Combatting the pandemic, Roche also forges ahead with critical Phase 3 Huntington’s disease clinical trial

Using its expertise to combat a coronavirus pandemic that has left more than 180,000 people dead worldwide and a third of the earth’s people on lockdown, pharmaceutical giant Roche is also forging ahead with its Phase 3 clinical trial for the Huntington’s disease gene silencing drug RG6042, now known by the generic name tominersen.

The final step in a clinical trial program, Phase 3 tests the efficacy of a drug. A successful Phase 3 allows a pharmaceutical company to apply to regulatory agencies for permission to market the drug. In a time of “social distancing” and a shutdown of normal life, Roche and HD clinical trial administrators are seeking to mitigate the risks associated with the spread of COVID-19, the disease caused by the coronavirus.

In an April 20 letter to the global HD community, Roche announced that it had completed recruitment for the trial, GENERATION HD1. A total of 791 symptomatic volunteers across 18 countries have been enrolled, just ten fewer people than Roche projected after the trial got under way last year – almost 99 percent of the target.

“This achievement is a result of the HD community’s commitment from the beginning, and we are very grateful to all trial participants, their families, the clinical trial sites and staff, and the broader HD community who have supported the design, initiation and recruitment phases of the study,” Roche global patient partnership directors David West and Mai-Lise Nguyen stated in the letter.

West and Nguyen reassured the community that “tominersen studies are ongoing at clinical trial sites around the world,” and, in collaboration with local health authorities, “ensuring patient safety and data integrity throughout the studies given the ongoing impact of COVID-19.”

On February 27, Roche announced the generic name for its HD gene-silencing drug candidate RG6042, formerly known as IONIS-HTT_Rx, developed by Ionis Pharmaceuticals, Inc. With assistance from Roche, Ionis ran the successful Phase 1/2a trial for the compound, shown to be safe and tolerable in trial participants. It also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid. (Slide courtesy of Roche.) 

Aiming to analyze data in 2022

“Given the dynamic situation with COVID-19, we decided to close recruitment at 791 participants globally in order to avoid additional pressure on clinical trial sites who were screening potential participants,” they added, noting that the number of participants is “sufficient” to assess tominersen’s efficacy.

Roche is “working closely with the research teams, trial sites and local authorities to reduce any new risks posed by COVID-19 and ensure the trial can continue as long as it is safe to do so,” the letter stated. Roche advises participants to “discuss individual circumstances with their respective study sites.”

“Where patients and families can no longer go into [the] hospital to receive treatment or assessments, research teams will be in close contact over the phone to monitor their health and discuss any potential adverse events or any other issues,” the letter added.

Roche expects to complete the trial and start analyzing data by 2022, after each of the volunteers has completed the 25-month program involving intrathecal (spinal) injections of tominersen or a placebo, tests, medical evaluations, and digital monitoring, West and Nguyen stated.

If tominersen demonstrates efficacy and safety, Roche will submit applications to national health authorities to obtain approval as a treatment.

“During these exceptional times, we continue to consider how we can best support the community and welcome any suggestions,” the letter concluded.

In an April 21 e-mail to me, West noted that GENERATION HD1 recruitment was “completed within expected timelines,” unaffected by the COVID-19 crisis. In line with plans announced last October, Roche will also extend the study to China “as soon as possible,” West added.

Combatting COVID-19

The April 20 statement on GENERATION HD1 followed a general statement by Roche on March 19 discussing the March 11 announcement of the pandemic by the World Health Organization and the company’s efforts to combat it.

“We recognise that the public and private sectors across the globe need to work together to help effectively manage this developing situation,” said the statement, noting that Roche was engaged in developing a COVID-19 “diagnostics test which was granted Emergency Use Authorization by the U.S. Food and Drug Administration.”

Scientists, physicians, and public officials have stated repeatedly that vastly increased testing for the virus is needed in the battle against the pandemic.

