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A Clinical & Patient Perspective of Wild-Type Amyloidosis

Wild-type ATTR is also referred to as ATTRwt. It is not caused by any known genetic mutations, such as in the case of hereditary forms of the disease (hATTR). This disease used to be called SSA or SCA, which stood for Senile Systemic Amyloidosis and Senile Cardiac Amyloidosis, respectively, which are now outdated terminologies. The disease is not known to be directly related to dementia, but it is related to aging.

Deposits of TTR amyloid can be found throughout the body, so it is a systemic amyloidosis disease.  The most common place it is found is in the heart. Wild-type ATTR is also known to cause some cases of carpal tunnel syndrome, which can be the first (early) symptom. Recent data suggests that lumbar spine involvement as well as a rupture of the biceps tendon in the forearm can precede cardiac involvement by many years.

This is a disease that has traditionally been found mostly in men, originally reported in those aged 80 and over. As awareness of the disease increases, wild-type ATTR average age at diagnosis is 75. It is often overlooked as an amyloidosis disease because so many people experience heart problems in their later years.

As with hereditary forms of the disease (hATTR), wild-type ATTR causes problems due to the breaking apart, misfolding and deposition of amyloid protein fibrils in healthy tissue. “Wild-type” refers to this form of the disease because it is the natural form of this protein, without genetic mutation. These deposits can interfere with the heart’s normal function, by causing stiffness of the heart tissue, making it more difficult for the heart to fill, leading to heart rhythm problems and heart failure.

 

In this special video, hear world-renowned expert Dr. Mathew S. Maurer and his patient John Basdavanos presenting to a group of medical students. Dr. Maurer provides a brief overview of ATTRwt, while John provides the patient perspective. Together, these insights offer a compelling story about battling a life threatening disease.

 

ASB: 2021 Mid-Year Review

At the Amyloidosis Speakers Bureau (ASB), the first half of this year was a continuation of 2020. Our re-positioning last year with a broader platform and adding in virtual offerings set us up well for 2021. Below we share highlights from the first half of the year. Enjoy!

EXECUTIVE SUMMARY

  • The first half of 2021 we gave 34 presentations, bringing our second school year of operation to a whopping 67 presentations to over 2,600 medical students. 
  • Since inception, the ASB has now made 114 presentations to over 5,600 medical students. Our materials have reached over 33,000 students. YAY!
  • We are thrilled that our activities continue to expand – not only are we returning to many medical schools we presented to last year, but we continue to add new schools to the roster. A complete list of schools we have presented to can be found at the end.
  • Our outreach now includes DO schools, and this Spring we presented to the largest in the U.S. — Lake Erie College of Osteopathic Medicine.
  • Based on feedback from a handful of course directors we have worked with, we have updated our message to medical school curriculum course directors in a way that conveys flexibility to work within their system, adaptability to match a speaker’s journey to their course topic, and transparency to screen speakers in advance. While still early, we are confident this will gain more attention.
  • Looking ahead as we emerge from the pandemic, we do anticipate a return to some in-person presentations starting in the Fall.  Virtual presentations are here to stay, and adding back in in-person will give us flexibility to meet school preferences. 
  • We average between 30-40 speakers, which allows for diversity in our speaker population’s disease type and organ involvement, and flexibility in their availability. This has served us well and proved valuable as we offer more customized presentations to schools. Even as we work hard to increase the number of presentations, we expect our current roster will accommodate our growth.
  • We are particularly delighted that our medical school student mailing list – students specifically interested in receiving ongoing information about amyloidosis – keeps growing (over 260!). Content is pulled from experts and other trusted organizations with the intention to offer ongoing brief insights into the disease.
  • This year, with the help of one of our patient speakers who is a professor/Ph.D. in social science, we are investigating how we can better assess and improve our speaker/ASB effectiveness and durability of our impact. Shortly, we will be analyzing the first six months of preliminary data to see what initial insights can be gleaned.
  • In May, we emailed medical school deans with our semi-annual update on our activities. We know some deans forward our update to course directors and have responded positively regarding our mission.
  • Two operational notes:
    • As you know, we lost our co-Operating Committee colleague Charolotte Raymond to this disease earlier this year. We believe it important to continue to be a patient-led organization, so we have proudly added Lane Abernathy to our Operating Committee. Lane began as a patient speaker with the ASB back in 2019, and expanded her involvement in early 2020 to help us deepen our support for our speakers and develop their presentations. She has been a wonderful supporter of our efforts and we appreciate all she does for the ASB.
    • In addition, four of our patient speakers have long voiced their interest in getting more involved, so we have integrated them into our efforts. 
      • Elizabeth Negrelli is working with Lane to support our speakers.
      • Sean Riley helps run Zoom presentations, as well as contribute writings to ASB Briefs, our medical school mailing series.
      • Dr. Kathy Rowan is working with us to better assess the impact our speaker presentations have on our medical student audience.
      • Julieann Ray Cheng is a dietician and a guest contributor to our food/healthy eating blogs.

 

SPEAKERS

The cornerstone of our effort is our group of wonderful patient speakers, who passionately volunteer their time to give back and share their stories of life with amyloidosis. On average, we have between 30-40 active speakers, diversified by geography across the continental U.S., by amyloidosis type, by organ involvement, by gender and age. This is a rather deep bench, but we have found it both helpful and necessary. Helpful in that we can maximize attendance if we work around the preferred dates and times suggested by the schools. Helpful in that we can match specific disease states with audience focus (e.g., a cardiac amyloidosis patient speaker to a cardiology student interest group). Necessary in that periodically, a speaker’s personal situation may change and they need to step back either temporarily, or permanently. We are fortunate to have a steady pipeline of new speaker interest, which we spend time screening, qualifying, and training. However, in spite of this interest, we feel our current size is appropriate for our current activities and anticipated growth so it will be infrequent that we bring on new speakers.

 

ADVISORS

We are proud to have an impressive group of medical experts and influencers in the world of amyloidosis, some of whom are also patients, as advisors to support our initiative. Our advisors are active in our efforts and contribute their specialized expertise in a variety of ways, such as medical school introductions, grant requests, educational development, and patient speaker assessment/development. We are extremely grateful for their assistance and believe that, thanks to their contribution, the ASB will make an even bigger difference in the diagnoses of this disease. You can see our prestigious list of advisors on our website page www.mm713.org/speakers-bureau/ 

 

TESTIMONIALS – OUR TRUE REPORT CARD

Feedback from students and medical school professors has been extraordinarily positive. It reinforces to us that candid and authentic patient stories are a valuable complement to the medical school curriculum, strengthening the learning and deepening the durability for these future doctors about this disease. This is exactly why we do what we do. Here are just a few of the testimonials from this year.

