Continued progress, but also caution, in the fight against Huntington’s disease

CHDI Foundation’s 14th Annual Huntington’s Disease Therapeutics Conference gets under­­ way today in Palm Springs, CA, in the wake of key developments in the search for the first HD treatments.

On January 28, pharma giant Roche announced that it had enrolled the first participant in GENERATION HD1, its historic global Phase 3 clinical trial of a gene-silencing drug that, if successful, could slow, halt, and perhaps even reverse HD symptoms. (Click here to read the announcement to the HD community by Roche ).

In the coming months, Roche aims to enroll a total of 660 clinical trial volunteers in 15 countries. They will receive either the drug (called RG6042) or a placebo in monthly spinal taps over 25 months.

The start of the trial comes less than a year after the presentation of the impressive Phase 1 trial results at last year’s Therapeutics Conference. RG6042 significantly reduced the levels of the mutant huntingtin protein in the cerebrospinal fluid of the clinical trial volunteers. Because of those results, Roche took the unusual step of skipping a Phase 2 trial and going directly to Phase 3.

Roche’s announcement follows a record year for new drug approval by the U.S. Food and Drug Administration (FDA), with 59 drug approvals overall, noted George Yohrling, Ph.D., the senior director of mission and scientific affairs for the Huntington’s Disease Society of America (HDSA). The previous record was 53 in 1996.

Of last year’s approvals, 34 involved orphan conditions like HD (fewer than 200,000 patients) – a sign, said Dr. Yohrling, that the pharmaceutical industry has not ignored those disease communities. He spoke in a January 16 webinar reviewing progress in HD research in 2018.

Roche to buy Spark

On February 23, The Wall Street Journal reported that Roche had agreed to pay $4.8 billion to acquire Spark Therapeutics, Inc., a Philadelphia-based biotech firm focusing on gene therapy approaches to genetic diseases, including HD. Spark’s co-founders include HD researcher Beverly Davidson, Ph.D.

With a record 360 participants from around the world, the CHDI conference opens this evening at the Parker Palm Springs hotel and runs through February 28. At the conference, I hope to obtain comment from Roche officials about how the acquisition could potentially expand Roche’s approaches to treating HD. Spark has engaged in pre-clinical HD research.

Above, scientists visit the CHDI Resource Fair at the 14th Annual HD Therapeutics Conference. Below, Gene Veritas (aka Kenneth P. Serbin) at the Parker Palm Springs (photos by Gene Veritas).

Exciting announcements about other trials

On January 22, the Dutch-American company uniQure announced that it had received approval from the FDA to start the first-ever HD clinical trial that uses a virus injected into the brain carrying a gene therapy agent to reduce the amount of harmful huntingtin protein. Viruses are used in vaccines and to treat cancer. They are under study for use in HD and other diseases. 

Unlike Roche’s RG6042, which would require long-term and probably lifelong treatment, uniQure’s gene therapy could permanently fix the problem of HD by “altering human DNA or inserting new genetic instructions into human cells,” observed HDBuzz.

However, it also noted that “gene therapy is a high-risk high-reward strategy. The benefits could be long-lasting – but so could any side effects.”

In this Phase 1/2 clinical trial, uniQure will primarily test safety and tolerability but also whether its drug is working as designed. It plans to start enrolling clinical trial volunteers in the U.S. in the second half of this year.

In late January, the California Institute for Regenerative Medicine (CIRM), the state’s voter-approved multi-billion stem cell initiative, announced a $6 million grant to prepare the way for a potential HD stem cell clinical trial. CIRM awarded the grant to the lab of Leslie Thompson, Ph.D., of the University of California, Irvine. The therapy could involve the transplanting of stem cells converted into neural (brain) stem cells shown in HD animal models to improve the function of compromised brain cells.

"Based on our pre-clinical studies in mice, human neural stem cells are highly beneficial, reducing the accumulation of a toxic form of the mutant huntingtin protein and improving HD symptoms and impaired electrical currents in the brain," Dr. Thompson explained in a news release.

FDA delays Wave trials

Another company’s plans have been slowed. The FDA has delayed two Phase 1 clinical trial by Wave Life Sciences using a drug – an antisense oligonucleotide – similar to Roche’s RG6042.

Whereas RG6042 reduces the amount of both mutant and normal huntingtin protein, Wave’s drugs target only the mutant.

“In the United States, we received approvals to proceed with the single-dose portions of both trials,” a February 6 Wave prospectus states. “However, the FDA indicated to us that we cannot progress to the multiple-ascending dose portions of these trials in the United States unless we conduct an additional preclinical [animal] study and present the resulting data to the FDA for its review.”

Realistic expectations

The news about Wave might be a cautionary tale for the HD community about realistic expectations. Only ten percent of clinical trial projects result in a drug reaching the market.

Alzheimer’s disease is another case in point. Over the past ten years, all 25 Alzheimer’s clinical trials have failed, noted Jody Corey-Bloom, M.D., Ph.D., the director of the HDSA Center of Excellence at the University of California, San Diego (UCSD), during her annual HD research update last October at the local HD support group.