Roche also confirmed initiation of COVACTA, a global Phase 3 clinical trial to evaluate the safety and efficacy of its rheumatoid arthritis drug Actemra/RoActemra in treating patients with severe COVID-19 pneumonia. The study started to enroll patients on April 3, with a target of 330 globally, including the U.S., Canada, and Europe.

Roche is also examining other drugs in its portfolio for potential testing to treat COVID-19.

(Click here to read more on Roche’s efforts against the coronavirus.)

A key supplementary trial

The February 27 announcement of the generic name tominersen took place at the 15th Annual Huntington’s Disease Therapeutics Conference, sponsored by CHDI Foundation, Inc., in Palm Springs, CA. (For an overview of the conference, click here.)

Scott Schobel, M.D., M.Sc., Roche’s associate group medical director and medical leader of the GENERATION HD1 effort, introduced the name when presenting the preliminary results of the so-called open label extension study (OLE) study of the compound. For 15 months, Roche continued to give the drug to all of the 46 participants of the successful Ionis trial, completed in December 2017. That same day, Roche posted the slides of Dr. Schobel’s presentation on its website.

The OLE reinforced the findings of the Phase 1/2a trial, which showed tominersen to be safe and tolerable in trial participants. Tominersen also lowered the amount of mutant huntingtin protein, a major suspect in the disease, in volunteers’ cerebrospinal fluid.

Also, when still in progress in early 2019, the OLE led Roche to temporarily halt GENERATION HD1 to redesign it in line with the OLE’s promising early data. 

In the original GENERATION HD1 design, participants would undergo monthly spinal tap (lumbar puncture) procedures over 25 months. One-third of participants would receive tominersen each month and one-third every other month. Another third would get a placebo.

In the updated trial, which resumed in June 2019, Roche decreased lumbar punctures to once every other month over the same period of time. In this revised design, one-third of participants are receiving tominersen every other month and one-third every four months. Another third will receive a placebo every other month. (Click here to read more.)

Less frequent dosing eases the burden on participants, their families, and clinical trial administrators.

The OLE also investigated potential biomarkers (signs of the disease and drug efficacy) for use in GENERATION HD1.

The OLE formed part of Roche’s strategy for skipping the usual Phase 2 trial to test efficacy and entering directly into Phase 3 to confirm efficacy in a larger population (click here to read more).

Scott Schobel, M.D., M.Sc., presenting open label extension study data for tominersen at the 15th Annual HD Therapeutics Conference (photo by Gene Veritas)

The ‘ultimate’ question: efficacy

After his presentation, Dr. Schobel met briefly with HD advocates to discuss his presentation and GENERATION HD1.

For the HD community, the takeaway message was the OLE’s confirmation of a less frequent dosage, and its helpful data for GENERATION HD1. Except for one person who decided to drop out to take a trip around the world, all of the OLE participants had continued taking the drug, putting them now at 20 months of follow-up, he explained.

Roche has great “confidence” in the sufficiency of the less frequent dosing in GENERATION HD1, Dr. Schobel emphasized.

With the OLE, Roche has “been able to learn” and apply it directly to GENERATION HD1 “in a way that we couldn’t have done if did a more traditional drug development path, which we feel great about,” he said.

What remains is the “ultimate” question: will tominersen be an effective treatment?

“We’re well-positioned with GENERATION HD1 to answer that question,” Dr. Schobel concluded.

If the trial is successful, tominersen will become the first treatment to slow, halt, and perhaps even reverse the symptoms of Huntington’s disease. 

(I hope to report soon on other ways in which COVID-19 has impacted the HD community and research.)

(Disclosure: I hold a symbolic amount of Ionis shares.)

At Therapeutics Conference, landmark study of young gene carriers highlights how Huntington’s disease researchers seek to solve critical puzzles

Armed with ever more impressive data and a deeper understanding of Huntington’s disease, scientists and drug hunters convened at the 15th Annual HD Therapeutics Conference this week, facing the complex puzzles that still hinder the quest for treatments for this deadly neurological disorder.

