After abrupt shutdown of Triplet Therapeutics, Huntington’s disease community regroups in the fight for therapies

 

Triplet Therapeutics, Inc., a Cambridge, MA-based start-up that aimed to transform the treatment of Huntington’s disease and related disorders, has shut down, citing a lack of new investment partners and the discovery that its proposed HD drug caused adverse effects in animal tests.

 

On October 11, Triplet CEO Nessan Bermingham announced the company’s closure on his LinkedIn page. The abrupt closure was another piece of tough news regarding potential therapies for HD.

 

In March 2021, Roche and Wave reported negative trial results for drugs aimed at reducing the toxic mutant huntingtin protein in patients’ brains. These drugs are antisense oligonucleotides (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.

 

Triplet’s strategy

 

Triplet had designed its own ASO, but with a different strategy: to stop the deleterious expansion of the mutant huntingtin gene (click here to read more). Known as somatic expansion, this process drives the disease and can hasten the onset of symptoms. By slowing this expansion, Triplet had hoped that its drug would head off the disease early.

 

Triplet scientists and others have viewed this approach as a more effective alternative to the “huntingtin lowering” strategy devised by Wave, Roche, and others.

 

Capitalizing on recent groundbreaking HD genetics research, Triplet, founded in late 2018, developed the only clinical trial program to slow or stop somatic expansion in HD. Triplet also had hoped to develop treatments for others among the 50 rare conditions with somatic expansion, which, like HD, are called repeat expansion disorders.

 

 

Brian Bettencourt, Ph.D., Triplet's former senior vice president for research, explains a slide illustrating the firm's pathway to a potential HD drug at the 15th Annual HD Therapeutics Conference, 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

“It is with great sadness we announce the closure of Triplet Therapeutics,” Bermingham wrote on LinkedIn.

 

The “underlying science of targeting repeat expansion disorders” remains “a viable approach from our vantage point,” Bermingham wrote. However, crucially, in animal studies, the data from Triplet’s HD drug “reflected prior experiences” with ASO toxicity in the central nervous system – a reference to the Roche and Wave results.

 

Specifically, the ASO showed signs of harming neurons (brain cells). “As a therapeutic modality, given Roche’s data, our data, lack of efficacy from Wave products, our belief is that neurons may be particularly sensitive to antisense oligonucleotides,” Bermingham told STAT.

 

Triplet secured $59 million in initial financing and investment. After the bad news in 2021 from Roche and Wave, Triplet struggled to raise the money needed for its planned next step: an early phase clinical trial of its ASO. “The clinical data really put a chill on the overall interest or risk perceived within Huntington’s disease,” Bermingham noted.

 

SHIELD HD continues to provide key data

 

To provide data about the disease for the clinical trial it was planning, Triplet has run a separate, two-year study, without a drug, of approximately 70 presymptomatic and early-disease-stage carriers of the HD mutation. Called SHIELD HD, the study involves cognitive testing, brain MRI scans, blood tests, and examination of cerebrospinal fluid drawn from spinal taps (click here to read more). The sites are Canada, France, Germany, the United Kingdom, and the U.S.

 

In March, Triplet scientists presented a preliminary analysis of this data at the 17th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the virtual nonprofit biotech focused exclusively on developing HD therapies. CHDI is the largest private funder of HD research.

 

SHIELD HD may end in the next few months. In Bermingham’s announcement about the closure of Triplet, he said that CHDI, “a great partner and patient advocate,” stepped in to help SHIELD HD sites complete their work.

 

Triplet’s representatives are now seeking potential partners to continue the company’s research, including a new plan for a clinical trial.

 

Assessing risk

 

In an online interview with me on October 21, Irina Antonijevic, M.D., Ph.D., the former chief medical officer of Triplet, explained that discovering toxicity of the ASO in the animal studies surprised the firm’s researchers. However, she emphasized that the toxicity was “minimal” at therapeutic dose levels, with the animals not suffering any functional loss.

 

As noted publicly, Triplet had also developed several, more potent backup ASOs, Dr. Antonijevic said. The more potent the drug, the smaller the dose needed, therefore reducing the chance of toxicity or an adverse effect, she added.

 

Nevertheless, in a more risk-averse investment climate, Triplet could not find the necessary partners to carry on its clinical trial program with the added concern about the toxicity, Dr. Antonijevic observed.