 

The speaker’s ability to put a face and experience behind a disease is so much stronger than a textbook will ever be. I will now be much more likely to appropriately add amyloidosis to a differential diagnosis moving forward in my clinical rotations and career.  William Bradford, MD Candidate, Tufts University School of Medicine

 

I love the concept of connecting us with both a concise resource (the video) and a specific patient to give a memorable experience. The sheer volume we learn as medical students can cause glossing over of uncommon diseases. I feel more likely to remember and more equipped to include amyloidosis in a differential.   Liisa Dollinger, MD Candidate, Case Western Reserve School of Medicine

 

As medical students we often only get the textbook definition of so many diseases, and when we read over the symptoms and treatments we merely just memorize and pass them over.  Mackenzie’s Mission brings so much more than just the textbook definition of Amyloidosis. It brings the emotion, the struggle, pain, frustration, things that we don’t see on paper. This is so important for us as future physicians to see and hear, because this disease is not just a question on the test it is somebody’s life. And, it truly reminded me of why I am here. More medical students need to hear this!    Zachary Hostoffer, DO Candidate, Lake Erie College of Osteopathic Medicine

 

Our school’s curriculum is organized by different organ systems, so I often think that multi-system diseases, such as amyloidosis, aren’t presented as clearly as other diseases only affecting one organ system. I learned so much about the complexity and severity of amyloidosis because of this presentation and I think hearing Beth’s story really helped me to understand why this disease often goes undiagnosed. Hearing her journey will remind me to advocate for my future patients with amyloidosis and other complex, incurable diseases.   Sydney Shade, MD Candidate, Geisinger Commonwealth School of Medicine

 

As a medical student, I have spoken to several patients and have participated in many patient presentations, but they always seem to miss the mark. We need to hear about the emotional aspects and challenges at home that accompany the journey to diagnosis and treatment. This presentation covered all of that with the clinical information included. Raymond Stemrich, MD Candidate, Geisinger Commonwealth School of Medicine

 

We are pleased with all we have accomplished thus far, energized by the feedback, and excited about the future! With much love and appreciation,

Mackenzie, Lane, and Deb

Operating Committee of the Amyloidosis Speakers Bureau, sponsored by Mackenzie’s Mission

 

Since inception in 2019, the Amyloidosis Speakers Bureau has presented to medical students, either as part of the curriculum or to student interest groups, of the following medical schools.

Albert Einstein College of Medicine

California University of Science & Medicine, School of Medicine, San Bernardino

Case Western Reserve School of Medicine

Central Michigan University College of Medicine

Chicago Medical School, Rosalind Franklin University of Medicine and Science

Cleveland Clinic Lerner College of Medicine

Columbia University Vagelos College of Physicians and Surgeons

Drexel University College of Medicine

Florida Atlantic University Charles E. Schmidt College of Medicine

Florida International University Herbert Wertheim School of Medicine

Florida State University College of Medicine

Geisinger Commonwealth School of Medicine

George Washington School of Medicine

Icahn School of Medicine at Mount Sinai

Lake Erie College of Osteopathic Medicine

Lewis Katz School of Medicine at Temple University

Loyola University Chicago Stritch School of Medicine

Mayo Clinic Alix School of Medicine, Rochester

Mayo Clinic Alix School of Medicine, Scottsdale

Northeast Ohio Medical University College of Medicine

Northwestern University Feinberg School of Medicine

NYU Grossman School of Medicine

Oakland University William Beaumont School of Medicine

Quinnipiac University Frank H Netter MD School of Medicine

Stanford University School of Medicine

Tufts University School of Medicine

University of Arizona College of Medicine, Phoenix

University of Arizona College of Medicine, Tucson

University of California San Francisco, School of Medicine

University of Central Florida College of Medicine

University of Chicago Pritzker School of Medicine

University of Cincinnati College of Medicine

University of Colorado School of Medicine

University of Connecticut School of Medicine

University of Florida College of Medicine

University of Hawaii, John A. Burns School of Medicine

University of Illinois College of Medicine, Chicago

University of Illinois College of Medicine, Peoria

University of Illinois College of Medicine, Rockford

University of Iowa Carver College of Medicine

University of Kansas School of Medicine, Wichita

University of Maryland School of Medicine

University of Massachusetts Medical School

University of Minnesota Medical School

University of Missouri Kansas City School of Medicine

University of Nevada Reno, School of Medicine

University of Pittsburgh School of Medicine

University of South Alabama College of Medicine

University of South Carolina School of Medicine, Columbia

University of Toledo College of Medicine

UNLV School of Medicine

Virginia Commonwealth University School of Medicine

Wayne State University School of Medicine

Wright State University Boonshoft School of Medicine

Yale School of Medicine

 

Tips & Recipes for Healthy Eating with Amyloidosis

 

Are you wondering what diet to follow after a diagnosis of AL Amyloidosis? With so many unknowns and what-ifs, it is a scary and overwhelming time. Guest writer Lori Grover, herself an Amyloidosis survivor, provides helpful insights into healthy eating.

So much is out of your hands as you wait for test results and treatment options. I was terrified when I received my diagnosis five years ago. I found focusing on the things I could control (like following doctors’ orders, taking medications on time, reducing stress, and eating a clean diet) gave me back a small sense of power over my life.

I recently had the privilege of chatting about diet and Amyloidosis with Julieann Ray Cheng, a fellow Amyloidosis warrior, dietician, and author of soon-to-be-published “The Delightful Dietician” cookbook, who offered specific guidance, tips, and recipes to help manage the disease.

While there is no diet specific to AL Amyloidosis, Julieann recommends following a healthy diet to help you stay as strong as possible while you face treatment.

 

5 Tips for Healthy Eating: Variety is Key!

The following suggestions are based on the Dietary Guidelines for Americans 2020-2025.

1. Include all the food groups: vegetables, fruit, protein foods, dairy, and fat.

2. Colour your plate. Be sure to include various fruits and vegetables to get all the vitamins, minerals, nutrients and antioxidants you need.

3. Customize your diet according to any specific restrictions given by your physician. Your doctors may tell you to avoid certain foods that can interact with your medications. If you have kidney involvement, you may also have to closely monitor electrolytes and minerals such as sodium, potassium, and calcium. As this will differ for every patient, be sure to follow your doctor’s recommendations closely.

