The 17th annual HOPES conference highlighted the clinical potential for targeting the DNA and RNA of the mutant huntingtin gene, as well as the importance of advocacy in transforming the Huntington’s disease community. University of California, Davis doctoral candidate Peter Deng discussed using artificial transcription factors to “switch off” the huntingtin gene; HDSA person of the year Amy Fedele shared through the HD community following her positive test for the gene; and neurologist Dr. Alexandra Duffy, D.O., provided an overview of exciting new developments in HD treatments. William Durham, who will be stepping down as faculty advisor to HOPES after 17 years, closed the conference with a speech emphasizing the importance of the human component of science, “science with a heart.”
Peter Deng, PhD candidate at University of California, Davis, “An Artificial Transcription factor for HD”
Alexandra Duffy, DO, neurologist at University of California Davis Medical Center “From Bench to Bedside: Advances in Huntington’s Disease Research”
Peter Deng, PhD candidate at University of California, Davis, “An Artificial Transcription factor for HD”
Peter Deng, a doctoral candidate at University of California, Davis, discussed his research on developing ways to target the DNA of a person with Huntington’s disease. By creating a molecule called an artificial transcription factor in the laboratory, he hopes to switch off the production of the toxic mutant Huntingtin protein.
Huntington’s disease in an autosomal dominant disease, meaning that a person only needs one copy of the mutant gene for the disease to occur. To prevent the mutant gene from its harmful effects, drugs can target three levels: the DNA, which is contains the information for how to make the protein, the RNA, which is a temporary transcript of the DNA that allows cellular machinery to “read’ the instructions, and the mutant protein itself. Deng argued that the benefit of taking aim at the DNA is that unlike mRNA, DNA is not constantly being recycled and remade; his dream is for “a cure from a single injection” of a drug.
Transcription factors bind to the promoter regions of DNA in order to alter gene expression; for instance, one transcription factor could lead to increased gene expression and thus production of mutant huntingtin protein, while another could lower expression. Deng hopes to take advantage of this cellular machinery by designing an artificial transcription factor that lowers the expression of the huntingtin gene. He is currently evaluating the efficacy of this procedure using mouse models. One of the major challenges he faces is designing a delivery method to distribute these artificial transcription factors to cells.
Ultimately, Deng’s vision is to “translate therapies from the bench” so that they can be applicable to “an end user, the people suffering from HD” to slow the progression of the disease.
Amy Fedele, HDSA person of the Year
This year, Amy Fedele was honored as HDSA’s “Person of the Year” for her advocacy and fundraising efforts on behalf of HD. Through the events she organized, Fedele raised over $400,000. In addition to these accomplishments, she holds a spot on the HDSA Board of Northern California. At the conference, Fedele shared her story of getting involved in advocacy and the HD community.
When Fedele was a teenager, her mother exhibited symptoms of HD, but was in denial about the cause of her symptoms. Fedele made the decision to get tested for the gene primarily to prove to her mother that the gene was in the family. In the aftermath of finding out that she was gene-positive, Fedele realized that the test results would have an impact on her life far beyond the scope that she had imagined.
Fedele discussed how she eventually integrated fundraising walks and support group meetings into her life, and the transformative effects of connecting with the HD community. One of her greatest sources of motivation for advocacy is seeing the smiles on the faces of people with Huntington’s and family members. When she approaches someone new in the HD community, her goal is “to connect, to share my story” and to provide encouragement.
Dr. Alexandra Duffy, DO, neurologist at University of California Davis Medical Center “From Bench to Bedside: Advances in Huntington’s Disease Research”
Dr. Alexandra Duffy provided an overview of the current landscape of rising treatments in HD including genetic strategies, non-genetic strategies, and the status of significant clinical trials. She focused on gene-silencing therapies, such as IONIS-HTTRx and WAVE, both of which target and cause the degradation of huntingtin RNA to prevent the production of the huntingtin protein.
IONIS-HTTRx has generated widespread excitement throughout the research community after the its Phase 1 and 2 trials revealed that it was associated with a significant reduction of the huntingtin protein in the cerebrospinal fluid of HD patients. The trials also supported the safety and tolerability of the treatment. IONIS -HTTRx works by using antisense oligonucleotides, short nucleotide sequences that bind to the huntingtin mRNA and cause the body to degrade the RNA, halting the translation from mRNA to protein. WAVE works in a similar way, with one significant difference: WAVE is allele-specific, which means that it should only target the mRNA of the mutant huntingtin gene, not the normal huntingtin gene. This is important because HD patients typically have one copy of the mutant HTT-gene, and one copy of the normal gene. The normal huntingtin protein is expressed throughout the body and may be important to the function of neurons, so it’s preferable that the drug does not get rid of the normal protein in the process of clearing the mutant protein.