 

“I think that they are just sort of very different risks,” she said. “Somebody takes maybe a risk to say, ‘Maybe this drug has a risk, but I have a disease, and I know what this disease will do to me.’”

 

For a drug company, the risk involves “investing millions” and waiting years to see if there is a return on investment, she said.

 

Tweaking drug safety, efficacy, and delivery

 

Triplet’s experience revealed how the field of HD drug development needs to tweak the safety, efficacy, and delivery of ASOs into the brain. Despite the challenges, a number of other firms and many researchers believe ASOs merit more study and clinical trials.

 

Roche has developed a revised clinical trial plan, including lower and thus potentially less toxic doses of its ASO. It will start a second trial of that ASO in early 2023.

 

Wave, building on its failed 2021 early stage trials of two ASOs, put a third drug into another small, early phase trial. Unlike the previous drugs, this Wave ASO successfully reduced the mutant huntingtin protein. Also, for the first time, it did this without lowering the level of the healthy protein – something that occurs with the Roche drug.

 

“This is, as far as we know, the first time anyone has ever selectively lowered only one copy [of a total of two] of a protein inside of a human body,” the HD science site HDBuzz commented on Sept. 30.

 

The method of delivery is important for all drugs, especially for ones introduced into the brain. The Roche and Wave trials use spinal taps (intrathecal injections). Triplet had projected using an

injection via a small reservoir implanted on the top of the brain. The firm uniQure is injecting its drug using brain operations.

 

Developing a pill

 

Drug developers point out that the most convenient HD drug would be a pill – taken orally, at home, and without medical assistance. These drugs are known as small molecules.

 

Several firms have embarked on small molecule clinical trial programs for HD.

 

An important trial of one of these small molecule drugs, a huntingtin-lowering pill developed by Novartis, was halted in August for safety reasons. Some of the trial volunteers on the drug developed problems with their nerves, known as peripheral neuropathy.

 

FDA requests more data from PTC

 

On October 18, another firm enrolling people in a clinical trial for a small molecule, PTC Therapeutics, Inc., was asked by the U.S. Food and Drug Administration (FDA), to provide further information before allowing a clinical trial of its HD drug, PTC518. PTC announced that enrollment is ongoing for the planned 12-month Phase 2 trial in several European countries and Australia.

 

Both branaplam and PTC518 are so-called splicing molecules.

 

“PTC pioneered the development of splicing molecules and we have learned about the essential elements to successfully develop these molecules,” Jeanine Clemente, the senior director of corporate communications at PTC, wrote me in an October 20 e-mail in response to my questions about the FDA decision. “We cannot comment on the FDA’s thoughts regarding branaplam or splicing molecules, in general.”

 

However, Clemente pointed out that PTC518 is highly specific and selective for the huntington gene.” She added that, in many important ways, “PTC518 is different than branaplam.”

 

HDBuzz also noted that PTC518 “may have more ideal drug properties, compared to branaplam.”

 

The FDA has asked PTC for additional data to support the dose levels and duration proposed in the trial, Clemente wrote.

 

Clemente added that PTC enrolled its trial entirely with patients outside of the U.S., including approvals to conduct the study at all proposed dose levels. “There have been no treatment-associated adverse events reported to date,” she stated. “We will continue to work with the FDA to potentially enable enrollment of U.S. patients in the trial.”

 

Keeping perspective in a difficult fight

 

Triplet will host a podcast later this year to discuss the “birth, life and death” of the firm, CEO Bermingham stated in his announcement of the closure.

 

The HD community must keep the Triplet shutdown – and all news regarding the ups and downs of the search for HD therapies – in perspective, noted Martha Nance, M.D., the director of the Huntington’s Disease Society of America Center of Excellence at Hennepin County Medical Center in Minneapolis.

 

“We would not do research if we already knew all the answers,” Dr. Nance wrote me in an October 18 e-mail. “HD patients and families have bravely faced their difficult disease for generations, and the doctors and scientists are doing their best, along with patients and families, to find a brighter path.”

 

As an asymptomatic HD gene expansion carrier who has not yet participated in a clinical trial, I had high hopes for the Triplet program, with its focus on attacking the disease in the early stages. I was deeply saddened to hear that the firm closed. I also felt in the gut once again the hard reality of marshalling resources – including financial support – for combating rare diseases.

