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.”

Striving for brave new brains

As I turned 52 on December 31 and a new year dawned on the world, I came ever closer to onset of Huntington’s disease, the cruel killer that took my mother’s life in 2006 at the age of just 68.

However, in 2012 I also will live with the hope that, as science and medicine progress with time, researchers will control and perhaps even eradicate HD.

Indeed, we stand on the verge of a new age. Neuroscience, brain scans, our understanding of genetics, and brain-machine interfaces will vastly improve the health and capabilities of the brain and perhaps enable the cure of HD, Alzheimer’s, Parkinson’s, Lou Gehrig’s, stroke, and numerous other maladies of the central nervous system.

On Christmas and my birthday I was able to celebrate the results of my annual check-up at the local HD clinic on December 20: the doctor marveled at how, despite carrying the same genetic defect as my mother, I have yet to show any apparent external symptoms of the disease (click here and here to read about my HD-avoidance strategies).

With the predicted biotechnological advances, those of us who are gene-positive may someday put bionic brains on our birthday wish lists – brains without risk of HD and that enhance mental capabilities far beyond anything we can currently imagine. Even sooner, advances in medicine may deliver drugs and techniques that counteract the cruel changes wrought in HD brains.

Breathtaking predictions

I contemplated these possibilities during my holiday reading, which included Judith Horstman’s The Scientific American Brave New Brain: How Neuroscience, Brain-Machine Interfaces, Psychopharmacology, Epigenetics, the Internet, and Our Own Minds Are Stimulating and Enhancing the Future of Mental Power, an exciting, easy-to-read synopsis of recent advances in brain science.

Horstman outlines how brain scientists predict breathtaking breakthroughs by mid-century – most with a firm foot in current reality.

According to scientific forecasters, “computer chips or mini-processors in the brain will expand memory; control symptoms of brain disease, from Parkinson’s disease to depression and anxiety; and wirelessly receive and transmit information so that you won’t need a cell phone or a computer to stay in touch.”

“Brain surgery will be a thing of the past except in the most severe cases,” Horstman continues. “Advanced neuroimaging will identify mental illness and brain disease before symptoms show and in general be used to ‘read’ minds and predict and control behavior. Microscopic robots – nanobots – will enter your bloodstream to diagnose and repair brain damage. Protein molecules will travel your brain in a similar way to turn on or off brain cells or genes responsible for brain diseases.”

Brave New Brain explores numerous other current and potential facets of brain health and related technologies, including:

● neurogenesis (the growth of new brain cells);

● deep brain stimulation and “brain pacemakers” (using electricity to stimulate brain health and performance);

● brain-nurturing mental and physical practices such as meditation, breathing, and yoga;

● the impact of digital technology on the brain and its integration into the brain;

● artificial intelligence;

● miniature cameras for broadcasting images of the inner workings of the brain;

● thought-activated neural implants (for example, for working mechanical limbs);

● prostheses of portions of the brain (people are already living with artificial retinas and cochleas, the auditory portion of the inner ear);

● and, in one forecaster’s view, the downloading of our brains onto chips “so our consciousness can live on forever, perhaps even downloaded into robots – or into an avatar, an ageless biological clone,” perhaps making us an endangered species increasingly replaced by cyborgs.

“Neuroethicists” and others worry that “humans will become machines,” Horstman observes. These individuals also point out new issues involving privacy in genetic testing; ownership of body parts, tissues, and genes; insurance discrimination; potential abuse of new technologies by employers and others; and the impact of all of these changes on social equality and our way of controlling criminals. Neuroethicists are grappling with these many issues.

Curing dementia

According to Horstman, Alzheimer’s, other dementias, and perhaps even mental retardation will be “preventable, curable, and even reversible in many people.”

The demand for cures is immense: some two billion people worldwide suffer from a brain-related illness, with an annual economic cost of more than $2 trillion, Horstman writes. Almost half of all people over age 85 develop dementia, and by 2050 an estimated 100 million individuals will experience this condition.

Offering a glimpse of how these cures could take place, Horstman writes of “brain boggling” nanotechnologies such as “preparing specialized protein molecules that swim to a predetermined site and are activated externally by probes or lasers that turn off or on specific genes.”

This kind of “nanomedicine” would allow medical treatments to leap across the formidable blood-brain barrier, which separates the bloodstream from the fluid that bathes and cushions our brains, Horstman explains.

Alnylam’s HD gene-silencing trial

The trends in neuroscience and related fields mean that scientists someday will likely control HD and perhaps, as Horstman describes, completely turn off the gene that causes it.

Key research in “gene silencing” already holds great promise.

In partnership with Medtronic, in 2012 Alnylam Pharmaceuticals plans to apply to the federal Food and Drug Administration (FDA) to conduct a Phase I clinical trial of a drug containing ALN-HTT, a small interfering RNA molecule (siRNA) that doctors will inject into the brains of trial participants.