Duffy also mentioned a number of other interesting developments in HD research. SRX246, a first-in-class vasopressin 1a receptor (V1AR) antagonist, has “intriguing” potential for decreasing irritability. V1AR is a type of receptor that appears throughout the brain, and binds to the hormone vasopressin. The drug aims to block the binding of vasopressin to V1AR. In addition, trials for Laquinimod, an investigative drug that alters the immune system, are ongoing. The SIGNAL trial tests the safety and tolerability of an antibody called VX15/2503, which blocks Semaphorin-4D (SEMA4D), a protein involved in growth and organization in the nervous system. The goal of the SIGNAL trial is to use the antibody to reduce neuroinflammation. Duffy also identified neuroprotective compounds, such as resveratrol and trineptanon, as an active area of research. Finally, she presented stem cell research as a field with the potential for novel applications to HD research.
Learn more about these treatments using the sources below.
For an article about the significance of IONIS-HTTRx, check out an article by hdbuzz.
In-depth information about the status and mechanism of the drug SRX246 is here.
Huntington’s Disease news provided updates on Laquinimod.
Preliminary data from the SIGNAL trial (VD15/2503) was announced in April 2017; here is a summary by the Huntington’s study group.
To learn about neuroprotective compounds, specifically resveratrol, check out this article by Huntington’s Disease news.
William H. Durham, PhD, Hopes Faculty Advisor, 2000-2018, “HOPES: Science with Heart”
One of the things we always wanted to do with this project was to show that science not only has a human face, but that science has a human heart. We always wanted to show that the practitioners of science working away in the labs, working on new therapies, working at the frontiers, and so on, are motivated by people like all of you in this room. That an underlying concern, a caring, drives the science. Peter Deng [conference speaker] talked earlier about the difference between significance and meaning, and in our academic lives, we often get those confused. What has always stood out to me in the HOPES Project is the meaningfulness of it all. Our students study science all day long, but with HOPES they also get to know the human side. They go to support group meetings, they go on the [fundraising] walk in San Francisco, they get to know families, they meet people affected, they hear the stories like Amy [conference speaker] told this morning.
That’s the “magic” of HOPES: the students come away with not only a deep passion for science, but they also appreciate the human component. The see that science is not some abstract enterprise off in a laboratory somewhere; that science really is motivated by human needs, human desires, human wants, and a fundamental right that we all have to a decent life. What I love about HOPES is seeing how the students appreciate that aspect of science. Sometimes for the very first time they see that science really has a human heart. Sure, economics are important; sure it matters how much VSOs [a conference topic] are going to cost. But an awful lot of the prices disappear when you are talking about the importance, the meaningfulness of human life. What I love is that HOPES has helped students appreciate that meaningfulness. It has added a dimension to science in their lives and, to me, that has been a really meaningful part of the whole HOPES enterprise.
I thank the students for the years of inspiration I have gotten, and I thank them for the enthusiasm, the dedication, and the annual joyful, fun-loving skits. I thank Professor Cathy Heaney, who is following me, for her willingness to pick up and carry on. I thank the families and the donors who have stuck with us all this time. This began as a dream. We had no idea what to do at the start. We had an inkling and that’s all. We began with a meeting like this; people gave us some advice, and they said, “You know what’s really missing? We have a lot of advocacy groups, and there’s a growing amount of scientific research. What’s missing and what we need is somebody who will translate the science for everyday people to understand. A website that did that would truly be helpful.” The story we heard this morning, Amy’s story [conference speaker] about a doctor who said, “I can tell you the result [of the genetic test for Huntington’s disease] but I don’t know what to do now:” that’s exactly what happened to me. A family said, “We have this in our family, what do we do now?” At the time, there was little or no accessible science anywhere.
So, we started with a very simple beginning. Some Stanford students responded to our call to create a website. In those days, I hardly knew what a website was let alone how to create one. But the students knew. Folks like Shawn [our current web designer] knew. And one of the first students to step forward was a young man named Darwin Chen, so fitting a name I thought to myself. He said, “We can do this!” He said, “I have several friends, some website designer friends, some creative writing friends, and so on, and we can do this.” So, we started out very small and modest, mostly with Darwin’s friends, and we had no idea how it would go. I was initially skeptical. I thought it certainly is an important thing to do, and certainly worthwhile for the human side of the story. But could we at Stanford pull this all off? Did we really have the right combination of skills? Do we have enough science with a heart?
It’s so rewarding, to see all that has followed from this first little group of “Yeah, we can do that.” The first website had on the order of six pages, can you imagine? And we were so proud of it: that it worked, that you could look at it and learning something. It had some basic information and some simple graphics about HD (Huntington’s disease). Now we have something vastly better, vastly more helpful to the HD community, with wonderful illustrations and accessible science. Many of you have told me how much the HOPES site has helped you and contributed to the information that you, your care partners, and your families have. That, to me, is very rewarding. It’s rewarding both that we have done something for the HD community in our own modest little way, and that we also have developed the science with a heart for the students who have been part of HOPES over the years.
For all of that, I thank each and every one of you in the audience today, and I thank all the past and present HOPESTERS. I am grateful for all you have done to help us and guide us. So, I say we go forth inspired by what’s happened here today, by what we’ve heard, the wonderful science under way, the clinical trials that are so important, and we all go forth to continue science with heart. We have many things to celebrate! Here’s to continued HOPES! Thank you very much.
This transcript has been lightly condensed and edited for clarity.