 

Companies like Triplet are venture capital-funded businesses pursuing high-risk, high-reward endeavors, and many such endeavors fail. So we are fortunate to have a nonprofit like CHDI as a backstop.

 

Dr. Nance’s wisdom reminded me of the need to join with my fellow HD and rare disease advocates to regroup in the fight for therapies.

 

“Finding a solution to brain cell death in HD is not easy,” she observed. “And as we edge closer to an answer, each failure seems more dramatic. It would be nice if the answer would just reveal itself, if the answer to HD was simple and easy, but we will not let the setbacks of the last two years prevent us from moving forward.”

Roche confirms second, more focused, trial of Huntington’s disease drug will start early next year

 

As anticipated, the pharmaceutical firm Roche will retest its Huntington’s disease gene silencing drug, tominersen, by enrolling a more limited group of volunteers for a new clinical trial, which should start in early 2023.

 

Roche announced the new trial, GENERATION HD2, on September 18 at a meeting of the European Huntington’s Disease Network (EHDN) in Bologna, Italy. Roche also issued a letter to the HD community.

 

Roche halted the GENERATION HD1 trial of tominersen in March 2021 because of lack of efficacy against HD symptoms.

 

However, after months analyzing the GENERATION HD1 data, Roche reported in January that tominersen might benefit younger patients with less advanced symptoms. The new 16-month study, GENERATION HD2, will verify efficacy in that group.

 

GENERATION HD1 enrolled clinical trial volunteers ranging in age from 25-65 and included people with more advanced disease.

 

GENERATION HD2 will limit participation to people aged 25-50 who have “prodromal (very early subtle signs of HD) or early manifest HD,” the Roche letter stated.

 

“I am very excited about this new trial,” Jody Corey-Bloom, M.D., Ph.D., wrote me in a September 19 e-mail.

 

Dr. Corey-Bloom directs the Huntington’s Disease Society of America (HDSA) Center of Excellence  at the University of California San Diego, a site for GENERATION HD1 and again for GENERATION HD2.

 

“A lot of thought has gone into the new trial,” Dr Corey-Bloom observed. “I think this is a very well-planned trial!”

 

Roche world headquarters in Basel, Switzerland (photo by Norman Oder)

 

Key adjustments in dosing

 

According to the Roche statement, GENERATION HD2 aims to sign up approximately 360 participants in approximately fifteen countries (Argentina, Austria, Australia, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, the United Kingdom, and the United States). Additional locations might be added.

 

The study will have three cohorts. One third will receive placebo, one third 60 mg of tominersen, and one third 100 mg. To ensure the objectivity of the trial, neither the participant nor study team will know what the participant receives.

 

In contrast with GENERATION HD1, the new trial also will administer lower doses of tominersen. In GENERATION HD1, all volunteers receiving the drug took 120 mg. In GENERATION HD2, participants taking the drug will get either 60 mg or 100 mg.

 

Another key difference involves the frequency of dosing. GENERATION HD1 administered the drug every two or four months, whereas the new study will dose at only four months.

 

These adjustments are a major goal of the study: to determine whether lower or less frequent dosing can be beneficial. Such lower dosing or less frequent dosing potentially avoids some of the problems seen in GENERATION HD1. In that trial, the higher dose did not benefit volunteers (click here and here to read more).

 

As in the first trial, in GENERATION HD2 tominersen will be administered via lumbar puncture (spinal tap).

 

Renewed but cautious hope for preventing HD

 

The Roche letter reported that GENERATION HD1 and all other related tominersen studies have closed.

 

“These studies comprised the first-ever Phase III [efficacy] clinical program to test the huntingtin-lowering hypothesis,” the letter noted, referring to tominersen’s mechanism of lowering the amount the huntingtin protein involved in HD. “Additionally, it was because of the HD community’s commitment to research that the trials recruited faster than anticipated, and thus generated data faster than anticipated.”

 

That commitment, the letter observed, “inspires all researchers to continue pursuing potential options for people impacted by the disease.”

 

Roche will announce additional information about GENERATION HD2 in the coming months.

 

After the devastating news about tominersen 18 months ago, its potential seemed dead. Now, though enthusiasm about tominersen has perhaps diminished, a new, albeit less ambitious, path perhaps has emerged for the drug.

