Cure Huntington’s Disease Initiative (CHDI) is a not-for-profit organization. The generosity and guidance of CHDI’s donors (who prefer to remain anonymous) enable it to focus solely on drug development. It has become the largest single sponsor of Huntington’s disease (HD) research, supporting more than 500 full-time scientists in contract research organizations (CROs), biotechnology companies, pharmaceutical companies, universities, and government laboratories. CHDI’s scientific team now includes 30 scientists, with expertise ranging from cell biology and genetics to medicinal chemistry and pharmacology, working together with 14 project managers and administrative, business, and legal staff. More than 80% of CHDI’s scientists have previously worked in biotechnology or pharmaceutical companies, further underscoring CHDI’s therapeutic goals. Staff scientists work closely with collaborators to define goals, specify deliverables, develop experimental programs, monitor progress, and maintain a therapeutic focus.

From its beginnings, CHDI has devoted considerable resources to human studies, with the convergent goals of understanding the biology of disease progression and of preparing for clinical trials. Because clinical trials for a potentially neuroprotective drug will require sophisticated monitoring of early changes in brain structure and function, CHDI’s human studies investigate HD-associated changes in cognitive and motor function, in biochemical readouts of cellular and brain activity, in patterns of gene expression, and in psychological assessments.

An essential part of CHDI’s strategy is to be a “collaborative enabler” of HD research, particularly for projects that will bridge the gaps that separate basic discovery, drug development, and clinical trials. These activities include:

1. funding of infrastructure (e.g., patient registries, repositories for biological samples and biochemical reagents, and animal models)
   
2. sponsorship of clinical studies of HD progression
   
3. development of new assessment tools and biomarkers, both for disease progression and for the engagement of drug targets
   
4. creation and distribution of research tools (e.g., new reagents and new animal models)
   
5. exploration of potential new targets and technologies
   
6. convening of multidisciplinary workshops to discuss emerging areas of particular relevance to HD research and drug development
   
7. support of new means of rapid and up-to-date communication among CHDI collaborators and, more widely, all HD researchers
   
8. adoption of research contracts whose terms require the conduct of proposed experiments with regular reporting of results and sharing of information and reagents rather than traditional research grants.

CHDI has self-consciously experimented with different strategies for accomplishing its goals, always with an eye to its long-term mission. Early efforts emphasized individual research projects, roughly following the pattern employed by NIH and other foundations. As CHDI paid increased attention to anticipating the conversion of preclinical program to human trials, it has come to focus on fewer and more extended programs.

These extended programs may involve different kinds of individual collaborators and partnering organizations, including academic laboratories, CROs, and pharmaceutical and biotechnology companies. CHDI also works to lower the barrier to entry into HD research for individual research scientists and biotechnology companies and by underwriting academic research projects through the National Institute of Neurological Disorders and Stroke, the Huntington’s Disease Society of America, and the European HD Network. It also supports the exchange of information and reagents within the HD research community.

The goal of CHDI remains constant—to develop therapies and to advance them to clinical trials—but its strategy and programs continually responds to advances in biomedical science and technology, to shifts in the biotechnology and pharmaceutical industries, and to organizational and financial changes in universities and government. Current challenges—both to CHDI and to other disease-directed foundations—include

1. how to handle vast amounts of data and information from the research community
   
2. how to use advances in systems biology to help the selection of therapeutic targets and to predict the effects of specific interventions
   
3. how to share information and knowledge among researchers, both in public and commercial settings
   
4. how to set up collaborative arrangements for “precompetitive” work—early stages of development during which competitors collaborate without com­promising their future competitive positions, and
   
5. how to find contracting, licensing, overhead, and management arrangements that will best speed the path to effective therapies.

CHDI Programs Depend on Collaborations with Academic, Industrial, and Government Partners

Like other disease-directed foundations, CHDI has a single goal: to find treatments for a single disorder—HD—as quickly as possible. The fastest access to resources for specific studies is usually through providers who already have them, so CHDI endeavors to work with collaborators with direct experience in a needed technology. CHDI programs depend on collaborations with academic, industrial, and government partners.

CHDI is a “virtual” organization, meaning that it has no laboratories of its own: every scientific project is executed off-site, though with the direct participation of CHDI staff. The strategy is to employ already established capabilities in universities, CROs, and biotechnology companies—to “buy” rather than to “build.”