One of those puzzles: how to not only treat symptoms, but to prevent them, especially in young presymptomatic carriers of the HD gene, so that they don’t have to spend their lives fearing the currently inevitable onset of this devastating disease.

On February 26, Sarah Tabrizi, FRCP, Ph.D., of University College London, answered key questions about what kinds of health consequences young presymptomatic gene carriers suffer decades before they’re likely to develop the disease in midlife.

Previous studies have demonstrated that brain shrinkage can occur as early as 15 to 18 years before predicted age of onset. Ranging in age from 18-40, the 64 gene carriers in Dr. Tabrizi’s HD Young Adult Study went through state-of-the art brain scans and cognitive testing, and also provided samples of blood and cerebrospinal fluid (CSF) for analysis. These at-risk volunteers are, on average, 24 years from estimated onset.

This study, in line with “The Path to Prevention” (one of five major themes of the 2020 conference), is aimed at helping identify the optimal time to treat gene carriers to slow or prevent their neurological decline.

“Comprehensive cognitive testing was normal,” as compared to 67 non-HD-affected individuals, reported Dr. Tabrizi in her presentation to the conference. “There were no significant psychiatric differences, which I found very interesting, because I would have predicted they would’ve been big differences.”

Dr. Tabrizi said that "there’s always been a thought that carrying the HD gene hard-wired you for psychiatric burden,” but the Young Adult Study suggests that such symptoms become more prominent closer to onset.

“I think that was – and I don’t say this lightly – a landmark presentation,” Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me today, adding that Dr. Tabrizi’s team carried out the study with “a high degree of rigor and granularity.”

“The participants seem to be remarkably well,” Dr. Pacifici observed. The absence of many of the neurological and other problems typical of HD is an encouraging prospect for developing safe and well-tolerated treatments that could “not just reverse, but actually prevent” HD, he said.

Dr. Pacifici lauded the study volunteers for their "unbelievably selfless participation," including submitting to the study's "incredibly rigorous battery."

Above, Dr. Sarah Tabrizi presenting her talk on the HD Young Adult Study at the 2020 HD Therapeutics Conference, February 26, 2020, and, below, a closeup of Dr. Tabrizi (photos by Gene Veritas, aka Kenneth P. Serbin)

Overall, ‘good news’ for young gene carriers

The young gene carriers in the study did appear to go through a small change in the area of the forebrain known as the striatum, consisting primarily of the putamen and the caudate, the deep brain regions that are most affected by HD. The striatum helps to control our movements and rewards system.

The study found a significant reduction in the size of the putamen, but an insignificant reduction in the caudate. Nevertheless, Dr. Tabrizi explained that, based on this study, these differences (in comparison with the normal subjects) were “not associated with predicted years to onset.”

“So what we now know, based on the data, is that the striatum never appears to be the same size as the control group,” she explained. 

The “very slightly smaller” striatum may suggest a “neurodevelopmental effect” (the way the brain develops) that is “well compensated for,” Dr. Tabrizi said, meaning that the brain adjusts without clear damage. She added that it “might be why the striatum is vulnerable later in life, because it has a double hit.” As mentioned by Dr. Tabrizi, this interpretation resonates with the research of Peg Nopoulos, M.D., who has studied the compromised development of the brains of people affected by juvenile HD.

Alternatively, neurodegeneration early on could be “too subtle and variable” to associate with predicated age of onset, Dr. Tabrizi noted.

Other imaging results showed no decrease in the white matter (the tissue in the brain made of nerve fibers and possibly involved in cognitive problems in HD) or any other aspect of the brain measured in the study, indicating that the subjects were still “very far from onset,” Dr. Tabrizi continued.

“This is really good news,” Dr. Tabrizi stated.

Douglas Langbehn, M.D., Ph.D., a psychiatrist and biostatistician at the University of Iowa who did the statistical analysis for the HD Young Adult Study, listens to Dr. Tabrizi at the Therapeutics Conference (photo by Gene Veritas).

The ongoing search for reliable biomarkers

The study also involved the ongoing search for reliable biomarkers (signs of disease and drug efficacy).