 

"Overall, the announcement of the new GENERATION HD2 trial at the EHDN meeting was well received by the audience in Bologna, which was a mix of clinicians, scientists, and families," HDSA CEO Louise Vetter, who attended the meeting, wrote me in an e-mail. "The fact that this trial is clearly a dose-finding study was notable, and it seem representative of the more conservative mood in the HD clinical science right now."

 

“While the results of GENERATION HD1 were certainly disappointing for everyone, they don’t mean that huntingtin-lowering isn’t a viable therapeutic approach,” Sarah Hernandez, Ph.D., the Director of Research Programs for the HD-focused Hereditary Disease Foundation, wrote me in an e-mail. “Targeting huntingtin directly targets the cause of HD and remains one of the strongest therapeutic hypotheses.”

 

GENERATION HD1’s results “also don’t mean that HTT lowering won’t eventually work for a broad population of people with HD,” Dr. Hernandez added. “They just mean that tominersen seems to require a more narrow patient group for efficacy. The new GENERATION HD2 trial seeks to define exactly what that patient group is, which could be very significant in moving the field forward.”

 

My hope is that GENERATION HD2’s aim to treat individuals earlier in the disease could generate valuable insights for a major goal in the science of HD and other neurodegenerative diseases: a therapy to prevent symptoms from appearing in disease gene carriers like me.

After other firms’ setbacks, Prilenia readies for readout on Huntington’s drug that improves daily function

 

August brought more difficult news for the Huntington’s disease community with the halting of yet two more clinical trials. However, Prilenia Therapeutics announced at a major research conference last week that it expects to obtain definitive results from a study of a drug proposed to improve function in the early stages of the disease.

 

Prilenia CEO and founder Michael Hayden, M.D., Ph.D., a leading HD scientist, reported that the Phase 3 clinical trial of pridopidine is on schedule, with administrators expected to release results early in the second quarter of 2023. (Click here for background on pridopidine, Dr. Hayden, and Prilenia.)

 

On August 25 Dr. Hayden provided a brief update on the trial, called PROOF-HD (PRidopidine Outcome On Function In Huntington Disease), at HD2022: Milton Wexler Biennial Symposium, sponsored by the HD-focused Hereditary Disease Foundation. It was held August 24-27 at the Royal Sonesta Hotel in Cambridge, MA.

 

If successful, the PROOF-HD trial will result in a landmark not just for HD, but neurodegenerative diseases in general. Its potential significance has increased because of the disappointing results from two important HD gene silencing clinical trials in March 2021 and the news this month that key trials by Novartis and uniQure had to stop dosing because of safety concerns.

 

In an August 27 interview with me, Dr. Hayden explained pridopidine’s benefits.

 

“It's the only drug that has showed some impact on stabilizing TFC [total functional capacity], keeping patients functional, keeping them managing their finances, keeping them at work, keeping them going for walks with their children and grandchildren, keeping them doing activities of daily living for longer,” Dr. Hayden said.

 

Analysis of pridopidine has demonstrated that patients taking the drug showed a slower decline in TFC. In early patients, pridopidine can maintain TFC and slow deterioration

 

Dr. Michael Hayden (left) confers with Peter McColgan, M.D., the clinical director for the HD program at Roche, during a break in the Milton Wexler Symposium (photo by Gene Veritas, aka Kenneth P. Serbin)

 

Neuroprotective effects

 

The earlier, revised analysis of pridopidine led to a “surprising but very welcome result,” Dr. Hayden continued. Pridopidine works as a “highly potent and highly selective sigma-1 receptor agonist.” An agonist is a drug that mimics a natural substance, while sigma-1 is “a molecular chaperone,” a chemical that helps proteins perform the important function of folding. He called pridopidine “the most potent and selective” sigma-1 agonist ever described.

 

In everybody’s cells, decreased sigma-1 has a negative impact on monitoring stress, including for the endoplasmic reticulum, a key organelle (subunit) that manages stress. In HD, this subunit experiences disturbances that cause an imbalance in the cell, Dr. Hayden said.

 

Overall, a reduction in sigma-1 makes neurodegeneration (slow and progressive loss of brain cells) get worse, Dr. Hayden explained.

 

However, pridopidine enhances sigma-1. The drug has “all in all neuroprotective effects,” by reducing cellular stress and even increasing the critical “connectivity” of the brain and the removal of “toxic products.”