4. Be prepared to battle nausea as chemotherapy may upset your stomach. On days when you receive treatment, you may not feel like eating much. Eat small meals, and prep for the days you don’t feel well. Have healthy foods on hand, like homemade soups in the freezer, for quick and easy meals.

5. Watch your fluids. Keep a bottle of fresh water with you and frequently sip to avoid dehydration and dry mouth. If you suffer from edema, your doctor may give you specific directions about how much fluid you can consume daily.

 

Foods to Avoid when you have Amyloidosis

Watch out for sodium.  A healthy diet when you have Amyloidosis includes no more than 2300 mg of sodium per day (certain disease conditions like heart failure and kidney disease may recommend 1500 mg of sodium or less per day). Many foods contain surprisingly high amounts of sodium, so keep an eye on the labels. Choose fresh, frozen, and no-salt-added canned fruits and vegetables. Stay away from processed foods, the salt shaker, spice blends or soup bases that contain salt.

Speak with your doctor before consuming alcohol. The current recommendation is two alcoholic beverages per day for men and one alcoholic beverage for women.  However, if you take regular medications,  it is best to avoid daily consumption of alcohol because it can place additional stress on the liver. Alcohol contains a significant amount of calories and is not essential to a healthy diet. It’s best to avoid or limit alcohol to special occasions.

Limit added sugar to 10 percent of your daily calories (200 calories or 50 grams of added sugars based on a 2000 calorie diet). Watch out for beverages like soda, coffee with added syrups, and sugary juices. A better choice is water with lemon or other fresh or frozen fruit to provide flavour. Foods that contain added sugars include breakfast cereals and bars, candy, high-fat milk and yogurt, desserts, and sweet snacks.  Consider fresh or canned fruit to satisfy your sweet tooth and provide your body with essential vitamins, minerals, and fibre.

Limit saturated fat to 10 percent of daily calories (200 calories or 22.2 grams of saturated fat based on a 2000 calorie diet). Fried foods, high-fat meats, whole-fat dairy, ice cream, coconut or palm oils, and butter contain saturated fat. Skip these whenever possible and choose healthy fat instead. Baking or roast foods, choose lean cuts of meat and remove the skin, and use olive, canola, sunflower, safflower, or soybean oil in place of butter, coconut or palm oil.

 

How Does Your Diet Rate?

 

 

The most important part of sticking to a healthy diet when you have Amyloidosis is to enjoy your food while you nourish your body. Making necessary adjustments will have an enormous impact on your overall health.

If you feel overwhelmed, consider making one change at a time and adapting the transition to your lifestyle. Most changes will set in and feel like your new normal after about three weeks. Look at each day as an opportunity to nourish your body with healthy foods.

Make the right choices, and your body will thank you! For more tips on implementing these healthy changes check out our posts Amyloidosis and Diet or our Treatment Survival Guide.

Finally, Julieann has graciously provided two delicious healthy recipes from her upcoming cookbook that she routinely prepares as she manages her amyloidosis diet.

Enjoy!

 

Lori Grover is a guest blogger for Mackenzie’s Mission. She was diagnosed with AL Amyloidosis in 2016 and writes to share experiences and lessons learned during her journey.  More wonderful blogs by Lori can be found on her page Amyloid Assassin.  Lori is a freelance copywriter, and a mom of two wonderful boys. She loves writing, reading, and all things crafty.

Julieann Ray Cheng is an Ohio-based dietician who was diagnosed with AL Amyloidosis in 2018. When not in the kitchen, she loves to travel with her family and shop for goodies. Keep an eye out for her cookbook “The Delightful Dietician,” available in the fall of 2021. 

 

Easy Vegetable Soup  (Servings:  6 – 10 oz bowls)

1 small onion, diced

2 teaspoons of olive oil or oil of your choice

4 stocks of celery, diced

2 potatoes, diced or 1 c small pasta noodles (if reducing potassium)

1 pound frozen mixed vegetables (carrots, corn, green beans, peas)

14.5 oz canned tomatoes, diced (may use low sodium or no added salt)

6 cups vegetable broth (may use low sodium or no added salt broth)

1 teaspoon garlic powder

½ teaspoon white or black pepper

In a medium saucepan add olive oil, diced onions, diced celery. Sautee on medium heat for 5 minutes.

Add vegetable broth, mixed vegetables, diced potatoes, garlic powder, and white or black pepper.

Bring to a boil and simmer for 15 – 20 minutes uncovered.

***If reducing the potassium omit the diced potatoes and diced tomatoes, add 1 cup small pasta noodles, ½ pound of mixed vegetables, and 2 cups vegetable broth.

By:  Julieann Ray Cheng, The Delightful Dietitian

 

Color Your Plate Chicken Sheet Pan Dinner  (Servings:  4)

4 chicken breasts

1 teaspoon garlic powder

1 teaspoon onion powder

½ teaspoon black or white pepper

1 teaspoon Rosemary

2 diced sweet potatoes, or 6 diced carrots (if potassium restriction is needed)

1 pound frozen tricolor peppers and onion blend

1 pound fresh or frozen broccoli or brussels sprouts

1 garlic clove, minced

2 tablespoons oil

Pre-heat oven to 400 degrees F.

Line a sheet pan with parchment paper for easy cleaning.  Spray with cooking oil.

Season chicken breast with garlic powder, onion powder, black or white pepper, and Rosemary.  Place on one side of the sheet pan.  Add diced sweet potatoes on the other side of the sheet pan.  Bake at 400 degrees for 30 minutes.

While the chicken breast and sweet potatoes are baking.  In a bowl add frozen tricolor peppers and onion blend, broccoli or brussels sprouts, garlic, and oil.

Remove pan from oven.  Add vegetable mixture to the sweet potatoes and toss.  Place back in the oven for an additional 25-30 minutes until the chicken reaches an internal temperature of 165 degrees F.

Remove from oven and allow to rest for 5 minutes before serving.

**If the chicken breast is cooked with skin, Place under broiler for 4-5 minutes to crisp the skin of the chicken and vegetables at the end of cooking time.

***If sweet potatoes are omitted, add carrots with other vegetables during the second half of cooking.

By:  Julieann Ray Cheng, The Delightful Dietitian

CRISPR/Cas9 – Editing the Code of Life

AN UPDATE  …..  WOO HOO!!!

Well, the results of the preclinical studies were presented on June 26, 2021 and it is fantastic news for hereditary ATTR amyloidosis patients!!!

Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.

CONCLUSIONS
In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.)

The New England Journal of Medicine
https://www.nejm.org/doi/full/10.1056/NEJMoa2107454

Our original blog post ….

 

The scientific world is abuzz … a Nobel Prize-winning technology called CRISPR/Cas9 can now edit our DNA. This programmable gene-editing technology, which is efficient, precise, and scalable, has inspired a gold rush of countless applications in medicine, agriculture and basic science. Early areas of focus include genetic diseases such as sickle cell and hereditary ATTR amyloidosis, offering new and exciting optimism.

Ground-Breaking Science in Gene Editing

“A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome – more than three billion DNA base pairs – is contained in all cells that have a nucleus.”  – Intellia Therapeutics

CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, is a microbial ‘immune system’ that prokaryotes — bacteria and archaea — use to prevent infection by viruses called phages. At its core, the CRISPR system gives prokaryotes the ability to recognize precise genetic sequences that match a phage or other invaders and target these sequences for destruction using specialized enzymes.

Previous work had identified these enzymes, known as CRISPR-associated proteins (Cas), including one called Cas9. But scientist Emmanuelle Charpentier, working first at the University of Vienna and later at the Umeå Centre for Microbial Research in Sweden, identified another key component of the CRISPR system, an RNA molecule that is involved in recognizing phage sequences, in the bacterium Streptococcus pyogenes, which can cause disease in humans.

Charpentier reported the discovery in 2011 and that year struck up a collaboration with American biochemist Jennifer Doudna. In a landmark 2012 paper in Science, the duo isolated the components of the CRISPR–Cas9 system, adapted them to function in the test tube and showed that the system could be programmed to cut specific sites in isolated DNA – an incredibly precise set of DNA-editing genetic scissors. In 2020, Doudna and Charpentier won the 2020 Nobel Prize in Chemistry for their gene-editing technology.

“The ability to cut DNA where you want has revolutionized the life sciences,” said Pernilla Wittung Stafshede, a biophysical chemist and member of the Nobel chemistry committee, at the prize announcement. “The ‘genetic scissors’ were discovered just eight years ago, but have already benefitted humankind greatly.”

 

How Does CRISPR/Cas9 Work? (3)

This technology acts as an incredibly precise set of molecular scissors, providing instructions to cut an identified gene in a specific position in the nucleus of DNA. There are two primary components to the CRISPR/Cas9 genome editing system:

  • The Cas9 protein, which initially recognizes the DNA and also acts like a pair of “molecular scissors” that precisely cleaves the targeted DNA sequence.
  • The guide RNA, which guides the Cas9 scissors to the desired target DNA sequence and activates the scissors so they cut.

https://www.intelliatx.com/crisprcas9/how-crisprcas9-works/

Background on Hereditary Transthyretin Amyloidosis (hATTR/ATTRv) (1)

Transthyretin amyloidosis is a slowly progressive condition characterized by the buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body’s organs and tissues. These protein deposits most frequently occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract. The age at which symptoms begin to develop varies widely among individuals with this condition, and is typically between ages 20 and 70.

There are three major forms of transthyretin amyloidosis, which are distinguished by their symptoms and the body systems they affect.

  1. The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions.
  2. The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system.
  3. The cardiac form of transthyretin amyloidosis affects the heart.

Mutations in the TTR gene causes the liver to product the TTR protein in a misfolded form. This misfolded protein can then build up in the body and lead to disease-causing nerve and other organ damage.

 

Clinical Trial Research (4)

According to CRISPRMedicineNews, one of the early clinical trials within gene editing is focused on hereditary transthyretin amyloidosis. In these trials, CRISPR-Cas is either used directly to treat the condition by editing an individual’s genome in vivo or indirectly through ex vivo engineering of a cell-based therapy. An update published November 17, 2020 discusses the clinical trial, which is now underway in the U.K.

CRISPR-Cas9 Trial For NTLA-2001 to Treat Hereditary Transthyretin Amyloidosis With Polyneuropathy

The second newly-added trial is sponsored by US-based Intellia Therapeutics and seeks to enroll 38 participants who are diagnosed with polyneuropathy (PN) due to transthyretin (TTR) amyloidosis (ATTR).

This open-label Phase 1 two-part trial comprises a dose escalation followed by a safety dose expansion study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of Intellia’s most advanced in vivo CRISPR-based therapy candidate, NTLA-2001.

ATTR is a hereditary progressive condition that is characterized by an accumulation of misfolded transthyretin (TTR) protein. The disease results from mutation(s) in the TTR gene, leading to mutant TRR protein that is unstable and easily forms aggregates that deposit as amyloid in various organs and tissues in the body. Organs or body parts most often affected include the nerves, heart, kidneys and eyes.

Life expectancy is typically 2-15 years from disease onset, and current treatment options include transplantation of affected organs and medications to slow progression of disease symptoms.

NTLA-2001 is the first investigative CRISPR-based therapy to be administered in vivo in humans. The new therapy comprises TTR-targeting gRNA and Cas9 mRNA, both of which are delivered in vivo via Intellia’s proprietary lipid nanoparticle technology. Pre-clinical studies support the notion that NTLA-2001 has potential as a one-time curative treatment. The first patient was dosed with NTLA-2001 last week and the study is expected to be completed in 2024.

Worldwide prevalence of spontaneous and hereditary transthyretin amyloidosis (ATTR). Source: Intellia Therapeutics. https://www.intelliatx.com/in-vivo-therapies/

 

Potential Game-Changer for Hereditary ATTR Amyloidosis

 “Once we’ve assessed safety and established an optimal dose, we intend to rapidly initiate trials for the clinical manifestations of ATTR. NTLA-2001 may halt and reverse ATTR progression by producing a deeper, permanent TTR protein reduction for all patients – regardless of disease type – than the chronically administered treatments currently available.” said Intellia Therapeutics President and CEO, John Leonard, M.D.

 Intellia’s proprietary CRISPR/Cas9 system could potentially address diseases with a single course of treatment because it permanently repairs the defective DNA. This represents a breakthrough improvement over current therapies, most of which require lifelong administration because they cannot correct underlying causes of the disease. However, this technology does not pass the genetic changes made to the patient to his or her offspring … the “fix” will not pass from generation to generation.

 

This is exciting news, giving new hope for families who have been ravaged by disease over generations.

 

 

 

 

———————————-

If you’d like to read more about Jennifer Doudna, here’s a book recently released by bestselling author Walter Isaacson, The Code Breaker.

