trial involving humans.

Clinical trials are comprised of four phases to test a treatment, find appropriate dosages, and detect side effects. If following the completion of the first three phases, researchers find the drug or intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its effects. Overall, the duration of a clinical trial spans years.

  • Phase I trial tests an experimental treatment on a small group of often healthy people (20 to 80) to judge its safety and side effects and to find the correct drug dosage.
  • Phase II trial uses more people (100 to 300). While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. These trials also continue to study safety, including short-term side effects. This phase can last several years.
  • Phase III trial gathers more information about safety and effectiveness, studying different populations and different dosages, using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people. If the FDA agrees that the trial results are positive, it will approve the experimental drug or device.
  • Phase IV trial for drugs or devices takes place after the FDA approves their use. A device or drug’s effectiveness and safety are monitored in large, diverse populations. Sometimes, the side effects of a drug may not become clear until more people have taken it over a longer period of time.

 

WHY PEOPLE CHOOSE TO JOIN A CLINICAL TRIAL

There are many reasons why people choose to join a clinical trial. Some join a trial because the treatments they have tried for their health problem did not work. Others participate because there is no treatment for their health problem. Some studies are designed for, or include, people who are healthy but want to help find ways to prevent a disease that may be common in their family. By being part of a clinical trial, participants may access new treatments before they are widely available. Especially with a rare disease such as amyloidosis, clinical trials may offer a meaningful impact to a patient’s quality of life.

In addition, people may feel that participating in a clinical trial allows them to play a more active role in their own health care. Participants may receive more frequent health check-ups and closer monitoring through the clinical trial. Other people say they want to help researchers learn more about certain health problems. Whatever the motivation, when choosing to participate in a clinical trial, one becomes a partner in scientific discovery. This can also help future generations lead healthier lives. Major medical breakthroughs could not happen without the generosity of clinical trial participants—young and old.

In the words of Dr. Vaishali Sanchorawala at The Amyloidosis Center at Boston University School of Medicine and Boston Medical Center:

Clinical trials allow researchers and physicians to test the safety and effectiveness of new, promising drugs. Before any drug can be approved, it must be rigorously tested in clinical trials. Without the participation of patients, new treatments and cures will never happen. In addition, participating in a clinical trial may be a great way for patients to access new treatments before they become available. Especially in a rare disease such as amyloidosis, clinical trials can be a vital resource for the care of patients.

 

POTENTIAL RISKS OF A CLINICAL TRIAL

There are no guarantees of success from a clinical trial, and there are risks. For starters, there may be serious side effects. Also, the therapy may not improve upon current treatment, or may not even work at all. Finally, as a clinical trial participant, you may be part of the control group, which means either standard treatment or no-treatment placebo. In other words, there are no assurances you would receive the new therapy.

 

FINDING A CLINICAL TRIAL

Thanks to the internet, folks can find lots of information regarding the wide array of open clinical trials. So much so that it may be overwhelming. Particularly with regards to amyloidosis, casting such a wide net may not be the most productive approach. Since finding an appropriate clinical trial is not as easy for rare diseases such as amyloidosis, here are a few excellent places to start.

  • My Amyloidosis Pathfinder (MAP). Developed by the Amyloidosis Research Consortium (ARC), MAP helps patients discover and learn about amyloidosis-related clinical trials. After answering a short questionnaire, MAP matches patients to trials specific to their condition and ones for which they may be eligible.
  • Boston University / Boston Medical Center. A recognized Center of Excellence for amyloidosis, BU has an ongoing robust array of clinical trials for different types of amyloidosis.
  • Mayo Clinic. A recognized Center of Excellence for amyloidosis, Mayo Clinic has an extensive clinical trial program in the area of amyloidosis.
  • ClinicalTrials.gov. This resource, provided by the U.S. National Library of Medicine, is a database of over 250,000 privately and publicly funded clinical studies conducted around the world (in all 50 states in the U.S. and 204 countries).

 

INFORMED CONSENT PROCESS

The informed consent process is a key part of the safeguard of a clinical trial. Before joining a clinical trial, each participant will be told what to expect (e.g., treatments, tests) and what might happen (e.g., benefits and risks, including possible side effects). It is also the point where participants should ask ample questions about the trial, which the clinical trial coordinator should be more than willing to answer.

Below is a list of questions compiled from sources, including the NIH and The Clinical Study Center, recommending what patients should consider asking before consenting to participation in a clinical trial.