 

Critically, pridopidine is “the only [HD] drug that has shown stabilization of neurofilament,” an important marker of disease progression, Dr. Hayden observed. An increase in levels of neurofilament, which makes up a brain cell's scaffolding, indicates dysfunction.

 

A Prilenia poster demonstrating the positive effect of pridopidine on total functional capacity and stabilization of neurofilament (photo by Gene Veritas)

 

A safe and tolerable drug

 

PROOF-HD seeks to confirm pridopidine’s efficacy so that it might be approved as a drug by the U.S. Food and Drug Administration (FDA).

 

“We submitted this to the FDA, and the FDA was hugely supportive,” Dr. Hayden said. Last November the FDA granted pridopidine a “fast track” designation to potentially speed drug approval, because HD is a “significant unmet need,” Dr. Hayden noted.

 

The designation “allows us to have a closer relationship with the regulators as we go through this process,” he said.

 

Despite the coronavirus pandemic, PROOF-HD began ahead of schedule in October 2020 and is on schedule to report results in about eight months. It recruited 499 clinical trial volunteers, more than the goal of 480, at several dozen sites in the U.S., Canada, and Europe.

 

So far, the standard safety monitoring board has found no reason halt the trial.

 

“So that's also encouraging that this is a very safe and tolerable drug,” said Dr. Hayden. 

 

A Prilenia slide with an overview of PROOF-HD, including the main goals (endpoints) (photo by Gene Veritas)

 

Seeking to prevent disease

 

In contrast with other top HD drug programs using brain or spinal injections, pridopidine is taken orally twice daily, “without any need for nursing care,” Dr. Hayden pointed out.

 

If PROOF-HD is highly successful, inviting a priority review by the FDA, Dr. Hayden said that pridopidine could become available for patients in mid-2024.

 

“My vision for pridopidine is that it could become a standard of care for neuroprotection,” Dr. Hayden stated in a January interview. “For diseases where we can define patients who are close to onset of a neurodegenerative condition, an oral therapy with a benign safety profile – which is what we are trying to establish in our current and planned clinical trials – could become a preventative treatment option.”

 

In a January 2021 Huntington’s Disease Society of America (HDSA) webinar, Sandra Kostyk, M.D., Ph.D, the co-principal investigator for PROOF-HD in the U.S., referred to pridopidine as a possible “disease-modifying intervention – something that slows the course of the disease.” The data indicate that early-stage HD patients could obtain “long-term beneficial effects” from an approved pridopidine drug for five years or more, she said.

 

A Prilenia slide about the advantages of small molecule drugs, the preferred method of treatment in HD. Pridopidine is in that category (photo by Gene Veritas)
 

An upcoming update, a caution, and hope

 

On September 7, HDSA will host a webinar further updating PROOF-HD and featuring Dr. Hayden, Dr. Kostyk, and Andrew Feigin, M.D., the trial’s principal investigator in the U.S. Click here to register.

 

“Of course, there's no certainty that this drug will be successful,” Dr. Hayden told me. “Forty percent of Phase 3 trials fail. So, we have a 60 percent chance. In a Phase 3 trial, things fail for all kinds of unexpected reasons, as sadly we've seen in the Huntington's field.”

 

Pursuing successful trials for pridopidine “has been a long struggle for everybody,” Dr. Hayden concluded. “This is hopeful, but we're not there yet. But hold on as we go on this journey as co-travelers in the attempt to find some way to moderate the course of this dreadful illness.”

 

(Future articles will cover other aspects of the Milton Wexler Symposium. Also see @HDBuzzFeed on Twitter and this article.)

 

Dr. Hayden (right) and Nicholas Caron, Ph.D., exchange ideas at the poster session of the Milton Wexler Symposium (photo by Gene Veritas).

Bridging the Huntington’s and early onset Alzheimer’s disease communities: a report from a family conference

 

In the quest to conquer chronic illnesses, members of disease communities need to build solidarity and learn from one another. I explored this theme in a 2018 article about the fellowship

that a sufferer of type 1 diabetes and I, a gene carrier for Huntington’s disease, had built in our student-teacher relationship at the University of San Diego.

 

On July 30, the common challenge of the daunting search for therapies for neurodegenerative diseases hit home again as I participated in the eighth international DIAD Family Conference, held at the Hilton San Diego Bayfront hotel in downtown San Diego. DIAD stands for “dominantly inherited Alzheimer’s disease,” also known by other names, including early onset familial Alzheimer’s disease.