The study detected mutant huntingtin protein in the subjects’ cerebrospinal fluid. “CSF mutant huntingtin was higher in those closer to [predicted] onset, suggesting that some injury is releasing mutant huntingtin [from the brain], but very subtle,” Dr. Tabrizi said.

Several other biomarkers were elevated in the subjects’ CSF, again indicating an early, subtle injury, but most of those subjects had readings showing levels very close to those of the unaffected control subjects, Dr. Tabrizi continued. Furthermore, six other biomarkers were normal, she added.

The Young Adult Study points to the one CSF biomarker in particular, neurofilament light, a marker of brain damage, as potentially helpful in measuring disease progression and treatment response in people decades from onset, Dr. Tabrizi concluded.

A drug that kept neurofilament light at very low levels could prevent degeneration of the brain, she added.

You can watch Dr. Tabrizi’s presentation in the video below.

A moving keynote address

With a record attendance of 380, the conference opened on February 24 with a moving keynote speech by Amy Merkel, a 45-year-old nurse from Wisconsin and the founder of Starfish Yoga.

A small company, Starfish focuses on encouraging constructive coping skills, primarily for people affected by past imprisonment, sexual abuse, and neurological disorders, including HD.

Amy, who titled her talk “Life is Good,” belongs to a family deeply affected by HD. She recounted her extended family’s decades-long struggles with HD. Amy received a standing ovation.

Stay tuned to this blog for additional reporting on the conference, including an overview provided in my interview with Dr. Pacifici.

Above, HD advocate Amy Merkel addresses the 15th Annual Therapeutics Conference, and, below, poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (photos by Gene Veritas).

An ‘electric,’ inspiring Thanksgiving for the Huntington’s disease community

Thanksgiving is my favorite holiday. I’ve reflected on it many times in this blog. For me, rather than the commercialism and stress associated with the holidays, it’s truly a day of relaxation, the warmth of friends and family, and gratitude.

This year, the Huntington’s disease community has bountiful reasons for thanks. Several clinical trials to test what might become the first effective treatments are in progress, and the community has demonstrated spirited participation.

The historic Roche gene-silencing program successfully started its crucial third and final phase, GENERATION HD1, earlier this year. The program includes an open-label extension of all 46 participants in the first phase, completed in December 2017, all of them receiving the drug RG6042 via a monthly injection into the cerebrospinal fluid (CSF).

“Two years ago, we showed for the first time – about 25 years after the discovery of the gene –the ability to lower CSF levels of mutant huntingtin [protein] in patients with HD, which was a very exciting first-in-human accomplishment, and that was really the springboard that allowed us to proceed to our global development program,” Scott Schobel, M.D., M.S., Roche’s associate group medical director and clinical science leader for RG6042, reported at the 26th annual Huntington Study Group (HSG) meeting on November 8. “So these heroic 46 volunteers were the foundation of that.”

GENERATION HD1 is “recruiting incredibly well,” Dr. Schobel said. “It’s been absolutely electric.” Total worldwide enrollment in GENERATION HD1 and related studies has surpassed 800. “It’s been a huge response from the community,” he added.

Several other programs provided updates at the HSG meeting.

Although much work remains to develop effective therapies, HD families and their supporters can feel proud for helping further the progress achieved in 2019.

Priscilla’s inspiring fight and peaceful paintings

An HD-stricken woman I know from Brazil, Priscilla Ferraz Fontes Santos, embodies the life-force of the HD cause. I saw Priscilla in 2013 at the sixth World Congress on Huntington’s Disease in Rio de Janeiro, and got to know her at #HDdennomore, Pope Francis’ special audience with the HD community in Rome in 2017.

Brazilians don’t celebrate Thanksgiving, but Priscilla’s words, paintings, and photos help us feel the peace and hope of our quintessentially American holiday.

Priscilla was stricken with juvenile HD as a teenager. She had played soccer, pursued acting, and completed her journalism degree, but the disease prevented her from finishing a second degree in tourism.