CHDI supports the application of new technologies to HD-related problems, although not technology development per se. Nor does CHDI support work on general neuropathological mechanisms, unless they are directly involved in HD.

CHDI differs from most other foundations in that its own scientists directly contribute to supported research programs, working with both academic and industrial collaborators to develop goals, to choose experimental strategies, to specify laboratory tactics, and to write reports and papers. Similarly, CHDI project managers directly engage the scientists and managers of each collaborating organization, establishing and checking timelines, tracking materials, verifying deliverables, and monitoring personnel deployment. In many ways, then, CHDI resembles a virtual biotechnology company, though CHDI is directed toward a single indication and is not-for-profit.

The goal of all CHDI’s efforts is to find treatments for HD. Once CHDI scientists decide to pursue a particular therapeutic target, they evaluate every feasible modality and every available technology. Recently explored approaches—in addition to small molecules—include antisense oligonucleotides, siRNAs, aptamers, peptides, single-chain antibodies, viral delivery, and cell-based therapies. Of course, as discussed later, competing priorities limit the number of concurrent programs.

CHDI’s complex enterprise, with its many internal and external players, requires stable and user-friendly repositories for data and documents. Because CHDI is a multisite organization (with offices in New York, Los Angeles, and Princeton) with collaborators around the world, its success also depends on open and effective communication.

CHDI also cooperates closely with HD-directed governmental programs, including the National Institute of Neurological Disorders and Stroke (NINDS). For example, CHDI has provided supplemental funds to support an NIH program announcement, “Validation of Novel Therapeutic Targets for Huntington’s Disease” (PAS-10-183). CHDI support allows NIH to fund up to four HD-related projects, whose applications are judged to be scientifically excellent but whose scores fall below those required for ordinary NIH funding. CHDI also collaborates with NINDS in funding an international consortium directed to developing cellular model HD with induced pluripotent stem cells (“iPS cells”). NIH funds the U.S. investigators of this consortium, while CHDI funds the non-U.S. investigators. Finally, CHDI and NINDS each supported the first long-term study of premanifest HD, “Neurobiological Predictors of Huntington’s Disease” (PREDICT-HD). NINDS has recently issued a Funding Opportunity Announcement (FOA) to support studies based on the data and biological samples from this 10-year study. The net effect of CHDI’s collaboration with NINDS has been to attract more investigators to HD research, to increase the opportunities for data mining and analysis, and to increase the total funding available for HD research in the U.S.

Studies of People with HD Are a High Priority

HD is the clearest and possibly the oldest example of a dominant genetic disease: inheritance of one mutant version of the disease-causing variant—from an affected parent of either sex—is enough to cause the disease to appear. George Huntington presented the first description of HD in 1872, almost 30 years before the rediscovery of Mendel’s revolutionary paper [1].

HD results from a single mutated gene (HTT) and the consequent changes in the functions and metabolism of a single large protein (called huntingtin, or HTT), which performs diverse cellular functions in essentially every cell of the body. HTT contains more than 3000 amino-acid residues, including a tract of glutamine residues (each encoded by a CAG sequence in the DNA), starting with residue #18. In people not affected with HD, the polyglutamine is from 15 to 25 residues long, whereas in people with HD it is longer, from 37 to 180 residues. Broadly speaking, the longer the polyglutamine tract, the earlier is the manifestation of disease. Because everyone has an HTT gene, it is incorrect to call it the “HD gene.” Versions (“alleles”) of the gene that have more than 36 CAG cause HD, and this chapter refers to any these pathogenic versions as an “HD allele.” There are also a few reported cases of HD arising from people who carry “intermediate HTT alleles,” with 27–35 CAG repeats. Increased longevity may increase the number of such cases, as suggested by M.R. Hayden.

At least 100,000 people in the United States carry the HD allele (with 36 or more CAG repeats), with approximately the same number in Europe. (The incidence of HD outside North America, Europe, and Australia is mostly unstudied. One goal of Enroll-HD, described later, is to examine HD incidence globally.) Of these, about one-third have developed the characteristic HD movement abnormalities, which are the current basis of diagnosis.