 

Late onset Alzheimer’s affects more than 5.8 million mainly elderly Americans but has no clear cause. In contrast, early onset Alzheimer’s ­– like Huntington’s – is a rare disease with a known genetic cause. Like HD, it strikes in the prime of life, when people as young as their twenties are affected.

 

Both HD and early onset Alzheimer’s are autosomal dominant conditions: carriers of a mutant gene will definitely develop the disease, and their children have a 50-50 chance of inheriting the disorder. In HD, the mutant huntingtin gene is the culprit. In early onset Alzheimer’s, one of three different mutations causes disease.

 

Early onset Alzheimer’s is rarer than HD. Approximately 41,000 individuals live with HD in the U.S. Globally, an estimated 45,000 people have early onset Alzheimer’s.

 

Sadly, as with HD, there is no treatment yet to arrest the progression of the disease.

 

As I learned at the conference, early onset Alzheimer’s, like HD, produces devastating, ultimately deadly symptoms mainly affecting a person’s memory and behavior. Common symptoms include: abnormal social behavior, agitation, confusion/disorientation, hallucinations, hypertonia (arms/legs are difficult to move/reduced flexibility), language impairment, dementia, Parkinsonism (movement abnormality: tremor, slow movement, muscle stiffness), seizures, and disinhibition.

 

 

Gene Veritas (aka Kenneth P. Serbin) at the 2022 DIAD Family Conference (photo by Gene Veritas)

 

Sharing insights with an Alzheimer’s researcher

 

I was invited to the DIAD Family Conference by Lindsay Hohsfield, Ph.D., co-founder of Youngtimers, a 501c3 nonprofit established in 2021 to promote education, support, and research for the early onset familial Alzheimer's community.

 

The group’s motto is: “we are too young to forget, too many to be forgotten.”

 

An Alzheimer’s researcher focusing on ways brain cells control inflammation, Dr. Hohsfield was inspired to enter the field after her father’s diagnosis with early onset Alzheimer’s. He died in his early 50s.

 

“When my father was sick, my family and I felt isolated and lost,” Dr. Hohsfield wrote in a letter on the organization’s website. “My hope is that with Youngtimers, no early onset familial Alzheimer’s patient and family will ever have to feel alone.”

 

Dr. Hohsfield has also explored the dilemma of “childbearing versus clinical trial participation” for Huntington’s and early onset Alzheimer’s families. Currently, pregnant women are excluded from clinical trials for those disorders. She calls for the establishment of a standard to address patient well-being and needs concerning this dilemma.

 

In May Dr. Hohsfield, a reader of this blog, interviewed me on Zoom about my article reflecting on the significant benefits of psychotherapy in my fight against Huntington’s. That article sparked a discussion in the early Alzheimer’s community about finding a life coach/mind coach to help cope with testing positive for that disorder and living life to the fullest. The interview with Dr. Hohsfield will be posted on the Youngtimers’ website.

 

Facilitating support sessions

 

Dr. Hohsfield and the conference organizers invited me to facilitate two one-hour drop-in support sessions for members of early onset Alzheimer’s families. Leveraging my long experience as an HD gene carrier and advocate, I was assigned to a table discussing “post genetic testing: coping with risk and how it changes over time.”

 

Other tables covered grief, communication, living with symptoms, and “catching your breath.”

 

In all, about a dozen people came to my table over the two hours. Usually, rather than having me facilitate, we exchanged ideas about genetic testing, prenatal testing, workplace confidentiality about our genetic status, securing insurance coverage, and more. 

 

The "post genetic testing" support sign at the 2022 DIAD Family Conference (photo by Gene Veritas)

 

The most poignant moment came when three members of an affected family asked how to navigate tensions in the extended family over the onset of symptoms one of them had suffered. That individual, having stopped being a breadwinner, needed medical care and caregiving.

 

This went beyond the scope of genetic testing, so I relied on memories of similar predicaments at my local HD support group. The other members of the group and I provided a sounding board for this family, encouraging them to use the resources offered by Youngtimers and seek out local support.

 

At these sessions all of us quickly bonded. We found comfort in our shared plight: facing a devastating neurological disorder.

