Transthyretin amyloidosis (ATTR) is a condition that gradually worsens over time and affects how certain organs work, especially the heart and the nerves. This unit will explore the causes of ATTR amyloidosis and how new gene therapies are being developed to potentially slow or stop disease progression.
About Transthyretin Amyloidosis
ATTR amyloidosis is caused by a variant (also known as a change or mutation) in the TTR gene, which.aspx?width=400&height=400)
provides instructions for making a protein called transthyretin. This protein normally helps transport vitamin A and thyroid hormones throughout the body. In people with ATTR amyloidosis, changes in the TTR gene cause the transthyretin protein to fold incorrectly, forming clumps called amyloids. These amyloids build up in tissues such as the heart, nerves, and kidneys, and form amyloid deposits, causing damage over time. This buildup can prevent organs from working properly, resulting in symptoms like heart failure, and nerve pain. The TTR gene variant can be passed along from the parents, and this is called hereditary amyloidosis. It can also be caused by age-related factors and is called wild-type ATTR amyloidosis.
Symptoms
ATTR amyloidosis can cause a range of symptoms, which vary based on which organs are affected. Many people first notice issues in their hands and feet, like numbness, tingling, or pain. These symptoms can worsen over time, leading to muscle weakness and trouble with balance.
In older adults, heart issues are common, and they may experience symptoms like shortness of breath, tiredness, and irregular heartbeats. Some people may also have digestive problems, such as nausea, diarrhea, or unintended weight loss. It’s important to note that individuals can have a mix of these symptoms, with some mainly experiencing nerve-related concerns while others may have heart or stomach issues.
Gene Therapy Approaches
Gene therapy for ATTR amyloidosis aims to limit production of amyloid deposits or amyloid buildup in the body by limiting the production of the TTR protein. Gene therapies are being explored with a few approaches to treat ATTR:
Gene Editing
Gene editing aims to prevent the production of the TTR protein by locating the TTR gene and ‘knocking it out’ by removing it entirely from the DNA sequence. This type of approach is done in vivo, meaning it is given directly into the body, and aims to be given one time. The genetic material is delivered to the cells by a viral vector. Scientists have learned how to remove the harmful, viral genes from these viral vectors, ensuring that only the helpful gene reaches the target cells.
Gene Silencers
A Food and Drug Administration (FDA)-approved treatment utilizes gene expression modifiers that work to turn a gene on or off. Gene silencers such as small interfering RNA (siRNA) or antisense oligonucleotides (ASOs) target a gene’s mRNA to prevent production of unwanted proteins. In this case, it prevents the liver from producing the TTR protein which forms the harmful amyloid deposits. Learn more about WAINUA for the treatment of nerve issues throughout the body (polyneuropathy) caused by hereditary ATTR amyloidosis (hATTR-PN) in adults.
Some ATTR conditions are caused by changes in the TTR gene, leading to the gene not producing enough TTR protein that helps our body work properly.
The main goal of these therapies is to slow down or stop the disease to improve the quality of life for individuals with ATTR amyloidosis.
There are new treatments being investigated in clinical trials for ATTR amyloidosis. Clinical trials are a required part of the research process for researchers to understand how a treatment works in the human body and ensure it is safe and effective. Before reaching clinical trials, treatments go through preclinical studies. This means they are tested on animals or a cell model in the lab to understand if they are ready to be investigated in humans.
Currently, there are some FDA-approved treatments for ATTR amyloidosis that focus on either slowing down the disease or helping to manage its symptoms. These treatments mainly aim to stabilize the transthyretin protein, reduce the buildup of harmful amyloid clumps, or help break down any amyloid deposits that are already present.
Ongoing clinical trials are crucial for testing new therapies and ensuring they meet the strict standards set by the FDA before they can be made widely available. To find out more about open clinical trials in the U.S. or around the world, you can visit the ASGCT Clinical Trials Finder and use the "diagnosis" filter to search for ATTR amyloidosis studies. Alternately, you can visit clinicaltrials.gov and use the “condition/disease” filter to search for related studies.
Participating in a Clinical Trial
For individuals affected by ATTR amyloidosis, standard treatments may help manage symptoms, but 
they do not address the underlying cause of the disease. As a result, some individuals may consider enrolling in clinical trials that explore new therapies, including gene therapies that target the genetic cause of ATTR amyloidosis. It is crucial to be well-informed before deciding to participate in a clinical trial. Key points to consider include understanding the purpose of the study, potential risks and benefits, and the commitment involved. Additionally, individuals with ATTR amyloidosis should discuss their options with trusted healthcare providers and consider how participation may impact their health and quality of life.
Eligibility
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These criteria help researchers ensure the gene therapy is working properly and to keep participants safe and may include factors such as age, physical ability, medical history, and more.
Risks
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In the event a person is not satisfied with the outcome, the person cannot receive another dose of the gene therapy or reverse its effects. However, research is underway to better understand whether re-dosing will be a possibility.
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In addition, participating in a clinical trial may prevent an individual from future participation in other trials or receiving other types of treatments.
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Gene therapy can be an alteration for the lifetime, so people should be aware that there could be long-term effects (both good or bad) that are not known at this time.
Benefits
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Participating in a trial may offer many potential benefits compared to not receiving any form of intervention for a fatal disease.
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Gene therapy aims to be a one-time treatment with lasting positive effects to slow or stop disease progression for up to a lifetime. However, there is no guarantee.
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If gene therapy is received earlier in the course of disease, it has the potential to stop any damage before it occurs.
Long-term follow-up
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It is the individual’s responsibility to comply with the long-term follow-up of a trial. FDA guidelines require the clinical trial research team to monitor safety and potential long-term effects of a gene therapy.
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Follow-up may require in-person appointments that vary in frequency and location, or completion of mailed packets with response forms.
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The need for long-term data collection for a gene therapy trial can last up to 15 years—another reason to consider all outcomes and responsibilities that come with committing to a clinical trial.
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There are a limited number of participants in trials, so a lack of attendance at follow-up appointments leads to not enough study data. This could negatively affect FDA approval of a new therapy and thereby limit access to the therapy by people who did not participate in the clinical trial.
Access
At this time, we do not know when more gene therapies will be approved by the FDA and commercially available for people living with ATTR amyloidosis. The overall process may take several more years, until it is deemed safe and effective by the FDA or regulatory agencies in other countries. In the meantime, people with the condition should review current treatment options with their providers and stay informed about new treatments, such as gene therapies, that may become available in the future.
Stay Informed
There are many patient advocacy organizations to follow or get involved with, such as the organizations listed below. They work hard to fund research and advocate for both affected persons and family needs, also a great way to connect with others affected by the disease if you are looking for support and advice