Conducting a brain operation, doctors will run thin tubing under the skin from a Medtronic-designed pump to a nodule at the top of the patients’ heads, and from that point a very fine needle will deliver the drug into the putamen, one of the regions of the brain most devastated by HD (click here to read more).

If the Phase I trial demonstrates the safety of ALN-HTT, Alynlam will proceed to Phase II to measure the efficacy of the drug.

Alnylam intends to use ALN-HTT to silence the huntingtin gene so that less huntingtin protein is produced to harm brain cells. If successful, the treatment would save brain cells from dying and slow down and possibly even reverse the course of HD.

A decade ago, this approach seemed like science fiction. Today, it provides immense hope that HD will be controlled in our lifetimes.

On December 28, 2011, Alnylam presented a highly positive report: testing of ALN-HTT in non-human primates demonstrated “widespread distribution of the siRNA and significant silencing of the huntingtin mRNA.” The drug was well tolerated.

Conducted in collaboration with Medtronic and a research team at the University of Kentucky, the study will greatly facilitate the FDA application for a human trial.

Isis Pharmaceuticals, Inc. is developing a similar approach for treating HD and hopes to apply for its own Phase I clinical trial, perhaps within the next year or two (click here to read more).

The pioneering HD community

As Horstman describes, such gene silencing techniques only scratch the surface of the great potential in brain-disease treatments. Indeed, we may someday look back on these initial attempts as primitive.

But they are revolutionary. We in the HD community are helping to pioneer this revolution in brain science by participating in research studies and clinical trials, fighting the terrible stigma associated with the disease, and, as I did last February, exiting the terrible “HD closet” to tell the world about the need to defeat HD and other neurological disorders.

HD families no longer stand alone. Our movement has gone global – with international conferences run by research organizations, numerous HD-related websites, and the establishment of Enroll-HD, a multi-country database of HD-affected, gene-positive, and untested at-risk individuals. Just last month a new HD group formed in China, the world’s most populous country.

We stand on the frontier of science, and for this reason in 2012 and beyond we can forge ahead proudly and bravely.

It’s up to us to lead the way. If we all unite and participate in this great movement, we can help build toward the bionic brains of the future.

Vertex and the new wave of Huntington’s research

An increasing number of pharmaceutical companies are targeting Huntington’s disease, raising hopes that multiple treatments and perhaps even a cure could be found for the current generation of individuals affected by this deadly brain condition, including gene-positive people like me.

Vertex Pharmaceuticals is a prime example of this trend, which includes such firms as Isis Pharmaceuticals, Inc., and Alnylam Pharmaceuticals.

In mid-2008 the San Diego unit of Vertex began a project to find ways to block the actions of mutant huntingtin protein, which causes the death of brain cells.

Today two small teams of scientists devote themselves full-time to the HD project at this important drug discovery firm. Although they stressed that the project is still very much in the early stages, Vertex scientists spoke enthusiastically about their plans to decipher and attack the disease.

Looking for a pill

The project originated with a collaboration with CHDI Foundation, Inc., the “cure Huntington’s disease initiative” backed by an anonymous donor, but Vertex has branched off on its own and has continued Huntington’s research with internal funding.

“We’re very early (in the research),” said Paul Negulescu, Ph.D., Vertex vice president for research and the site head of the San Diego facility. “But we do believe that it may be possible to influence the course of this disease with small-molecule therapies in the years ahead.”

Dr. Paul Negulescu, Vertex San Diego site head, and Dr. Beth Hoffman, vice president of biology and head of the HD research project (photo by Gene Veritas).

By “small molecules” Dr. Negulescu means that Vertex aims to produce a pill or series of pills that HD people and gene-positive individuals could take to control the effects of mutant huntingtin. Pills represent a far less invasive method of treatment in comparison with others such as an injection, the insertion of a catheter into the brain or the spinal cord, or an operation.

Lessons from cystic fibrosis

Vertex hopes to extend its research on two promising drug candidates for cystic fibrosis (CF) into the Huntington’s field.

Like HD, CF is a genetically caused condition in which proteins malfunction. The potential drugs help a key protein in CF do its job of keeping the airways of the lungs moist and therefore capable of fighting off dangerous bacterial infections, the most devastating, and ultimately deadly, symptom of CF.

One of those candidates, VX-770, is already in Phase III clinical trials. Vertex will review the data from the trial in the first half of 2011. If successful, the company will then seek approval from the federal Food and Drug Administration (FDA) to market the drug, which would be taken as a pill.

The community approach

Vertex collaborated closely with the Cystic Fibrosis Foundation and the CF community to develop VX-770 and its other candidate, VX-809.

“We’re going to apply the best science that we can and learn the lessons that we can from the CF program, not only scientifically but in terms of how to work with a disease community that is focused on a single disease,” Dr. Negulescu said of the HD project.

“There are many things that a community brings to a research effort – not only patients and their passion about their disease and helping us understand what’s really important to them, but also to basic research, and, in some cases, like with CHDI and our early efforts with them, access to funding. All of that comes together to create a better chance for success, to make progress on the disease. That’s our model. That’s how we want to go after it, as a community, as a network.”