 

Framing HD in a broader light

 

The DIAD Family Conference was sponsored by the Dominantly Inherited Alzheimer Network Trials Unit, the Alzheimer’s Association, and the National Institute on Aging. It was held in conjunction with the Alzheimer’s Association International Congress, July 31-August 4, in San Diego.

 

In between several moving family presentations to the nearly 200 attendees, the audience heard updates from Alzheimer’s physicians and researchers on the progress of research, including ongoing global clinical trials to prevent the disorder.

 

As I have witnessed at Huntington’s conferences, the Alzheimer’s scientists pointed out that research advances have brought the field to an unprecedented moment in the search for treatments. Leading Alzheimer’s researcher Randall Bateman, M.D., stated that it is a question of not “if” but “when” effective therapies become available.

 

After the conference, I met with Jason Karlawish, M.D., a University of Pennsylvania specialist on late onset Alzheimer’s and the author of the key 2021 book The Problem of Alzheimer’s: How Science, Culture, and Politics Turned a Rare Disease into a Crisis and What We Can Do About It.

 

This book has helped me frame my efforts to understand the history of the HD cause in a broader, comparative light.

 

A deeply personal and fulfilling introduction

 

My participation in the DIAD Family Conference will help me to understand the strengths and weaknesses of the Huntington’s movement in comparison with others facing similar challenges. I hope that, however modestly, it helps point the way towards increased collaboration in the quest for therapies.

 

I look forward to learning more about early onset familial Alzheimer’s disease, its causes, and symptoms.

 

I was moved by the many stories of struggle, but also humor and optimism, from affected individuals and their families.

 

After this deeply personal and fulfilling introduction to the early onset Alzheimer’s community, I felt energized.

 

I look forward to when both communities can celebrate the discovery of therapies.

With the constitutional right to abortion gone, an uncertain medical future for Huntington’s disease families

With the U.S. Supreme Court’s radical toppling of long-standing abortion rights on June 24, families affected by Huntington’s disease and thousands of other rare and neurological disorders face a profoundly uncertain future regarding medical care in the United States.

 

The majority opinion in the 5-4 decision overturned the 1973 Roe v. Wade ruling, which was reaffirmed in the 1992 Planned Parenthood v. Casey decision. Those previous rulings guaranteed a woman’s right to an abortion before viability of the fetus.

 

Now, the authority to regulate abortion has been returned to Congress and the states. The court voted 6-3 in Dobbs v. Jackson Women’s Health, confirming a Mississippi ban on most abortions after fifteen weeks of pregnancy.

 

The majority position held that the Constitution does not confer a right to abortion.

 

Complicating a heart-wrenching situation

 

HD families have relied on prenatal genetic testing and abortion to prevent passing on the genetic mutation to their children. My mother died of HD in 2006, and I tested positive for the mutation in 1999.

 

In 2000, our gestating daughter tested negative for HD in the womb, forestalling the need for us to consider abortion. She just graduated from college.

 

Sadly, many families have lost children to juvenile HD (JHD).

 

Now, access to abortion will disappear or be severely restricted in almost two dozen states.

 

“This complicates an already incredibly difficult and heart-wrenching situation for women affected by HD,” leading advocate Lauren Holder wrote me in a Facebook message regarding the abortion ruling. An HD gene carrier, Holder has one at-risk child, and other who tested negative during the pregnancy. She lost her father Stephen Rose, Jr., 62, to HD last year.

 

“If I could recommend one thing, it would be to not let [our reaction] stand as just a sad or irate post on social media,” Holder urged. “If we want this to change, we have to be willing to speak up and advocate for ourselves, for women’s rights, at the state level now.”

 

Lauren Holder (left) with her late father Stephen Rose, Jr., who died of HD in 2021 (personal photo)

 

HD sheds light on bioethical challenges

 

As I reported in 2011 (click here and here), controversy over abortion in the HD community reflects the national societal divide.

 

However, confronting HD’s devastating symptoms and stigma, our community’s early and deep experience with genetic and prenatal testing, preimplantation genetic diagnosis (PGD), suicide, assisted suicide, euthanasia, disability legislation, mistreatment by the police, a crushing caregiving burden, and other challenges have made us bioethical pioneers.