Many juvenile patients do not live past 30. Priscilla is 36. She takes no drugs to control her involuntary movements and other symptoms but instead relies on alternative and spiritual approaches, including yoga. However, she also follows HD clinical trials and hopes for a cure.

Starting November 22 and ending December 10, Priscilla and her art teacher are staging an exhibit of Priscilla’s paintings in Serra Grande, a town in the state of Bahia. They have called it “Colored Atmosphere.”

Priscilla with two of her paintings (family photo)

“The past two and a half years, I have been taking painting and art classes, and I have discovered for myself the pleasure and well-being that painting brings,” Priscilla wrote in an introduction to the exhibit. “As I await the cure, I have gained the courage to overcome many difficulties and meet challenges with the ever-present support of my family, friends, and health professionals who care for me.”

Priscilla ended with this wish: “I hope that you enjoy my paintings and that they awaken in you all of the strength, beauty, and joy with which I painted them.” (I translated the text from the original Portuguese.)

Priscilla is an “inspiration of strength and positive thinking” for all of us, Priscilla’s mother Lígia wrote in a message in Brazilian WhatsApp group dedicated to the HD cause.

Priscilla practicing yoga (family photo)

Symptom-free, but awaiting treatments

As always, I am profoundly grateful for not having yet developed any of the inevitable classic symptoms of HD, which struck my mother in her late 40s and ended her life at 68.

I turn 60 next month – an age at which my mother had full-blown HD and could no longer care for herself.

Last week, I presented my new book on Brazilian history to an audience at the University of San Diego. I had never imagined I would still be able to write at age 60.

Even more importantly, I’m able to continue supporting and loving my wife Regina and daughter Bianca. A sophomore at the University of Pennsylvania and HD-free, Bianca will spend Thanksgiving with friends in Connecticut. However, in a few weeks she will be home for winter break.

I am crossing my fingers that GENERATION HD1 and other trials can produce an effective treatment – and that I can hold on long enough to benefit and share more precious time with my family.

Unraveling the mysteries of the mitochondria in Huntington’s disease – and getting fast, clear, and useful results from research studies

In the collaborative quest for Huntington’s disease treatments, deepening affected families’ understanding of the key scientific challenges is vital. It can demystify the process of research, inspire involvement in investigative studies and clinical trials, and ultimately bolster the chances of defeating this horrible malady.

Noting the global nature of HD research, last month I highlighted key work on the West Coast of the United States. Andrew F. Leuchter, M.D., and Michael Levine, Ph.D., plan to measure brain energy waves to decipher the signals emitting from HD-affected individuals. Their work could ultimately lead to new drugs (click here to read more).

On the East Coast, at the Magnetic Resonance Research Center (MRRC) of the Yale School of Medicine, Doug Rothman, Ph.D., and his collaborators will conduct two unique studies that seek to unravel long-standing mysteries about Huntington’s and the mitochondria, the complex powerhouses of most of our cells.

“All the brain cells depend on them very heavily,” Dr. Rothman said during an interview at the MRRC on April 12.

Mitochondria came onto the evolutionary path about a billion years ago, he noted. They use oxygen to burn fuels (such as glucose, or common sugar) to provide energy for brain cells. In focusing on the mitochondria, Dr. Rothman’s studies aim to shed light on the serious energy deficits caused in HD and to provide tools for improving clinical trials.

As the Huntington’s community ramps up to a growing number of those trials, the paramount work of these scientists can help insure clear and useful results.

A mitochondrian (Wikipedia diagram by Mariana Ruiz Villarreal)

Novel and unique human studies

In people carrying the HD genetic abnormality, why do so many brain cells become damaged and eventually die, leading to HD symptoms? For decades, scientists researching this question mainly in animals and cell cultures have found much evidence implicating the mitochondria in the cells’ problems. However, they still don’t know exactly what the problem is.

Using the latest brain-scan technology, Dr. Rothman’s studies will involve human participants. They will focus on the mitochondria and the decline in cellular energy production, one of the main characteristics of HD.

