A key new ally in the search for Huntington’s disease treatments

With the new partnership between Roche and Isis Pharmaceuticals, Inc., reported here on April 11, the search for Huntington’s disease treatments has gained an accomplished and ambitious ally in the person of Luca Santarelli, M.D., Ph.D.

Dr. Santarelli, the 44-year-old head of neuroscience and small molecule research at Roche’s world headquarters in Basel, Switzerland, will oversee the Roche-Isis effort to bring Isis’s proposed gene-therapy drug to a long-awaited crucial clinical trial, tentatively scheduled to start in the first half of 2014.

A native of Italy, Dr. Santarelli in the early 2000s made an astounding discovery about Prozac-type antidepressants while conducting postdoctoral research at Columbia University in New York City: these drugs actually led to neurogenesis, the birth of new neurons in the brains of adults.

With these findings, Dr. Santarelli joined Nobel laureate Dr. Eric Kandel, Dr. Rene Hen of Columbia, and Dr. Fred Gage of the Salk Institute for Biological Studies in San Diego to found a company, Brain Cells, Inc., that focused on the development of novel antidepressants for stimulating neurogenesis.

In 2005, Dr. Santarelli joined Roche. He quickly rose in the company ranks and now oversees efforts to design drugs for brain disorders and related conditions, including schizophrenia, depression, Alzheimer’s disease, multiple sclerosis, spinal muscular atrophy, and neurodevelopmental disorders such as autism and Down syndrome.

Nature’s Trojan horses

Now, turning their attention to HD, Santarelli and Roche researchers will collaborate with Isis to speed progress towards the clinical trial, infusing $30 million into the project.

They also will seek ways to make the potential Isis drug easier for trial participants and eventual patients to absorb. Instead of Isis’s potentially riskier and certainly less comfortable method of implanting a quarter-sized port near the rib cage connected to a catheter running to the area of the spinal cord, Roche aims to create a drug that patients could take through an intravenous or subcutaneous (under the skin) injection. (It’s still too early to tell where in the body patients would receive such a potential subcutaneous injection.)

To design this kind of drug, Roche will use a so-called “brain shuttle,” a new approach to transporting drugs past the highly impermeable blood-brain barrier, which protects the brain from foreign objects.

The blood-brain barrier also makes it difficult for so-called large molecule drugs to enter the organ and thus has presented researchers with a major hurdle to treating brain disorders and diseases.

Dr. Santarelli, in a phone interview on April 22, was asked to explain the brain shuttle in everyday terms.

“It works by hijacking a biological system that is normally used to shuttle proteins into the brain,” he told me. “It uses cellular receptors outside the blood brain barrier and uses them as Trojan horses to take in a cargo.”

Dr. Luca Santarelli (photo courtesy of Roche)

The cargo could include an antisense oligonucleotide, or ASO, the specially designed piece of artificial DNA made by Isis that, in mice experiments, has reduced the amount of the harmful huntingtin protein in brain cells and produced a “Huntington’s holiday,” a disappearance of the symptoms.

“A cargo can be an ASO,” Dr. Santarelli continued. “It could also be a peptide or an antibody. Receptors are on the outside (of the blood-brain barrier), but they also move to the inside. They are built by nature to allow certain large molecules (to move in).”

Explaining the concept

No brain shuttle drug yet exists. I was eager to know exactly what kind of shuttle Roche might have in mind and how it could work with the ASOs.

However, because of the trade secrets involved in private drug research, Dr. Santarelli declined to comment.

Nevertheless, he emphasized that the brain shuttles are “built by nature to allow the transfer of large proteins inside the brain.” Different shuttles have different capacities, he added, and they work in a “controlled fashion.”

“The concept of proteins that shuttle large molecules has been known for a while,” he said, referring to the decade-plus research on the phenomenon.

Dr. Santarelli cited the example of the shuttle known as transferrin.

“We know that transferrin works in this way,” he said. “Transferrin is a protein that carries around iron in the bloodstream. Iron doesn’t go around freely. It’s absorbed and transferred around to the organs. It (transferrin) binds with iron – iron gets released into the brain.”

Advantages of the brain shuttle

By carrying an ASO into the brain in this revolutionary manner and avoiding the discomfort of a lumbar (lower-back) puncture or other long-term invasive approach, the brain shuttle approach helps drug discovery in two key ways.

First, it allows researchers to include people in clinical trials who previously were not eligible – namely, people genetically at risk for a disease but without symptoms. In terms of ethics and comfort, it is difficult to justify their participation because of the risk posed by invasive procedures.

With the brain shuttle, however, discomfort is reduced. So is the ethical barrier, because the injury risk diminishes.

Secondly, by including presymptomatic people in drug studies, researchers can measure how a drug affects a patient before the disease develops, thus providing clues about how to stop the disease from ever occurring.