As part of this community approach, Vertex invited me to present my story about living gene-positive for HD. On September 24 I gave a talk before 50 Vertex employees. It was titled “Gene-positive for hell: my family’s struggle against Huntington’s disease." (Click here to read more.)

On October 22 Dr. Negulescu and nine other Vertex scientists attended the tenth annual Celebration of Hope Gala of the San Diego chapter of the Huntington’s Disease Society of America. It was the largest contingent of scientists from a single company in the history of the fundraising event. (Click here for my account of the gala.)

Going after ‘smaller diseases’

Vertex also focuses on drugs for the alleviation of viral diseases, pain, cancer, autoimmune disorders, epilepsy, and inflammation.

Recently Vertex’s completed three large Phase 3 trials of one of these drug candidates, telaprevir, in people with hepatitis C. Based on the Phase 3 results, Vertex recently applied for approval of telaprevir from the FDA. (Click here to read a news report on telaprevir.)

“One of the hallmarks of Vertex is that we’re willing to go after the smaller diseases,” said Beth Hoffman, Ph.D., the Vertex vice president of biology and the coordinator of the HD program. "We also are willing to dig into the biology of the disease in order to make better drug candidates.”

Dr. Hoffman (photo by Gene Veritas)

HD has become important for Vertex “because scientifically there’s a good basis of understanding for what causes this disease, the genetics,” Dr. Negulescu said. “We’re taking this seriously as a disease and as an early-stage research program.”

Misfolded proteins

As in CF and many other diseases, scientists believe that malformed, or “misfolded,” proteins are the culprit in Huntington’s.

Vertex researchers are trying to observe whether misfolding occurs in HD and to what extent.

They are also looking for ways to reduce the amount of the huntingtin protein in cells. They have already made some progress on this front, but they must also find a way for a drug to differentiate between normal and mutant huntingtin. Ideally, the drug would reduce the effects of mutant huntingtin while leaving normal huntingtin alone or only minimally affected.

Huntingtin exists throughout the body and is essential for life, although scientists have yet to understand exactly what it does. Part of Vertex’s work is to help unveil that mystery.

“The CF program gave us confidence that a small molecule can affect the fate of the genetically impaired protein, to have it do what it’s supposed to do,” said Dr. Negulescu. “It might be possible to do the same thing with the huntingtin protein.”

On the cutting edge

One of the San Diego unit’s greatest strengths is its expertise in high-throughput screening (HTS), the automated, rapid testing of compounds. HTS allows the researchers to test the effect of hundreds of thousands of compounds on brain cells placed in tiny wells. The CF researchers used HTS to discover VX-770 and VX-809.

Dr. Hoffman demonstrates the preparation of a plate for use in the high-throughput machine at her left as HD team leaders Dr. Branka Mitrovic and Dr. Mike Liu look on (photo by Gene Veritas).

“We can go to 3,456 wells on a plate,” said Dr. Mike Liu, who heads one of the Vertex teams, of one of the machines. The scientists are observing multiple types of brain cells and the behavior of both normal and mutant huntingtin.

Dr. Negulescu described HTS as “sort of like panning for gold,” but at a very high speed.

A high throughput plate (photo by Gene Veritas).

Vertex uses several kinds of HTS devices, including a high-throughput microscope, where scientists can observe the effects of compounds on brain cells.

“What we’re doing is really on the cutting edge of what’s out there in the HD field,” Dr. Liu said.

The San Diego unit stood among the early pioneers of HTS when it was known as Aurora Biosciences in the 1990s. In 2000 the Hereditary Disease Foundation of Los Angeles, which also focuses on HD, contracted with Aurora to do one of the very first high-throughput screenings of compounds for potential treatments in HD (click here to read more). Vertex, which is based in Cambridge, Massachusetts, acquired Aurora in 2001. Vertex was founded in 1989.

Helping brain cells

Another facet of the HD project involves neurogenesis: the repair of damaged brain cells or the replacement of dead ones with new ones. This research is at an earlier stage than the work on proteins. One approach might involve the stimulation of neural progenitor cells to become brain cells and connect to other brain cells, said Dr. Hoffman.

Dr. Branka Mitrovic leads the second Vertex team, which is examining ways to stimulate the production of growth factors, vital substances for the creation and nourishment of the brain. HD patients suffer from a shortage of such factors.

Dr. Branka Mitrovic (photo by Gene Veritas)

Dr. Mitrovic explained that Vertex is using some of the latest research technologies to look for compounds that may enhance the ability of the patient’s brain to self-repair.

In the effort to stop the negative impact of mutant huntingtin, Vertex hopes to find a drug or drugs that will “stop disease before it progresses too far,” Dr. Negulescu said. Such remedies might also prevent asymptomatic gene-positive individuals like me from developing the disease or at least arrest it in its early stages.