  • What is the purpose of the study?
  • Who is sponsoring the study, and who has reviewed and approved it?
  • Who will be in charge of my care?
  • What treatment or tests will I have? Will they hurt?
  • What are the chances I will get the experimental treatment?
  • What are the possible risks, side effects, and benefits of the study treatment compared to my current treatment?
  • How will I know if the treatment is working?
  • How will you protect my health while I am in the study?
  • What happens if my health problem gets worse during the study?
  • How will the study affect my everyday life?
  • How long will the clinical trial last?
  • What will happen after the conclusion of the study?
  • Where will the study take place? Will I have to stay in the hospital?
  • Will you provide a way for me to get to the study site if I need it?
  • Will being in the study cost me anything (e.g., treatment, tests, travel)? If so, will I be reimbursed for all expenses (including other charges such as child care)? Will my insurance cover my costs?
  • Can I take my regular medicines while in the trial?
  • Who will be in charge of my care while I am in the study? Will I be able to see my own doctor?
  • Will you follow up on my health after the end of the study?
  • Will you tell me the results of the study?
  • Whom do I call if I have more questions?
  • How will you keep my doctor informed about my participation in the trial?
  • Does the study compare standard and experimental treatments?
  • If I withdraw, will this affect my normal care?
  • What are the chances that I will receive a placebo?
  • What steps ensure my privacy?

 

Taking part in a clinical trial is solely the decision of the participant, although they may want to discuss it with their medical team prior to finalizing a decision. If one decides to join the trial, they will be required to sign an informed consent form that presents the key facts of the study and indicates they have been told all of the details and want to be part of the study. Importantly, the informed consent form is NOT a contract. Participants can leave the trial at any time and for any reason without being judged or put in a difficult position regarding medical care. Researchers much keep health and personal information private. Also, during the trial, participants have the right to learn about new risks or findings that emerge.If researchers learn that a treatment harms any of the participants, they’ll be removed from the study.

 

PARTICIPANT PROTECTION & SAFETY

Before committing to participate in a clinical trial, it is important to understand participant safety. Congress has put laws in place to protect against abuses, and today every clinical investigator is required to monitor and make sure that every participant is safe. These safeguards are enforced by the Federal Government. Every clinical trial follows a protocol that describes what the researchers will do. The principal investigator, or head researcher, is responsible for making sure that the protocol is followed.

In addition, there are multiple scientific oversight groups to aid in the control of clinical trials.

  • Institutional Review Board (IRB): Comprised of doctors, scientists, statisticians, and lay people, IRBs provide scientific oversight for all clinical trials in the United States. IRB members regularly review studies and their results, making sure risks (or potential harm) are minimized.
  • Office for Human Research Protections (OHRP): The U.S. Department of Health and Human Services’ (HHS) Office for Human Research Protections (OHRP) oversees all research done or supported by HHS. The OHRP helps protect the rights, welfare, and well-being of research participants. They provide guidance and oversight to the IRBs, develop educational programs and materials, and offer advice on research-related issues.
  • Data Safety Monitoring Board (DSMB): Comprised of research and study topic experts, this board is required for every NIH phase III clinical trial. Their role is to review data from a clinical trial for safety problems or differences in results among different groups of relevant studies. If they find that the experimental therapy is not working or is harming participants, they will halt the trial right away.
  • Food and Drug Administration (FDA): In the United States, the FDA provides oversight for clinical trials that are testing new medicines or medical devices. They review applications before any testing on humans is done, checking to ensure a proposed clinical trial has proper informed consent (see earlier) and protection for human subjects. In addition, the FDA provides oversight and guidance at various stages throughout the trial.

 

Scientific oversight informs decisions about a trial while it’s underway. For example, some trials are stopped early if benefits from a strategy or treatment are obvious. That way, wider access to the new strategy can occur sooner. Sponsors also may stop a trial, or part of a trial, early if the strategy or treatment is having harmful effects. Protecting the safety of people who take part in clinical trials is a high priority for all involved. Each trial has scientific oversight, and patients also have rights that help protect them.

 

DECIDING WHO PARTICIPATES IN CLINICAL TRIALS

After signing the informed consent form, the clinical staff will screen the candidate against the clinical trial criteria. The screening may involve cognitive and physical tests. Inclusion criteria for a trial might include age, stage of disease, gender, genetic profile, family history, and whether or not the candidate has a study partner who can accompany them to future visits. Exclusion criteria might include factors such as specific health conditions or medications that could interfere with the treatment being tested. Generally, individuals can participate in only one trial or study at a time. Different trials have different criteria, so being excluded from one trial does not necessarily mean exclusion from another.

Clinical trials need numbers … many volunteers must be screened to find enough people for a study, and with rare diseases such as amyloidosis, important trials are often significantly delayed due to a lack of participants. This can seriously slow down the rate at which new drugs are discovered, tested, and made available to patients.

 

CONCLUSION

Not all clinical trials have successful outcomes. However, every disease-related drug and therapy treatment prescribed today is the result of clinical research. Clinical trials are absolutely necessary to determine that a treatment is safe and that it has a real positive effect on a particular disease, better than that observed by a placebo or the current standard of care.

Final thoughts from Isabelle Lousada, founder and CEO of Amyloidosis Research Consortium:

Clinical trials play a critical role in evaluating novel therapies, establishing the best treatment pathways, and increasing our knowledge about amyloidosis.

 

SOURCES

Amyloidosis Research Consortium

Boston University / Boston Medical Center, Amyloidosis Center

The Clinical Study Center

Mayo Clinic

National Institute on Aging

National Institutes of Health

U.S. National Library of Medicine

 

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