 

Sources:

  1. https://crisprmedicinenews.com/clinical-trial/transthyretin-amyloidosis-attr-nct04601051/
  2. crisprmedicinenews.com
  3. https://www.intelliatx.com
  4. https://crisprmedicinenews.com/news/crispr-cas-clinical-trial-update/
  5. https://www.nature.com/articles/d41586-020-02765-9
  6. Doudna Lab, Berkeley, California
  7. CRISPR Therapeutics, Cambridge, Massachusetts
  8. Innovative Genomics Institute, Berkeley, California

 

Charolotte Raymond

Celebrating a Warrior, Partner, and Friend – Charolotte Raymond

Our first communication with Charolotte was Fall 2018. Since 2017, after giving a presentation to the medical students of Dr. Gordon Huggins at Tufts University School of Medicine, she developed this vision for a speakers bureau and was looking for a group to partner with that could bring the infrastructure and financial support to life.  After knocking on a few doors, Muriel Finkel of the Amyloidosis Support Groups suggested she knock on ours – Mackenzie’s Mission.

At the same time, Mackenzie’s Mission, founded a year earlier, was still searching for that right “raising awareness” initiative. At the onset we went for public social medial posts and website blogs, but we quickly knew that random and public outreach wouldn’t been effective on our small scale. A public onslaught for awareness required a massive media platform and lots of money, or a lucky viral campaign like ALS’ Ice Bucket Challenge. Neither felt attainable. Mackenzie wanted an initiative that was targeted and focused, and aimed at a segment that could make a difference. 

Charolotte’s first email to us in August 2018 began, “I have been building a team of speakers to go to medical schools and talk about their experiences with Amyloidosis. It is an idea I wanted to discuss with you. I like that you are not sitting back, that you are truly proactive!! It is people like you that are going to be changing the face of this illness!” 

Next was a call where Charolotte described her vision. Mackenzie responded with the most enthusiastic, “YES, we have to do this.” For her, it was the moment of clarity on her dreams to raise awareness. The concept was simple – focus on the pipeline of future doctors, educating them through patient stories. Brilliant. It brought a complement to the often scant discussion of amyloidosis in curriculums, an emotional element to see, hear and better understand the patient perspective, and opportunity reach a multitude of specialties before they declare their path, all in one place.

In the ensuing months in between her treatments, we had extensive conversations — about everything and anything. Ranging from big concepts like operating structure and roles/responsibilities to execution details like priorities, funding and resources.  We were aligned on some thoughts, and unsure about others. We knew Mackenzie’s Mission could bring the legal platform, and operationally had the ability to bring this to life. There was one growing reality emerging through all of this – we were 100% aligned on the vision and simply enjoyed each other with positivity, laughter, and a rapidly developing respect for everyone’s views and opinions. Our triumvirate was diverse by disease, age, and experience. Together, it pointed to a powerful collaboration of effectiveness and efficiency, while having fun along the way.

By January, 2019 we felt we had the framework for Charolotte’s initial vision, shaped and re-shaped to execute. Thus on February 1, 2019, the Amyloidosis Speakers Bureau was launched. We spent the next handful of months laying the foundation – website, materials, and recruiting a wonderful group of speakers. In addition, we established a group of advisors — renown amyloidosis experts and key community leaders — that brought credibility, support, and respect for our initiative.

Our first school year – Fall 2019 to Spring 2020 we held 44 presentations. Interrupted by the global COVID pandemic, we re-tooled from being in-person to virtual. Our offering was now broader, more robust and flexible. We learned so much and were always willing to pivot, a mindset which had us always looking forward, listening for feedback, and never forgetting our focused mission.

Today, in the Spring of 2021 and a few months away from concluding our second school year, have booked 61 presentations with a pipeline of a half dozen more to schedule. We have about 40 speakers, diverse by disease type, experience, and organ involvement. They are the centerpiece of our initiative and we thank them dearly for being a part of the ASB. We have presented to over 5,000 medical students, and information about amyloidosis has reached over 30,000 medical students — all in just our first two years.

As Charolotte’s health ebbed and flowed, we saw her fierce love of life and willingness to battle back this disease. She never gave up and never wavered in her happiness seeing her vision make a difference in the amyloidosis community. Thanks to our Zoom world, she often was able to join school presentations and see the fruits of our labor in action. We know it brought her great pride and joy. She is survived by her beloved husband Robert N. Raymond of Delray Beach, Florida; daughters Kristen Weatherbee Smith of Delray Beach, Florida; Sherry and husband Robert Ortiz of Rochester; sons Eric and wife Kathleen of Rochester, Roderick of Somersworth; grandchildren Sean, Melissa, Kaylah, Katelyn, Lettie, Brennan, Zoe, Isabella, Alexander, great grandchildren Rylee, Finley and many extended family, and countless special friends.

The Amyloidosis Speakers Bureau will forever be a lasting legacy that always remembers Charolotte.

xoxo Charolotte. We love you, Mackenzie and Deb

Obituary

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.

 

 

———————————————————-

 

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.

 

 

On the Other Side of COVID

How are you doing? I mean, how are you really doing?  Often we answer automatically with a superficial, “I’m fine, thanks.” Let’s start a long-overdue conversation. Life is hard, and we are not okay.

As for me, I’m medium. I’ve fared worse times, but the isolation, uncertainty and fear are getting to me.

We are all struggling – sickness, job loss, money problems, isolation, separation. Whatever COVID – 19 looks like for you, I’m guessing it’s not great.

I’m no stranger to adversity. One of the most challenging times of my life was the day my beautiful sister died suddenly from a brain aneurysm. Another was the day I was diagnosed with AL Amyloidosis and given a fairly bleak outlook. (I miss her every day, and it took two years of chemo and a clinical trial to get me into remission, but here I am).

I have known heartache as we all have. I am not telling you this to gain your sympathy or pity. Because I genuinely don’t want you to feel sorry for me. I am telling you this to make a connection.

We all know pain. We have all suffered. It’s not a who’s had a crappier year contest.

It’s about conversation – open, real discussions on connection and comfort and being part of something bigger. We need these things. We are hard-wired to crave human contact. That’s one of the big reasons we are all struggling right now.

What got me through those hard times? As cheesy as it sounds, mindset, love, comfort, connection, and support. Will I get through this too? YEP. And so will you.

Just keep repeating to yourself, “This is not my permanent destination. Life will not be like this forever.”

 

How Will I Get Through the COVID-19 pandemic?