As Dr. Corey-Bloom explained, most of those Alzheimer’s trials successfully removed seemingly harmful plaque from the brain, but they didn’t cure the disease. 

Such plaque isn’t a factor in HD, however, perhaps increasing hope that the Roche Phase 3 trial has a better chance of producing effective results, she observed. Dr. Corey-Bloom’s well-regarded UCSD clinic is one of the sites for GENERATION HD1.

An end to the ‘wait and see’?

In her presentation, Dr. Corey-Bloom addressed several of the key questions about GENERATION HD1 that have emerged in the HD community, including concerns about the injection of the drug by spinal tap (lumbar puncture).

She noted that spinal taps are a regular part of treating a condition known as pseudotumor cerebri, which produces severe headaches and, if left untreated, blindness. Patients get monthly spinal taps.

“We’ve had people that have probably done lumbar punctures monthly for several years, and they seem to do okay,” she commented.

She was optimistic that, if GENERATION HD1 is successful, Roche and physicians will seek alternatives to spinal taps. They will also pursue expanding access to the drug to presymptomatic gene carriers, she added. (That includes me.)

Dr. Corey-Bloom ended on a positive note.

“I’m always talking about things that will eventually come,” said of previous talks, in which she has cautioned the HD community against unwarranted enthusiasm. “Now we actually have clinical trials, and we have clinical trials that look like they are going to be effective. That’s probably the strongest statement that I’ve made, because I’m always trying to tell people, ‘Let’s just wait and see.’”

However, with the Alzheimer’s trials in mind, Dr. Corey-Bloom also reminded the audience that there is no guarantee GENERATION HD1 will actually affect the disease.

She crossed her fingers for good luck. We in the HD community will need to continue our hard work collaborating with her and the many other researchers engaged in the quest for treatments.

You can watch Dr. Corey-Bloom’s presentation in the video below.

Advocacy pays off: Huntington’s disease stem-cell research advances in California

Grass-roots advocacy for Huntington’s disease stem-cell research is paying off.

Using funds from the state of California secured with the help of advocates, leading HD stem-cell scientists are taking important steps towards developing potential ways to treat, reverse, and perhaps even cure HD.

These funds come from the California Institute for Regenerative Medicine (CIRM), the $3 billion initiative approved by the state’s voters in November 2004 to establish grants and loans for stem-cell research aimed at rapidly developing treatments for a host of diseases.

Leading stem-cell advocates had successfully worked to get the measure on the ballot as a state initiative after President George W. Bush had signed an order blocking the establishment of new human embryonic stem-cell lines, which scientists needed to expand research in the field. President Barack Obama later rescinded that order.

CIRM projects have spurred the creation of new embryonic stem-cell research, as well as other kinds of stem cells.

Millions in funding

While the CIRM oversight board has representatives concerned with Alzheimer’s disease and diabetes, among other conditions, it has no representative from the Huntington’s disease community.

Nevertheless, in 2007, as CIRM prepared to award its first research grants, California’s grass-roots HD activists began campaigning for the board to address Huntington’s stem-cell projects.

In October of that year, I arranged for Bill Johnston, the public relations director of the San Diego Chargers and the president of the San Diego Chapter of the Huntington’s Disease Society of America, to appeal to the oversight board during a public meeting in San Diego. As he spoke, Johnston held his wife Ramona, who has HD. This was the very first time that a member of the HD community had appeared before the board.

I also spearheaded the organization of the December 2007 CIRM “Spotlight on Huntington’s Disease,” held at the University of California, Los Angeles. The presentation included talks by two leading scientists, as well as a plea for HD research from activist Frances Saldaña and her daughter Margie Hayes, one of three siblings who developed juvenile HD and the mother of two at-risk children. (For more on these first meetings, click here.)

As mother Frances Saldaña (left) looks on, Margie Hayes tells about her struggle against HD at the CIRM Spotlight on Huntington's Disease, Los Angeles, December 12, 2007 (photo by Gene Veritas).

CIRM President Dr. Alan Trounson (left) with Alexa Shaffer and mother Sharon. Sharon has HD, and Alexa is at risk. They told their stories at a CIRM board meeting in San Diego on September 25, 2008 (photo by Gene Veritas).

Advocates throughout California joined hands in this cause, with other HD family members speaking before the oversight board at its regular public meetings in different parts of the state. (For the sake of brevity, I won’t list the names of the numerous dedicated individuals involved in these efforts.)

Together with the researchers’ meticulously prepared grant applications, this advocacy has generated solid results: to date, HD stem-cell research projects, based mainly at the University of California, Davis (UC Davis), and the University of California, Irvine (UCI), have received $7.9 million in CIRM funding.

Striving for an HD ‘Disease Team’

Tomorrow, January 24, Jan Nolta, Ph.D., the director of the UC Davis Institute for Regenerative Cures, will submit an application to CIRM for a $20 million project to fund an HD “Disease Team.” The team will aim to develop the very first human clinical trial for an HD stem-cell treatment, which would involve attacking the disease at its genetic roots and infusing the brain with an important growth factor known as BDNF.