Because of HD’s dominant hereditary pattern, each affected person (and each unaffected or uncertainly affected sibling) has almost certainly watched a parent suffer the same fate, making the future all the more concrete and frightening. While HD afflicts individuals, it affects whole families, further amplifying the number of people whose lives are changed by HD. Although HD may have devastating effects on affected families, many people from these families have become HD activists, and many participate in human studies and clinical trials. The active engagement of the HD family community has been an important inspiration to many individual HD researchers, both among CHDI scientists and their collaborators and, more generally, within the entire HD research community.

The characteristic effects of HD on movement—dance-like gestures (chorea) and loss of balance—typically start around age 40 (earlier with larger numbers CAG repeats). Subtler signs of HD—irritability, apathy, and depression—may appear a decade earlier. Over the course of some 25 years, a person with an HD allele undergoes a devastating decline of physical, mental, and emotional capacities. As brain circuits fail, an affected person gradually loses the ability to control movement, to maintain motivation, to regulate mood, and to plan and execute life’s everyday tasks.

HD provides an opportunity—almost unique among neurodegenerative diseases—to look prospectively for changes in people who have an HD allele but who have not yet developed the motor signs that are the basis for the current formal clinical diagnosis. Understanding that observations made in humans carrying the HD allele may give important hints for intervention, CHDI’s clinical group has supported several studies of “premanifest” or “prodromal” HD. (Many HD clinical researchers use one of these two words [“prodromal” and “premanifest”] to designate the state of a person who carries an HD allele but who has not developed the specific motor signs currently necessary for a formal diagnosis. Prodromal HD includes alterations in the volume of specific brain regions, diminished cognitive capacity [particularly in “executive function”], and some characteristic emotional changes, including apathy, depression, and irritability.)

The development of an intervention will require detailed knowledge of how HD affects people who carry the HD allele. CHDI has therefore devoted much effort to programs that measure changes that accompany and underlie disease progression, particularly in early stages, where intervention is likely to be most efficacious. Human studies may also provide clues for target selection.

CHDI recognizes the importance of understanding the biology and the clinical progression in people who are carrying an HD allele. Several projects have sought to identify proteins, peptides, and small molecules—in plasma and in cerebrospinal fluid (CSF)—that changed with disease progression. In collaboration with the Human Proteome Organization, for example, CHDI sponsored a multicenter project to detail the CSF proteome (the collection of all proteins expressed in CSF) and to look for changes in premanifest and early HD. While biochemical biomarkers are unlikely to provide surrogate end points for clinical trials, they would certainly help investigators to follow effects of interventions and, ideally, to measure the engagement of selected drug targets.

CHDI has supported three comprehensive studies of disease progression in premanifest people—Prospective Huntington At Risk Observational Study (PHAROS), PREDICT-HD, and TRACK-HD. These studies have included brain imaging, motor changes, eye movements, cognitive testing, and psychiatric evaluation. Similar projects now include the selection of a cognitive battery, the development of a functional rating scale for early HD, and the formulation of a descriptive mathematical model for disease progression.

CHDI has also supported the infrastructure of the Huntington Study Group and the European HD Network, and it has funded two projects—COHORT (mostly in the US and Canada) and REGISTRY (mostly in Europe)—whose goals are to collect clinical information and biological specimens from people who carry an HD allele. A new project—Enroll HD—will unify COHORT and REGISTRY and extend this joint to Latin America with the aim of developing a global HD patient registry. Enroll-HD will build on the many successes of the North American and European efforts in standardizing assessments, collecting biological samples, and handling data. The goals of Enroll-HD are to refine current knowledge of HD’s natural history, to help improve HD care throughout the world, and to provide a recruiting platform for future clinical trials.

CHDI Has Increasingly Focused Its Efforts into a Few Core Programs

CHDI originated in the “Cure HD Initiative” of the Hereditary Disease Foundation (HDF). This initiative began in 1997 as a way of providing support for projects that might contribute to understanding and treating HD. Rather than waiting for investigators to formulate relevant proposals, however, Ethan Signer (the initiative’s founding Executive Director and now a Senior Scientific Advisor to CHDI) sought appropriate researchers to undertake projects that he and the initiative’s advisory committee identified. During the time of the initiative, scientific work on HD expanded enormously, to more than 600 scientific publications in 2002 (compared with about 350 in 1997). The initiative provided support for each academic investigator as a contract with his or her university rather than as a traditional research grant or fellowship.