 

  1. Shift your mindset to “I will get through this.”

Make it a priority in your life to actively keep a positive mindset. Pretty sure I was born a pessimist. Luckily, optimism is a skill that we can all learn. It’s an unfortunate circumstance in life, but bad things happen to all of us. We can’t always control the events, but we can control our reactions.  Do you want to be a victim or a hero?

  • You always have a choice. Be intentional with your reactions—practice pausing to give yourself time to respond.
  • Find the joy – actively seek it out. A cup of tea, the way the sun shines in your window, a delicious meal. If you’re having trouble finding it, create it.
  • Practice stress relief, meditation, and gratitude. Schedule time every day to relax, reflect and count your blessings.
  • Please stop bombarding yourself with all the negativity in the world (take a break from the news and social media).

 

  1. Get Busy!

All those things you’ve never had the time to complete?  I’m guessing you might have time now.

  • Learn a new skill (life-long learning is good for your health, can reduce stress levels, improve memory, and offset cognitive decline). [1]
  • Get outside and discover your neighbourhood. Make a list of places you want to visit when the world opens up again (bonus…maybe you’ll find a local small business you can support).
  • Try a new hobby, pick up an old one, test out a new recipe or food you have never tried.
  • Finish up those tasks you have been avoiding (those closets aren’t going to organize themselves). The simple act of checking something off a to-do list causes our brains to release the feel-good hormone dopamine. [2]
  • Uneasy around technology? Maybe now is the time to test it out.

 

  1. Create a daily routine

For many of us, our regular routines have been thrown off track! Set yourself up with a new COVID routine, even if it is temporary. Our brains love order, and you’ll feel less stress if you are in control of your time.

  • Include things you can check off a to-do list to gain a feeling of accomplishment (even if it’s have a shower and wear pants today).
  • Schedule time to do something you enjoy. The simple act of looking forward to something releases those feel-good hormones, [3]and helps to brighten your mood.
  • Be sure to include connecting with people somehow (maybe a daily chat with a friend or family member, or joining an online meeting).

 

  1. Do something to help others.

A win-win situation! Not only does it benefit whoever is on the receiving end of your kindness, but it makes you feel good about yourself and generally makes the world a better place. It doesn’t have to be a huge grand gesture – a little kindness goes a long way!

  • Call someone to check in on them.
  • Send flowers or a surprise to a loved one.
  • Drop a little treat on a neighbour’s doorstep.
  • Paint rocks/signs and leave them on walking trails.
  • Donate your time to a charity.
  • Think about what you are good at and do that – do you bake? Knit? Fish? Golf? How can you use your talents to do some good and make the world a better place?

 

  1. Be kind and seek out a connection.

We all need to be kind to each other and ourselves right now. Part of the reason this isolation is so challenging is that we are hard-wired to seek human connection, especially in times of hardship and stress.

Jen Marr, CEO and founder of Inspiring Comfort, and Author of Paws to Comfort, explains “During difficult times, our bodies release the stress hormone cortisol, along with a little oxytocin (the relationship hormone). It’s like your body is saying: we are hurt, go find someone.”

  • Reach out to a loved one – think of it as physical distancing rather than social distancing. Get creative with the way you connect with others.
  • Join an online support group.
  • Create a group with people who have similar interests, like a book club or knitting club where you all work on the same projects.
  • If you are struggling, ask for help.

 

We are all built to do hard things. And you are stronger than you might feel right now. Take it one day at a time, one step at a time. Brighter days are ahead.

 

——————

Lori Grover is a guest writer for Mackenzie’s Mission. She was diagnosed with AL Amyloidosis in 2016 and writes to share experiences and lessons learned during her journey.  More wonderful blogs by Lori can be found on her page Amyloid Assassin.  Lori is a freelance copywriter, and a mom of two wonderful boys. She loves writing, reading, and all things crafty. 

[1] Harvard Business Review

[2]  Psychology Today

[3] Psychology Today

 

1st FDA-Approved Drug for AL Amyloidosis

After decades of relying on treatments approved for other diseases, on January 15, 2021 the FDA approved the first drug for AL Amyloidosis. Truly a game-changing, monumental advancement in the treatment of this disease.

 

On January 15, 2021, the Food and Drug Administration granted accelerated approval to daratumumab plus hyaluronidase (Darzalex Faspro, Janssen Biotech Inc.) in combination with bortezomib, cyclophosphamide and dexamethasone (CyBorD) for newly diagnosed light chain (AL) amyloidosis. “AL amyloidosis is a devastating and potentially fatal blood disorder that, until now, did not have any U.S. FDA-approved therapies. This makes today’s approval of DARZALEX FASPRO a critical step forward for patients in the U.S. in dire need of treatment options,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

ABOUT AL AMYLOIDOSIS (1)

Amyloidosis is a disease that occurs when amyloid proteins, which are abnormal proteins, accumulate in tissues and organs. When the amyloid proteins cluster together, they form deposits that damage the tissues and organs. AL amyloidosis most frequently affects the heart, kidneys, liver, nervous system and digestive tract. Until now there were no approved therapies for AL amyloidosis in the U.S., though it is currently being treated with chemotherapy, dexamethasone, stem cell transplants and supportive therapies. It is estimated that there are approximately 3,000 to 4,000 new cases of AL amyloidosis diagnosed annually in the U.S.

CLINICAL TRIAL

Efficacy was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial in 388 patients with newly diagnosed AL amyloidosis with measurable disease and at least one affected organ according to consensus criteria. Patients were randomized to receive bortezomib, cyclophosphamide, and dexamethasone (VCd arm) or with Darzalex Faspro (D-VCd arm).

The hematologic complete response (HemCR) rate based on established consensus response criteria as evaluated by an independent review committee was 42.1% for the D-VCd arm and 13.5% for the VCd arm (odds ratio=4.8; 95% CI: 2.9, 8.1; p<0.0001).

The prescribing information includes a Warnings and Precautions that serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received Darzalex Faspro in combination with bortezomib, cyclophosphamide and dexamethasone. Darzalex Faspro is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

The most common adverse reactions (≥20%) in patients with light chain (AL) amyloidosis who received the D-VCd regimen are upper respiratory tract infection, diarrhea, peripheral edema, constipation peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea and cough.

HOW DARZALEX FASPRO WORKS

Darzalex Faspro is an immunotherapy that works with your body to fight disease, preventing the abnormal plasma cells from creating excess light chains.