“Anything that impairs the energy supply will severely impact brain function and will eventually impact cellular health,” Dr. Rothman said, adding that researchers suspect that mitochondrial dysfunction plays a part in many other neurological disorders.

Doug Rothman, Ph.D. (photo by Gene Veritas)

The first study seeks to identify a mitochondria-linked biomarker (a sign of disease or a disease mechanism) that could lead to a faster, more efficient way of testing potential HD remedies. The second aims to answer a major question: are less active mitochondria a cause or an effect of the disease?

“There’s lots of preclinical studies that suggest mitochondrial alterations,” Dr. Rothman said, referring to animal studies. “What’s nice is that the MR [magnetic resonance] technology allows this aspect of mitochondrial function to be measured non-invasively in vivo.”

These studies are “novel” and “unique” because they will involve “patients who have the gene,” he added. “Before it would have to be done on a preclinical model. There was no way to directly study humans until the development of the MR technology.”

Described below, the specific types of MR scans in Dr. Rothman’s studies will be used on HD-affected individuals for the first time, he said.

Pioneering the technology

Dr. Rothman helped pioneer this technology. It is recognizable to most people in the form of the MRI scanners that became common in medical diagnostics worldwide over the past two decades.

In working toward his Ph.D. at Yale, received in 1987, Dr. Rothman specialized in a technique known as NMR, nuclear magnetic resonance.  When used in humans NMR is now referred to as MRS, magnetic resonance spectroscopy. He and other specialists have applied MRS to the study of disease. In 1989 he was appointed to the Yale Medical School faculty, and in 1995 he became the director of the Magnetic Resonance Research Center.

As researchers refine these techniques, they have become ever more capable of picking up the resonance – literally a radio frequency – of the chemicals that make up living organisms, including humans.

In both MRS and the more familiar MRI, radio pulses are given to subjects inside huge magnets.  The radio pulses excite (stimulate) chemicals in the body while a person lies in the machine, analogous to a bell being struck. Each compound then resonates (again analogous to a bell) at a characteristic radio frequency. By measuring the radio signal from the different resonating chemicals the chemical composition of different brain regions can be determined.

Dr. Rothman stressed that the technology is safe. “You’re not exposed to any radiation at all – literally just radio frequency,” he said of the scanners, which detect the radio frequencies coming out of the body.

“You literally could set up an FM radio and pick these up,” he continued. “Really, the system’s main difference from a standard radio is just the sensitivity and stability, because we’re talking about very small differences of frequency, as opposed to say a megahertz, as you have in FM radio.”

The scanner sends the readings to a computer for analysis.

Understanding brain metabolism

Using MRS, Dr. Rothman and his colleagues at the MRRC contributed to breakthroughs in understanding the biochemistry of type 2 diabetes. He also helped make important discoveries about the biochemistry of the liver and muscles.

At the same time, he and others discovered ways to measure levels of chemicals in the brain. Those chemicals included metabolites, which provide energy, and neurotransmitters, which are involved in signaling between brain cells.

For the first time in human brain scans, Dr. Rothman and his colleagues detected key chemicals such as ethanol and glucose. They also saw the major neurotransmitters glutamate and GABA (gamma aminobutryric acid), substances mentioned frequently in the world of HD research.

This group of scientists made other important advances in the understanding of brain metabolism. Of particular potential importance for HD, they discovered the energy cost for supporting brain glutamate and GABA neurotransmitter activity, providing a direct link between mitochondrial health and brain function.

As a result of their discoveries, Dr. Rothman and a group of colleagues saw how levels of glutamate and GABA are altered in depression, epilepsy, and other psychiatric disorders, and how drugs can impact those levels.

Dysfunction seen in animals

Several years ago, Dr. Rothman added Huntington’s disease to his focus. Funded by CHDI Foundation, Inc., the multi-million-dollar nonprofit virtual biotech dedicated to finding HD treatments, Dr. Rothman and his lab staff conducted research on mitochondria and brain cell metabolism in two types of transgenic HD mice.