By 2003, when CHDI became independent of HDF, the initiative had provided support for more than 150 projects, almost all in academic laboratories. CHDI’s donors soon supported three complementary organizations:

1. High Q Foundation, which supported basic research relevant to understanding HD pathogenesis and progression, including many of the project originally funded by the HDF initiative
   
2. CHDI Inc., which focused on drug discovery and drug development
   
3. HP Therapeutics Foundation, which—among its other activities—organized a project (“Systematic Evaluation of Therapies for HD [SET-HD]”) to evaluate the feasibility of clinical trials for scores of suggested HD drugs.

In 2008, CHDI Inc. was renamed the “CHDI Foundation,” which then supported the full gamut of HD research activities from basic discovery research through clinical development.

CHDI’s philosophy and operations have dramatically changed from those of 1997 and 2003. Most importantly, CHDI leadership soon became aware of the need for new expertise, particularly in the areas of drug development and clinical trials. This realization led to the recruitment of a Chief Scientific Officer, a Chief Clinical Officer, and Vice-Presidents for Chemistry, Translational Biology, and Systems Biology, each with experience in drug development and each able to build teams with previously untapped expertise. As CHDI grew, it similarly recruited talented professionals with needed experience in law, operations, information technology, and human resources.

As its preclinical research portfolio grew, CHDI’s leadership also came to realize the importance of focus. Each individual program might require the extended efforts of several CHDI science directors and 20 or more external biologists and chemists. With time, CHDI became increasingly concerned about its capacity: just how many projects could CHDI effectively pursue, given its established scale and resources?

In 2004, Robert Pacifici, CHDI’s then-new Chief Scientific Officer, suggested narrowing CHDI’s preclinical efforts to 20 potential drug targets and programs. With increased experience, the number of major preclinical programs diminished to about 15. These programs fall into five broad areas, listed in Figure 25.1. CHDI now devotes some 50% of its drug-development efforts to a program to reduce the concentration of mutant HTT RNA. Another 25% of CHDI’s efforts address the posttranslational modification of HTT, seeking to alter its pathogenic action. The remaining projects fall into three broader programs, whose goals are to reverse or compensate for pathogenic changes in (1) synaptic function, (2) energy metabolism, and (3) autophagy (see Figure 25.1).

CHDI’s Highest Current Preclinical Priority

HD results (almost always) from an HTT allele with more than 36 CAG repeats. Most researchers think that HD results from the action of the abnormal HTT protein with a polyglutamine track of more than about 36 glutamine residues, though the possibility remains that abnormal RNA might itself be pathogenic, perhaps in addition to the abnormal protein. In either case, strategies that reduce mutant HTT RNA (with more than 36 CAG repeats) should reduce or prevent pathogenesis, whether HD results from abnormal RNA or from abnormal protein. Therefore, CHDI’s highest current preclinical priority is to reduce mutant HTT RNA and HTT protein.

CHDI currently supports the efforts of Isis Pharmaceuticals (Carlsbad, CA) to use antisense oligonucleotides to reduce HTT RNA, as well as those of Alnylam Pharmaceuticals (Cambridge, MA) to use small interfering RNAs (siRNAs) to accomplish the same goal. In both cases potential therapeutic agents must be delivered directly to the brain. Following the approach taken in its trial for amyotrophic lateral sclerosis (ALS), Isis plans to inject antisense oligonucleotides into cerebrospinal fluid via intrathecal injection (into the fluid surrounding the spinal cord). Alnylam, in collaboration with Medtronic (Minneapolis, MN), plans an alternative approach: pumping siRNAs directly into the brain through a thin catheter. CHDI is also working with other investigators and companies to explore other ways of reducing HTT RNA (e.g., with the zinc-finger technology developed by Sangamo BioSciences, Richmond CA), of delivering DNA cargoes to brain (e.g., with viral and liposome-based methods of traversing the blood-brain barrier), and of measuring the effects of treatments on HTT levels (e.g., with HTT-binding ligands for positron-emission tomography [PET]). Some HTT-lowering strategies aim to distinguish mutant from wild-type HTT, to preserve normal HTT function while reducing the pathogenic actions of the abnormal protein and RNA (see Figure 25.1).

CHDI Contracts Protect the Freedom to Operate in the Arena of HD Research

Working as a virtual organization, CHDI requires exchanges of materials and information among its varied collaborators, and hence seeks to ensure and protect the freedom to operate in the arena of HD research

Stay updated, free articles. Join our Telegram channel

Join