Darzalex Faspro is a subcutaneous injection, typically administered with several additional drugs intended to minimize reactions. Treatment usually begins with weekly injections for eight weeks, followed by bi-weekly injections for another eight weeks, and then monthly injections thereafter.

FDA APPROVAL

The FDA approved this application 7 weeks ahead of the FDA goal date. This application was granted accelerated approval based on response rate.

With FDA approval, this gives healthcare professionals even more ammunition in the treatment of amyloidosis, and should positively impact (i.e., reduce) complexities that patients often experienced in order to receive insurance company approval. Darzalex Faspro (daratumumab and hyaluronidase-fihj), approved for AL amyloidosis, now joins three other FDA-approved drugs for TTR amyloidosis  (Onpattro (patisiran), Tegsedi (inotersen) and Vyndamax (tafamidis)).

Progress!

—————–

  1. Genmab announcement

Not Just A Game: Protein Structure Prediction

Michael Rosen, an admired and respected investor for decades, penned this excellent blog that summarizes the state of protein structure prediction and how it has evolved since 1994 to today. So well written, below we offer his article in its entirety, along with our heartfelt thanks.

 

There are twenty amino acids in the human body. Amino acids are the chemical links that make up proteins. Proteins perform all sorts of essential tasks. Hemoglobin, for example, is the protein molecule in red blood cells that carries oxygen from the lungs to the body’s tissues and returns carbon dioxide from the tissues back to the lungs. Keratin is the type of protein that makes up your hair, skin, and nails. The spike (S) protein plays a key role in the receptor recognition and cell membrane fusion process in SARS-CoV-2.

There are approximately 30 trillion cells in the human body. Each cell contains between one billion and three billion proteins. How can a mere 20 amino acids make billions of proteins?

The answer is how each protein folds on itself to form its final shape. We can see this through X-ray crystallography, which sends electromagnetic radiation to interact with molecular crystals that reveal each atom of a molecule. This is great, but X-ray crystallography is time-consuming and very expensive.

The great molecular biologist, Cyrus Levinthal, estimated that there are 10300 possible configurations of a typical protein. Brute calculation of each variation is impossible: it would take longer than the age of the universe (almost 14 billion years) to identify each combination. Another approach is required if we hope to know the structure of proteins.

Every two years since 1994, scientists have gathered for a competition to see who could create an algorithm that could accurately predict the shape of proteins using only a list of its amino acids. The competition is called the Critical Assessment of Protein Structure Prediction, and the answer is no one. Participants are given 43 proteins to model, and the best programs were able to get two or three right. Until 2018, when DeepMind’s AlphaFold program successfully predicted 25 of the 43 proteins (the second-place program got three right). The competition was held again last month, and DeepMind’s newer version, AlphaFold2, achieved an astonishing accuracy of 92.4%.

A folded protein can be thought of as a “spatial graph”, and DeepMind (based in the UK and owned by Alphabet) built a neural network that uses evolutionarily related sequences, multiple sequence alignment (MSA), and a representation of amino acid residue pairs to refine and interpret this graph while reasoning over the implicit graph that it’s building. By iterating this process over a few days, AlphaFold developed strong predictions of the underlying physical structure of the protein and was able to calculate which parts of each predicted protein structure are reliable using an internal confidence measure.

AN OVERVIEW OF THE MAIN NEURAL NETWORK MODEL ARCHITECTURE. THE MODEL OPERATES OVER EVOLUTIONARILY RELATED PROTEIN SEQUENCES AS WELL AS AMINO ACID RESIDUE PAIRS, ITERATIVELY PASSING INFORMATION BETWEEN BOTH REPRESENTATIONS TO GENERATE A STRUCTURE.

 

This is an extraordinary accomplishment: from a list of the 20 amino acids that comprise a protein, AlphaFold was able to predict the shape of that protein, out of 10300 possibilities, to an accuracy of 92.4%. Earlier this year, AlphaFold predicted several protein structures of the SARS-CoV-2 virus, including ORF3a and another coronavirus protein, ORF8, whose structures were previously unknown. Experimentalists have confirmed the existence of both these structures.

The implications of this achievement cannot be overstated. A misshapen protein is thought to be the cause of Alzheimer’s and many other diseases. If we could only identify the shape of that protein, we could have a chance to correct it. For the first time, with AlphaFold, we now have that chance. We will be better able to determine which drugs are likely to bind to a particular protein and to effectively design proteins to catalyze chemical reactions.

In 2003, the Human Genome Project (and Celera Genomics) successfully mapped the entire human genome. Since then, the Universal Protein database has collected 180 million protein sequences, but only 170,000 have had their structures determined because of the time and expense required to do so. AlphaFold represents an exponential leap forward in being able to determine protein structures, and thus is a huge step toward the effective treatment of diseases.

As investors, we obsess over the vicissitudes of our political discourse (such as it is) as if it were a sporting contest. We scrutinize each economic release and infer the hidden meanings of a central banker’s pronouncements. Most of what fills our working days is noise, and we are easily distracted from the achievements that will profoundly determine our future. AlphaFold’s success is one such achievement.

This is not the first time we have heard from DeepMind. Three years ago I wrote about AlphaGo, DeepMind’s game program that defeated world champion Lee Sedol in Go (https://www.angelesinvestments.com/insights/investment-insights/3rd-quarter-2017-ghost-moves). I noted that there are 10170 legal arrangements of the stones on a Go board, more than there are atoms in the universe. Like the placement of Go pieces, the number of protein shapes are too massive to crunch through every combination. And as with AlphaGo, AlphaFold found a shortcut. DeepMind took its champion gaming skills and applied them to unlocking the mysteries of biochemistry.

It’s not just a game; it is how our civilization advances.

 

 

Enjoy!

 

If you’d like to read more of Michael’s excellent blogs, on topics wide-ranging, please visit www.angelesinvestments.com

If you’d like to read more about the competition, bi-annual results, and the organization behind the project, please visit www.predictioncenter.org

2020: The Year of the Pivot

Let me begin by saying THANK YOU for supporting Mackenzie’s Mission last year.

We are so thankful for our supporters! You may have donated cash or securities, participated in one of our raising awareness campaigns, or given us a grant to support our raising awareness initiative. You may have been an Amyloidosis Speakers Bureau speaker, liked/shared our Facebook posts, or taken the time to read our blogs to learn about amyloidosis. Whether you did one of these or many, you helped us push forward our fight against this disease and we appreciate your support.

HOW DID WE DO IN 2020? 