Using MRS scans, in both groups of mice the team found a decline in metabolism in three key regions of the brain (cortex, thalamus, and striatum). They also discovered a reduction in brain cell glutamate and GABA signaling activity.

“The changes were much more profound as the models reached the late premanifest or manifest stage,” Dr. Rothman said during a presentation of the research in February at the CHDI-sponsored 10th Annual HD Therapeutics Conference.

These findings suggested that mitochondrial dysfunction plays a role in HD. This and his upcoming studies are part of a larger group of biomarker studies necessitated by the advent of clinical trials.

You can watch Dr. Rothman’s presentation in the video below.

Evidence for Mitochondrial Dysfunction in Mouse Models of Huntington's Disease? from Gene Veritas on Vimeo.

High-powered brain scans

With CHDI support, Dr. Rothman hopes to carry out the human studies in the second half of this year.

Each study will require about 40 volunteers: 20 early-stage HD-affected individuals and 20 gene-negative volunteers to act as a comparison group. Each study will involve a brain scan and take two or three days, including travel time. The study will cover the cost of travel, food, and lodging. Volunteers can take part in both studies, if they wish.

In the first study participants will undergo a so-called proton scan lasting 60-90 minutes. The Rothman team will use Yale’s 7 Tesla scanner. The number of Teslas corresponds to the power of the magnet, with higher Tesla giving greater sensitivity (the ringing discussed above has a higher amplitude and frequency).

“Seven Tesla is about the highest magnetic field that can be used for human studies,” said Dr. Rothman. “Your molecules move around and jitter and release a radio signal that interferes with the measurement, and so we need as about as high a sensitivity as possible. Interestingly, within a chemical, the protons all have different frequencies. So you can actually identify a chemical based on the pattern of resonance frequencies.”

At this level, the scientists can measure more types of metabolites and with greater sensitivity, allowing them to distinguish between glutamate and another neurotransmitter, glutamine. Both are involved in a cycle involving GABA, brain cell signaling, and metabolism. The research team aims to determine whether glutamine or glutamate is most altered by the disease.

Yale's 7 Tesla scanner (photo by Gene Veritas)

Optimizing treatments

The researchers will focus primarily on glutamine, because it is the most sensitive chemical marker in the brain, but it’s not easily measured in humans at 3 Tesla or lower (scanners with less sensitivity), Dr. Rothman explained.

The more sensitive the biomarker, the better the chance of measuring the effects of the disease and potential treatments, he added.

This biological fine-tuning raises the possibility of studying the disease and testing therapies in small groups, perhaps even single subjects – a far more efficient, inexpensive, and faster way to treatments than the traditional, larger studies involving dozens or scores of individuals.

“The hope is that it would be possible to get immediate feedback before any behavioral-motor changes and use that to optimize individual subjects’ therapy,” Dr. Rothman elaborated.

Tracing the journey of sugar

In the second study Dr. Rothman will use ¹³C (carbon-13) MRS, the same technique used in the HD-mouse mitochondria project (discussed above) and in human scans for a variety of conditions. Carbon-13 is a natural, stable isotope that makes up about 1.1 percent of all the carbon on earth. Researchers use it to label substances so they can be tracked through the body.

Participants will lie in a 4 Tesla scanner for about two hours. They will be continuously injected with ¹³C-labeled glucose through a catheter in one arm. From a catheter in the other arm small blood samples will be taken to read levels of ¹³C and glucose. Glucose is used because it is the main fuel that the mitochondria burn to provide the brain with energy.

Lab assistants will monitor participants’ glucose levels to make sure they remain stable. Afterwards, the participants will receive orange juice and lunch in a standard recovery room, where assistants will make sure that their glucose levels have returned to normal.

As Dr. Rothman explained, the ¹³C MRS technique will allow his team to watch the glucose go through the various stages of the energy cycle in the brain. This metabolic process includes the transformation of glucose into lactate, then into glutamate by way of what is known as the TCA (tricarboxylic acid) cycle in mitochondria. The rate of flow of glucose into the mitochondria is proportional to the amount of energy the mitochondria produce.