 

Those issues include human embryonic stem cell research, crucial for developing a greater understanding of HD and potential therapies. I commented on religious leaders’ concern about the research in a September 2017 presentation on Pope Francis’s historic meeting the previous May with the HD community in Rome, where he declared HD to be “hidden no more.” My family and I attended.

 

Francis had encouraged the HD scientists present to avoid research involving human embryos, “inevitably causing their destruction.”

 

“Bioethicists, both within and without the [Catholic] Church, can learn from the HD community,” I asserted. “This is not an easy issue, but it requires dialogue. Unfortunately, some media outlets focused on this aspect of the meeting, ignoring the historic moment and how Francis exuded love towards us in the HD community.”

 

Defenders of the sanctity of human embryos continue to support a ban on this research.

 

Some abortion opponents have also proposed that embryos have legal status as persons.

 

PGD in jeopardy?

 

The blistering Supreme Court dissenting opinion by the three liberal justices described the decision as “catastrophic,” taking away women’s freedoms, threatening other rights, and eroding the court’s credibility.

 

Because of the majority’s position, the dissenting justices affirmed that the Supreme Court will “surely face critical questions” about how the ruling will be implemented.

 

“Further, the Court may face questions about the application of abortion regulations to medical care most people view as quite different from abortion,” the dissenting justices wrote. “What about the morning-after pill? IUDs? In vitro fertilization?”

 

Earlier this month, in anticipation of the expected overturn of the right to abortion, HD advocate Allie LaForce recognized that changes in the laws in some states might lead her and her untested, at-risk husband, Minnesota Twins baseball pitcher Joe Smith, to change their approach to assisting families with PGD through their foundation, HelpCureHD. PGD involves in vitro fertilization. LaForce is currently pregnant after using PGD.

 

LaForce and Smith have considered the possibility of paying for families to travel out of state for PGD if they live in a place that has restricted the practice. The extra cost might reduce the number of families HelpCureHD can help.

 

A cautionary tale from Brazil

 

Previously, I noted my long study of the disturbing history of abortion in Brazil, where it is illegal except in cases of rape and incest, danger to the life of the mother, and anencephaly, a fatal condition in which a fetus lacks a complete brain.

 

Each year, hundreds of thousands of women are hospitalized in Brazil because of complications of illegal abortions, and, overall, thousands have died. This tragedy provides a stark warning for the U.S. as it attempts to adjust to the Supreme Court decision.

 

I wholeheartedly agree with the emphasis on the medical – as opposed to religious ­– nature of the abortion question. I also believe in a woman and her family’s right to choose. In Brazil, I carefully studied – and came to identify with many of the ideas of – the local version of Catholics for a Free Choice.

 

The Supreme Court does not consider letters from the general public in its decisions. In April, I had begun exploring how to contribute to an amicus brief, which can only be filed by individuals or organizations registered with the court. I hoped to send a copy of an article I had published in 1995 in The Christian Century on abortion in Brazil as well as copies my blog articles on HD, abortion, and bioethics.

 

The stunning May 2 leak of the court’s draft majority decision made any potential input a moot point. The final version largely tracked the draft.

 

Respecting individual decisions

 

In the late 1990s, during a conversation about abortion with one group of poor women in a Rio de Janeiro slum, they told me: “cada caso é um caso,” that is, each woman’s situation is different.

 

After my 2011 articles on HD and abortion in the U.S., I came to that same conclusion after reflecting on the contrasting predicaments of the couple who aborted their gene-positive child and the 20-year-old JHD-affected woman who decided to have her untested, at-risk baby.

 

In the immediate aftermath of the news of the abortion decision, I was struck by the comments of Phil Metzger, the lead pastor of Calvary San Diego, a local Christian church

 

“My reaction is mixed, which you might not expect to hear from a pastor of a church,” Metzger said in a radio interview. While the decision was a victory for abortion opponents, it was also a moment to remember those struggling with the reversal of Roe v. Wade, he observed.

 

“Every place, I don’t care what institution it is, statistically, somebody in that group had an abortion,” Metzger continued. “So we have to ask ourselves, ‘Are they my enemy?’ They're not. And whatever reason brought them to making these hard choices, God loves them.”

 

Metzger’s words echo the middle ground sought by some in the abortion debate but drowned out by the fierce political and legal battles.

 

Sadly, the “hard choices” just got immeasurably harder for many women, especially those disadvantaged by poverty and, now, distance from the states where abortion will remain legal for at least the time being.