More optimistic than ever, CHDI head scientist sees unprecedented mobilization in the fight to treat Huntington’s disease

 

In the wake of last week’s 20th Annual Huntington’s Disease Therapeutics Conference, the chief scientific officer for CHDI Foundation, Inc., declared that HD scientists had mustered unprecedented efforts toward therapies (treatments).

 

“I’ve been in the drug discovery business for over 30 years now,” Robert Pacifici, Ph.D., the CHDI head scientist, told me in a 37-minute video interview after the conference, referring to the key theme of crucial modifier genes, a focus of the meeting. “I’ve never seen the mobilization of efforts as quickly and as deliberately – from the identification of those genes to the understanding of how those genes mechanistically are having their effect – to actually developing candidate therapies that are modifying those processes.”

 

Dr. Pacifici observed that, in the HD field, “everybody’s pushing wherever they can to accelerate therapeutics. But we all know that sometimes you just hit roadblocks, you hit bottlenecks.”

 

He said that those difficulties can be overcome with “new technologies, new methods, new techniques,” which often result in “breakthrough moments. They allow you to do things that you just could never contemplate doing before.”

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 20th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

The efforts forming around this hottest of topics in the HD field are “incredibly exciting,” Dr. Pacifici said. The “big news” over the next two years should include getting drugs that imitate the effect of the modifier genes – which research has demonstrated delay the onset of HD symptoms – into clinical trial programs.

 

As reported in this blog, the now defunct Triplet Therapeutics had aimed from 2020-2022 to develop and test a modifier gene drug (click here to read more).

 

Dr. Pacifici said that he is “more optimistic” than ever that HD drugs will get approved.

 

I attended the conference. Below you can watch a video of my interview with Dr. Pacifici.

 

 

 

Attacking the harmful protein

 

While this year’s Therapeutics Conference did not include any major positive announcements like the approval of a drug, Dr. Pacifici observed that it also did not bring the kind of disappointing news experienced by the HD community in 2021 with negative results from trials run by Roche and Wave Life Sciences.

 

The conference did bring reports from both Roche and Wave about their revised clinical trial programs. PCT Therapeutics and uniQure also reported on their ongoing clinical trials.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. This is the first of three approaches to defeating HD, Dr. Pacifici recalled.

 

I will detail these updates soon.

 

‘Lucky’ and ‘unlucky’ genes

 

The second, more recent approach involves the search for drugs to imitate the modifier genes, as Dr. Pacifici noted above. These genes are related to somatic instability – the tendency of the expanded HD gene to expand further with time. This process can be triggered by negative modifier genes.

 

Dr. Pacific described those genes as “lucky” or “unlucky.” A good modifier gene can delay HD onset, whereas the bad one can hasten the start of the disease, he explained.

 

These genes act as “sentinels” in the bookkeeping of our DNA, Dr. Pacifici added. “We want our DNA to stay clean and error-free.”

 

Dr. Pacifici emphasized how more than 12,000 HD-affected individuals and their relatives in genetic research helped lead to the discovery of the modifier genes a decade ago. A study of a large group of people’s DNA is known as a Genome Wide Association Study (GWAS).

 

Fixing broken cells

 

The third approach to treating HD involves yet another set of genes that emerged from the HD GWAS. They were a key topic at the conference.

 

Dr. Pacifici stated that these genes are “every bit as validated” as the ones involving somatic instability. “We just don’t know the effect yet,” he said.

 

Dr. Pacifici added that understanding these genes will help answer a key unanswered question about HD: “what is it actually inside a cell at the molecular level that’s broken” and how to fix it.

 

All three of these areas could be targeted by an eventual cocktail of HD drugs, Dr. Pacifici said.

 

Key new genetic research and ‘rock star’ HD families

 

“We keep on thinking of ways of getting even more information out of persons with HD,” Dr. Pacifici said.