“We can also measure the flow from glutamate to glutamine, which gives us the rate of glutamate neurotransmission, a direct measure of brain function,” he added.

As a result, the team can measure the rate of energy production in individual brain cells, as well as the rate of brain signaling (neurotransmission).

Dr. Rothman summarized: “We have a measure of both the energetics of the neuron – how much energy is the mitochondria making – and a measure of the function of the neuron – how much it’s signaling, how much glutamate it’s releasing through the flow into glutamine.”

The team will attempt to answer two questions: whether energy production decreases in early-stage HD individuals, and, if so, whether the drop results from impairments in the mitochondria.

Based on animal studies and previous human studies using other techniques, Dr. Rothman and his team believe they will find diminished energy production in the mitochondria.

“But that doesn’t, by itself, tell us that the mitochondria are causing it,” he said. “It could be many other things.”

Dr. Rothman making an adjustment on Yale's 4 Tesla scanner (above) and standing the in recovery room where ¹³C study volunteers will have glucose readings monitored afterwards (below) (photos by Gene Veritas)

Verifying the impairment

The ¹³C experiment will examine the rate of energy production of the mitochondria. To further tease out the questions about the role of the mitochondria in HD, Dr. Rothman and his team want to measure the demand on the mitochondria for energy production. 

To do so, they will run a second experiment during the ¹³C scans. Using phosphorous magnetic resonance spectroscopy, they will analyze the level of other compounds used for brain cell energy. Specifically, they will measure the synthesis of ATP (adenosine triphosphate) from ADP (adenosine diphosphate) (click here to learn about this process). The breakdown of ATP back into ADP by the mitochondria releases energy to fuel cellular processes, he said.

“In the muscle it fuels contraction,” Dr. Rothman said. “In the brain it fuels neurotransmission. If the mitochondria have a defect or have a low number or activity, they have to be driven harder for the same amount of energy production.”

For this measurement to occur, the participants must have their brains stimulated. “So both people with HD and control subjects will be given visual scenes in the magnet that will force the visual cortex we’re measuring to be active,” Dr. Rothman explained.

If the HD subjects have a mitochondrial impairment, the team will be able to determine whether the mitochondria “are being forced to work harder, because their capacity is less,” he said.

In combination with the ¹³C MRS readings, this experiment will help the scientists conclude whether “the problem is at the mitochondria,” Dr. Rothman said. This knowledge will help in the design of potential remedies and the clinical trials to test them.

The ¹³C study will measure energetics and signaling, as shown in this rendition of the glutamatergic synapse (image courtesy of Dr. Rothman)

Gratitude for the scientists’ work

Dr. Rothman said he expects the proton study to take about 18 months and the ¹³C study about 24 months. Once the studies commence, a call for volunteers will go out from the MRRC. If recruitment goes well, the studies may finish sooner, he said.

Upon the completion of the proton study, CHDI will evaluate the feasibility of glutamine as a treatment biomarker in comparison with glutamate and other MRS biomarkers under study, he added. Later Dr. Rothman’s team will file a report on the studies with CHDI, and they aim to submit their work to a scientific journal.

The engagement of Dr. Rothman and Yale Medical School in HD science exemplifies the seriousness of CHDI and HD researchers in the quest for treatments.

With the goal of unraveling the mysteries of the mitochondria, Dr. Rothman’s experiments can potentially complete key parts of the HD treatment puzzle. The search for effective biomarkers and increased knowledge about the role of the mitochondria can speed the movement of discoveries from scientific bench to patient’s bedside.

As a Yale graduate and carrier of the HD genetic defect, I was especially thrilled to interview Dr. Rothman. My alma mater may very well be helping to save me and thousands of others from the ravages of HD.

I am grateful each day for the commitment of Dr. Rothman and scientists around the globe to defeat HD.

Gene Veritas (aka Kenneth P. Serbin) at Yale University in New Haven, CT, April 2015 (photo by Gene Veritas)