This was our third full year of operation, busy and loaded with lots of activities to advance our mission — to make a difference in the fight against Amyloidosis. We work to make a difference in two ways.

  • Raise awareness about Amyloidosis, which we believe can lead to earlier diagnosis and better outcomes for patients.
  • Support medical research on Amyloidosis, seeking the cause of the disease and more effective treatments to improve and extend lives.

Raising Awareness

You may recall that back in February 2019 we launched the Amyloidosis Speakers Bureau (ASB), the cornerstone of our raising awareness effort going forward. Now closing out 2020, our second year was certainly a challenging one, but proudly one where we nearly achieved our goals which we have summarized in our ASB: 2020 Year-End Review. I hope you will take a few minutes to read the Review and learn about our stunning progress!

In addition, we were busy launching videos and new blog posts.

The feedback we have received has been heartwarming and energizing. While being an inspiration to others is wonderful, we are moved by the conversations we have had with others affected by this disease. We share a common bond with uncommon experiences. Knowing we are not alone in this fight gives us all strength. Also, ASB testimonials we have received from both medical professors and medical students reinforces our thesis that education through patient stories strengthens their education about this disease which, we firmly believe, will positively impact the timeliness of future diagnoses and improve patient outcomes.

What two medical school professors had to say:

From Theresa Kristopaitis, M.D., Professor, Assistant Dean for Curriculum Integration, Loyola University Stritch School of Medicine

The opportunity for second year medical students to hear the story of a patient with amyloid is invaluable. The presentation addressed aspects of pathophysiology they are learning and the human side of medicine. This presentation format offered an excellent teaching opportunity to inform doctors-in-training about this serious disease. Our students gained insight into the patient’s journey through diagnosis, treatment and the challenges ahead. We all appreciated the patient’s generosity in sharing her experiences. Having patients teaching medical students about amyloidosis will have a lasting impact on our future doctors with increasing awareness of this disease and ultimately will help future patients. 

From Gordon Huggins, MD, Associate Professor of Medicine, Tufts University School of Medicine, Cardiologist, Tufts Medical Center

I am writing this enthusiastic letter of recommendation on behalf of the Amyloidosis Speakers Bureau (ASB), a unique educational resource to instruct medical students about amyloidosis. By making patient speakers and educational materials curated by ASB’s medical advisors available to medical schools, it is my hope that the Amyloidosis Speaker Bureau will help form durable impressions on medical students and physicians that will translate to more widespread awareness, faster diagnoses, earlier initiation of treatment, and ultimately better survival for amyloid patients. I encourage you to integrate the resources made available by the ASB into your annual curriculum, as it has the potential to significantly alter the course of this disease.

What medical students had to say:

Ike Chinyere, MD Candidate, University of Arizona College of Medicine – Tucson

I wish this was integrated into the didactic curriculum, particularly in cardiology (“CPR block” at our school). 

Sophia Chen, MD Candidate, Lewis Katz School of Medicine at Temple University

We touched upon amyloidosis very briefly in our medical curriculum but hearing about the disease and how it significantly impacted a person’s life makes it so much more memorable and humanizing. It’s easy to just rattle off a list of symptoms when describing the disease but hearing exactly how those symptoms affect a person’s quality of living and how the long diagnosis process really takes a toll on a person’s mental well-being makes the disease so humanizing. 

Rachel To, MD Candidate, Chicago Medical School, Rosalind Franklin University of Medicine and Science

The patient speaker’s testimony was engaging and really brought to light the perspective and challenges faced by those afflicted with amyloidosis. As medical students, we learn about amyloidosis in our curriculum but meeting a patient with amyloidosis and hearing their story is completely different. Would highly recommend that every medical student should hear a patient testimony about amyloidosis!

Alexander Hirsch, MD Candidate, Yale School of Medicine

Being able to hear from a patient with a specific disease, whether common, rare, or somewhere in between, is so important for both our academic education as well as our development as doctors. During the preclinical years, it can be easy to get lost in the textbook descriptions of patients and forget about what real patients actually go through. Talking to real patients makes me remember why I went into medicine in the first place. 

Supporting Medical Research

As we have said over and over, nothing happens in research without money. And knowing the NIH currently funds only 11% of its applications, this leaves a heavy burden on private foundations and individuals to help close the shortfall gap. So, our work to raise money matters.

  • Due to COVID-19 our third annual Play FORE The Cure golf tournament – our only formal fundraising event – was cancelled for the safety of our participants. We hope to hold this event in 2021!

A significant percentage of our monies raised (excluding ASB grants and directed donations) was donated to four world-class research institutions.

  • Mayo Clinic’s Amyloidosis Research Fund and Dr. Morie Gertz
  • Boston University’s Amyloid Research Fund and Dr. Vaishali Sanchorawala
  • Tufts Medical Center’s Amyloid and Myeloma Research Fund and Dr. Raymond Comenzo
  • Scripps Research’s Kelly Lab and Dr. Jeffery Kelly

WHAT ARE OUR GOALS FOR 2021?

Raising Awareness

  • Focus our energies on the Amyloidosis Speakers Bureau (ASB), expanding our medical school outreach. This is where we believe we can make the biggest impact from our efforts. Engagement from the amyloidosis patient community, securing meaningful grants, and proceeds from donations/fundraisers will be key to complement the operational and legal infrastructure required.
  • Develop a framework to help assess the ASB’s effectiveness.
  • Publish educational blogs to the growing medical student mailing list, as well as to our broad mailing list.
  • Explore additional opportunities, both large and small, which enable us to further spread the word on the importance of early diagnosis.

Supporting Medical Research

  • Donate a meaningful percentage of our non-ASB donations and fundraising proceeds to leading research institutions whom we know are working to advance the knowledge and find answers about this disease.

 

I am encouraged by the impact Mackenzie’s Mission is already making after just a few short years. Connecting with the amyloidosis community and working together to make an impact is extremely rewarding. There is much work to be done, but with so much help from the community and our supporters I know we can win this fight!

With warm regards for a wonderful and renewed 2021,

Mackenzie

 

AN UPDATE ON ME

This past year I devoted my time largely to Mackenzie’s Mission and the work of the Amyloidosis Speakers Bureau. Outside of the foundation, I am starting a position as a clinical technician at a local hospital, gaining valuable patient experience as I prepare to apply to Physician Assistant school in April 2021. Earlier this year I was fortunate to be able to visit Antarctica, ticking an item off my bucket list of visiting all seven continents. As for my disease, I remain on a regimen to keep my disease under control and continue to feel great.

 

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