 

CHDI has announced that all 22,000 participants in Enroll-HD, the global registry of HD patients and relatives, will be full-genome-sequenced. That means their entire DNA will be  mapped.

 

“That’s a lot of data,” Dr. Pacifici noted. “It’s going to be the next set of breakthroughs, where we understand not just little bits of DNA information but the whole story for every participant.”

 

This will be “incredibly impactful,” he said.

 

The HD families that have provided all of this crucial data underlying these approaches to treatments are true “rock stars,” Dr. Pacifici said. Their interaction with HD scientists is critical, he concluded, to advancing scientific breakthroughs.

As a ‘biological being,’ I embrace science’s fight against disease

 

I am a biological being.

 

This phrase came to me about a decade ago, and I have been hoping to write about its meaning for a long time.

 

Now, with scientific research at key American institutions such as the National Institutes of Health and university labs under attack from the Trump administration, the phrase resonates with me stronger than ever.

 

From the time I was hospitalized in 1977 with two herniated discs after shoveling heavy snow through decades of participation in Huntington’s disease research studies, I have been acutely aware of my body as the object of biomedical observation.

 

Seeing scans of deteriorating HD brains at scientific conferences leaves me deeply worried about the shrinking of my own brain – the inevitable result of the fact that I carry the HD gene.

 

In March 2022 I observed preliminary data presented by Triplet Therapeutics from SHIELD-HD, a two-year research study of 70 presymptomatic and early-disease-stage carriers of the HD mutation. Triplet aimed to use SHIELD-HD to support plans for a groundbreaking clinical trial to attack a key driver of HD, somatic expansion, the mutant huntingtin gene’s tendency for continued expansion with age. The program was scuttled because the firm folded in October 2022 as it lacked investment funds.

 

The 2022 SHIELD-HD data showed deterioration in the brains of the gene carriers.

 

For the first time, I saw information about the impact of the HD gene on my own brain. I had volunteered for SHIELD-HD, undergoing MRI brain scans and cognitive tests and giving samples of blood and my cerebrospinal fluid (CSF) at the HD clinic at the University of California, San Diego.

 

Below are photos of me in the clinic in August 2022, just two months before the Triplet shutdown. The first shows a neurologist injecting an anesthetic to prepare for the drawing of my CSF. In the second photo the doctor draws a small amount of my CSF. It was the last of my several CSF drawings over the course of SHIELD-HD. Scientists see analysis of CSF, which bathes the brain, as a major tool in the search for therapies for HD. 

 

Having CSF drawn is a safe procedure but can be painful. Each time I drove home by myself within a couple hours of the drawing. I am very glad I did it.

 

 

 

 

Analysis of SHIELD-HD

 

With the end of Triplet, final analysis of the key SHIELD-HD data was completed by CHDI Foundation, Inc., the largest private funder of HD research. The analysis was presented at the 19th Annual HD Therapeutics Conference, sponsored by CHDI, in February 2024.

 

A future article will further explore my participation in SHIELD-HD and the importance of that program for HD research.

 

The 20th Therapeutics Conference: a sign of collaboration

 

As a biological being, I embrace science, not useless conspiracy theories. At the University of San Diego, where I teach and research, I began a new course this month called “A History of the Brain: Examining Huntington’s Disease.” One key lesson from the history of brain science: reliance on superstition was replaced with scientific observation – the key to solving neurodegenerative disorders like HD.

 

On a large scale, so has the HD community participated in and supported science – from the start of the hunt for the gene in the 1970s to programs today such as Enroll-HD. Tens of thousands of individuals from around the world have taken part, despite the fact that HD is a rare disease, with about 40,000 affected individuals in the U.S.

 

CHDI, the Huntington’s Disease Society of America, the Hereditary Disease Foundation, Help4HD International, and other HD organizations also rely on science and cooperate with scientific institutions.

 

A magnificent example of scientific collaboration will take place starting this evening in Palm Springs, CA, as the 20th HD Therapeutics Conference gets under way at the Parker hotel.