Just last month, Dr. Nolta published a scientific article demonstrating promising results in pre-clinical experiments, which must precede human trials (click here to read more).

Dr. Nolta uses a well-known type of stem cells, called “mesenchymal stem cells.” A long-time expert on these cells, Dr. Nolta refers to them as “paramedics” because of the way they congregate around and repair damaged cells.

Dr. Nolta at the HD bench at the Institute for Regenerative Cures (photo by Gene Veritas)

Last May I spent a day interviewing Dr. Nolta and observing the work of the UC Davis institute, co-founded by the university and CIRM (click here to read more about my visit and Dr. Nolta’s work).

Once again, we will mobilize our California network of advocates, this time in support of the HD Disease Team application. We want to stress the urgency of finding treatments for this killer disease and the importance of HD research in advancing the stem-cell field.

New stem-cell lines

At UCI, HD stem-cell research has progressed rapidly under the leadership of Dr. Leslie Thompson, a professor in the UCI School of Medicine’s Departments of Psychiatry and Human Behavior, the interim director of the Center for Mitochondrial and Molecular Medicine and Genetics, and a holder of various other positions within the university.

With one CIRM grant of $900,000, awarded in 2008, Dr. Thompson and her researchers are creating new neuronal (brain) stem cells. They produce these cells by taking skin-cell samples from both HD-affected and non-HD people, “reprogramming” them to become stem cells, and then “differentiating” them into the neuronal stem cells.

From these new cells, they eventually hope to obtain medium spiny neurons, the kind of brain cell most affected by HD. The disease occurs because these cells malfunction, become damaged, and die. Using the neuronal stem cells, the research team can study HD at work in a live, real-time human setting.

This grant also funds research on human stem cells taken from embryos discarded by couples who underwent PGD (preimplantation genetic diagnosis) in order to have HD-free children. In this project, Dr. Thompson and her researchers have succeeded in establishing one new line of human embryonic stem cells, which will be used to study HD.

Announced in late 2010, a second CIRM grant of $3.8 million funds a UCI project that seeks to develop a stem-cell treatment for study in HD mice. The initial experiments in this project demonstrate that the mice’s symptoms improve after the introduction of mouse stem cells into their brains. The second stage is examining the effect of human stem cells on the mouse brains.

Later, Dr. Thompson hopes to apply for another HD Disease Team grant to develop ways to apply her research for potential stem-cell treatments in humans.

In future articles, I will explore in greater depth how Dr. Nolta’s and Dr. Thompson’s respective projects could lead to effective treatments.

The impact of our work

Interviewing Dr. Thompson in her office on January 20, I felt a deep sense of accomplishment.

In an instant, I felt as if time had fast-forwarded me from 2007, when she and I prepared intensely to organize the CIRM Spotlight on HD, to the present, when the results of the statewide advocacy efforts are blooming in the UCI labs.

I had advocated with and for Dr. Thompson, and now I was sitting across from her and hearing good news.

Dr. Thompson (left) with Frances Saldaña at the Huntington's Study Group meeting in San Diego, October 16, 2010 (photo by Gene Veritas)

In voting for the CIRM, and then advocating for specific HD projects, we had achieved a historic breakthrough for HD research.

In hearing Dr. Thompson discuss the establishment of a new stem-cell line from the PGD embryos, I felt how profoundly political our advocacy has been, and how it directly impacts the quest for treatments and a cure.

The moment was exhilarating.

Gene Veritas: Back when the big controversy was occurring, when Bush said, “No more new lines,” this is a --

Leslie Thompson: A new line.

GV: This is a new line that, thanks to the CIRM and the law in California, was supposed to occur.

LT: Thanks to the CIRM. Correct.

GV: So we’re seeing an actual impact of a political decision here to do something.

LT: Yes. All of it. All of [the stem-cell work]. Because we wouldn’t be able to do this work without CIRM funding.

We can all advocate for the cause

Advocacy is one of the biggest challenges for the HD movement. It demands long hours of preparation, the study of complex issues, networking, and efforts to gain access to public officials and other powerful individuals.

It also requires patience, dedication, and teamwork. We California advocates have recognized these requirements and tried our best to practice them.

On the stem-cell front, we have in our favor a great set of universities with top-flight scientists like Dr. Nolta and Dr. Thompson. Both are well-known in the HD community, and both dedicate time outside of work to supporting it. Dr. Thompson finds inspiration in HD families. A newcomer to HD research, Dr. Nolta took on this new field after coming into contact with the local HD medical specialist, Dr. Vicki Wheelock, and the community she serves.

Advocates and scientists have meshed well throughout the crusade for stem-cell treatments.

Finally, I believe our advocacy has proved effective because of the willingness of affected families to tell their stories in public – despite the pain or awkwardness it might cause – at CIRM meetings and to the doctors and physicians involved in HD research.

All of us in the HD community can become advocates. We need people to work on all levels – from meeting with government officials to writing letters. And we must always speak out.

You never know. Someone with the willingness and resources to help might just be listening. You can inspire that person to act.

(To learn more about California HD advocacy, please click here. To learn about national advocacy efforts, please click here.)