Only a few years ago, this kind of approach to neurological drug research seemed futuristic. The lack of opportunities to participate in clinical trials and the absence of a strategy to prevent the disease in asymptomatic people have proved especially frustrating for the HD community, where people like me await in great fear the onset of a disease foretold by genetics.

A unique Alzheimer’s trial: intervening early

With Isis, Dr. Santarelli and Roche are working to raise the hope of preventing asymptomatic gene carriers from ever experiencing onset.

Roche is especially well-positioned because, as Dr. Santarelli pointed out, it focuses on both drug development and disease diagnostics.

Roche’s “strategic objective” is to intervene “as early as possible” in the course of the disease, he emphasized.

“As an organization, we’ve done this in Alzheimer’s,” he explained.

In developing its proposed Alzheimer’s drug, now under study in a clinical trial involving 800 patients, Roche has taken the unique step of including individuals who have not yet developed dementia, but have merely mild cognitive impairment, Dr. Santarelli said. (Click here for further background.)

In the trial Roche is using molecular testing to diagnose and select trial subjects at risk for Alzheimer’s. This is done by performing a lumbar puncture to obtain a sample of cerebral spinal fluid (CSF) to check the presence of amyloid, the substance that forms plaques in the brain of Alzheimer’s patients and is considered one of the causes of the disease.

If successful, the Roche drug will not only clear plaques from the brains of the Alzheimer’s patients but also delay (or stop) the progression of the disease, Dr. Santarelli said.

The diagnostic technique used in the trial to measure CSF amyloid is experimental and has yet to reach the market, Dr. Santarelli noted.

He stressed that the Roche approach involves both the more traditional clinical (observational) measurement of the patients’ symptoms and, with this new measurement technique, a molecular measurement.

Roche's “culture of combining diagnostics and therapeutics” will definitely provide useful for the development of HD drugs, Dr. Santarelli observed.

A number of other HD research efforts also focus on the search for molecular measurements.

Patient involvement

Because of the highly experimental nature of the brain shuttle and the newness of Roche’s neurological diagnostics, Dr. Santarelli could not forecast when these approaches will bear fruit in HD research.

“We have to go through all the experimentation,” he said of the partnership with Isis.

Whatever the timeline, Roche will depend on collaboration with the HD community, as it has with advocates for other diseases.

“You guys are playing an extremely important role for lowering barriers to making progress in this area,” he said. “I feel personally honored that I can make a contribution in this area.”

Big decisions while facing the threat of Huntington’s disease

At every turn of life, we all make big decisions such as choosing a career, a mate, a home, and the number of children to conceive.

Living with the knowledge of a positive test for a devastating condition such as Huntington’s disease radically complicates such decisions. Coupled with the deep stigma associated with HD, the fear of the onset of symptoms magnifies the stress and doubt that come with such turning points.

As I have frequently revealed in my writings and in speeches about HD, I have faced life-changing decisions about a feeding tube for my HD-stricken mother, my genetic test, and the test of our daughter while still in the womb. (Thankfully, she tested negative!)

Planning for the inevitable symptoms of this currently untreatable disease has also profoundly altered my career, leading me into a new field far different from my original focus on Brazilian history: the history of science, technology, and medicine.

With my definitive exit from the “HD closet” last fall, I have begun to integrate this new intellectual passion into my professional life.

Professional excitement

Lately, however, I’ve relived the intensity of how the threat of HD affected my professional decisions.

With the surprise resignation of Pope Benedict XVI on February 11 and the emergence of several potential successors from among Latin America’s cardinals, my expertise on the Roman Catholic Church’s actions in the region and its relations with the region’s dictatorships – topics usually of no interest to the media and the general public – suddenly were in demand.

The election of Pope Francis I created great excitement: his initial attitudes and actions indicated that he might very well attempt to clean up the corruption and abuses that have plagued the institution.

At the same time, it rapidly became apparent that the new pope had had his own complex and (to some) controversial relationship with the Argentine dictatorship, which carried out a “dirty war” against Argentines from 1976-1983.

In the period before and after the election of Pope Francis I, I gave eleven interviews and answered a number of other queries from newsmagazines and radio and TV outlets.

My personal excitement culminated with the publication on March 17 of an op-ed article, outlining the potential paths of the Church under Francis I, in one of Brazil’s most prestigious newspapers, the Folha de S. Paulo, followed  by a quotation from me about the Argentine branch of the Church in a front-page story in The New York Times.

As I told a number of friends, never before and probably never again will my scholarly work on the Catholic Church command so much attention in the United States.

Throughout all this, I began to relive the past thrills and satisfaction of researching the Church, publishing books on the topic, and discussing my work in the Brazilian media.