 

Stay tuned for reports about the meeting.

Savoring 20 years of my Huntington’s disease blog

 

This month I am celebrating the 20 years of this blog.

 

I began At Risk for Huntington’s Disease on January 10, 2005, wanting to “squeeze as much life into my days as possible” before experiencing the debilitating HD symptoms that led to my mother’s death a year later. Because I lived in what I called the “terrible and lonely HD closet” – fearful of genetic discrimination – I used the pseudonym “Gene Veritas,” “the truth in my genes.” That name reflected the fact that I had tested positive for the HD gene in 1999.

 

My mother died at 68, after two decades of debilitating symptoms, which was very painful to watch.

 

I turned 65 last month. By this age, I had expected to have full-blown HD, which would have left me unable to work, drive, or write.

 

But, according to my latest neurological checkup, I don’t yet have apparent HD symptoms!

 

In general, the more abnormal the gene, the earlier the age of disease onset. My mother and I have the same gene mutation, suggesting a similar disease path. However, although my mother’s symptoms started in her late 40s, one or more modifier genes, the functions of which were discovered a decade ago, have perhaps delayed my disease onset.

 

This article is number 336. Each day of good health is a blessing.

 

Gene Veritas (aka Kenneth P. Serbin) with his blog (photo by Regina Serbin)

 

The impact

 

In 2012, I exited the HD closet by publishing an essay – and using my real name, Kenneth P. Serbin – in The Chronicle of Higher Education. It was titled “Racing Against the Genetic Clock.” Going public opened new vistas of advocacy and enabled me to blog with greater transparency.

 

In December 2022. I published a detailed analysis of the blog in “Striving for a Realistic and Unapologetic View of Huntington’s Disease” in the Journal of Huntington’s Disease. It described how the blog has helped give voice to the HD community by exploring the major challenges faced by HD families, becoming a key reference for those families, and chronicling the quest to defeat the disorder.

 

As I observed, the blog has also “helped document the new and harrowing experience of living in the gray zone between a genetic test result and disease onset.”

 

At Risk for HD has addressed multiple topics including advocacy, caregiving, family trauma, coping strategies, genetic testing, discrimination, leaving the HD closet, participation in research and clinical trials, as well as religion, faith, and spirituality.

 

When my mother was diagnosed with HD in 1995 – two years after the discovery of the gene – little hope existed for treatments that could slow the progression of HD. However, in the past decade, advances in academic labs and biopharma firms have led to key clinical trials that show potential for affecting the course of HD and perhaps even a cure (click here to read more).

Telling the story of those complex developments has become a major focus of At Risk for HD. With the growing number of research projects, I have necessarily highlighted those that appear closest to producing actual drugs such as the Roche gene silencing program, which I have covered extensively.

 

In 2021, the first Roche trial showed lack of efficacy. In 2023 Roche started enrolling volunteers in a more focused trial to see if the drug might work at least in some patients. Other key trials are in progress or being planned.

 

Hoping for an HD-free world, savoring life

 

Writing the entries of At Risk for HD has given me great meaning and purpose, which researchers have identified as increasing well-being and positively impacting the course of the disease.

 

For now, I plan to continue blogging as long health permits – and until the quest for a cure is complete.

 

In February, I hope to attend the crucial 20th Annual HD Therapeutics Conference at the Parker Hotel in Palm Springs, CA. The conference is sponsored by CHDI Foundation, Inc., the largest private funder of HD research.

 

In 2011, I delivered the conference keynote speech before 250 scientists, physicians, and biopharma reps – a decisive step towards my complete exit from the closet in 2012 and chronicled in this blog.

 

I have described the conference as the “Super Bowl of HD research,” covered in many blog articles and videos of scientists (see, for example, this one).

 

With the rest of the HD community, I hope for the announcement of effective treatments. I very much look forward to reporting on progress.

 

Just as important is the need to savor life – another key lesson of my journey with the HD community, this blog, and my friends and family.