My wife seemed especially happy to see me enjoying, for the first time in a very long while, recognition for my original career path. For her, it was a relief from that dogged, sometimes seemingly one-dimensional aspect of my life involving the fight against HD.

Second-guessing the past, but welcoming the future

As a result, I began second-guessing my decision in 2007 to turn down a job to help run a prestigious Latin American studies center in Florida in order to remain in biotech-rich San Diego to focus on the fight against HD. Staying put also helped safeguard my family’s financial future by allowing my wife to keep her good job and better-than-average retirement plan – absolutely essential if HD were to leave me disabled.

I thought of the HD people I had recently read about who had roughly the same degree of genetic mutation as I did and managed to avoid symptoms until their sixties and even continued to work after onset.

However, in the process of second-guessing, I recalled how I made that decision when the memories of my mother’s demise just a year and a half before still haunted me.

In hindsight, it’s easy to argue that I should have taken the other job and not worried so much about HD.

However, hindsight also reminds me of how HD completely destroyed my mother’s ability to work, to communicate, and to care for herself.

My wife and I made our big decision with the best information available to us at that moment.

I quickly reminded myself that rather than reliving the past, I must look to the future, value the intellectual flexibility of my university, and fulfill the plans I have mapped out for myself. I will be seeking connections with my university’s neuroscience program and social outreach project in order to promote brain health as a national priority.

Indeed, my dean has fully supported me after my exit from the HD closet. I felt especially reaffirmed with the publication of a feature article about my journey with HD on the university’s website.

The decision to pursue the history of science, technology, and medicine has exposed me to new vistas of the human story. HD is a challenge – but also a gift that has led to profound intellectual and personal growth.

The real successes and challenges

I savored my public moment as a Latin America scholar.

However, it stood in sharp contrast to the intensity and immensity of the challenge to avoid HD symptoms and contribute to the defeat of the disease.

While friends and colleagues were impressed with the recognition of my expertise, I quietly pondered the truly significant accomplishment for me during the week of Francis I’s election: the successful arrangement of a meeting between Paulo Vannuchi, Brazil’s former Minister of Human Rights, and Taíse Cadore, the president of the Associação Brasil Huntington. They discussed the crucial need to involve Brazil’s Ministry of Health in the fight against HD in Brazil, which will host the 2013 World Congress on Huntington’s Disease from September 15-18.

Ultimately, scientists’ work will go for naught unless events such as the World Congress can draw more people into the HD cause and involve them in the all-crucial research studies and clinical trials.

Participating in a study

On March 13, as I monitored the Internet for news of the papal conclave, I spoke to a researcher at the Huntington’s Disease Society of America Center for Excellence at Iowa Hospitals and Clinics, one of the sites for a key study known as PREDICT-HD, an observational study of the earliest signs of HD that needs asymptomatic, gene-positive volunteers.

PREDICT-HD will help establish ways to measure the efficacy of potential treatments.

Participating in PREDICT-HD represents another big decision for my family and me. The study requires the presence of a spouse or partner, who must answer a questionnaire about the gene-positive individual. All three of us must spend two days traveling and at least two days in Iowa.

The PREDICT-HD also involves a voluntary spinal tap so that cerebral spinal fluid from gene-positive people can be studied for the effects of HD and ways to measure the efficacy of potential treatments.

Spinal taps are routine but, like any procedure, involve risks such as a debilitating headache that could require emergency room treatment. In my case, it means that I will probably notify my health insurance plan for the very first time of my gene-positive status. I want to make sure I can safely undergo the tap, and I want to have my plan doctors on standby in the event of complications.

In and of itself, informing my health plan about HD represents yet another significant shift in my medical, psychological, and emotional approach to the disease.

Channeling the positive energy

As the HD researcher and I finished our discussion about PREDICT-HD, I saw the announcement of breaking news about white smoke from the Sistine Chapel: a new pope had been chosen.

Minutes later, my daughter and I watched as Francis I appeared on the balcony of St. Peter’s Basilica in Rome and humbly prayed the Our Father and Hail Mary with the crowd gathered below – the same prayers she and I say together each night, alternating in English and Portuguese, before she goes to sleep.

I felt a new beginning for the Church.

In the days since then, I have frequently asked myself how I can channel the deep fulfillment and positive energy from my study of this troubled but nevertheless key institution into the effort to relieve the suffering caused by Huntington’s and so many other devastating diseases.

As I wrote in my op-ed piece on the pope, Francis I “seems to be saying that believers, and the rest of the world, must rediscover the fundamentals of human existence.”

In his inauguration homily on March 19, Francis I stated that “authentic power is service.” As pope he must protect “the hungry, the thirsty, the stranger, the naked, the sick and those in prison.”

For me, this means protecting my family from the consequences of HD and striving to do my small part to help others.