Introduction to Research

Clinical research (also known as natural history) studies examine the progression of the disease over time. These can be conducted by looking at a patient’s medical charts collected over a period of time (a retrospective, or past-looking, study); these can be conducted by studying the patient in the clinic through surveying the patient and family and by conducting tests such as MRI and other examinations in the clinic on a yearly basis (a prospective, or forward-looking study); or these can be a study that combines aspects of both of these.

Clinical research studies are essential in rare disease research. There are no risks to the patients, and the research benefits the entire disease community. The more researchers understand every aspect of the disease, at every age and in every facet of the body, the better they can design a treatment for the disease. In addition, by studying the disease over time, researchers can best understand when and by what means to treat the disease. Before a first-in-human treatment trial will be approved by the Food and Drug Administrations (FDA), researchers will be expected to answer these sensitive questions about precisely what happens to children and young adults with Mucolipidosis Type IV, and at what age, and why. The more people who participate in clinical research, the better our presentation to the FDA will be. In addition, families enrolling in clinical research enable researchers to collect more information on how to manage the disease even in advance of a treatment.

One aim of treatment-focused research is to identify and validate a biomarker. A biomarker is a measurable biological phenomenon that is directly related to the presence of disease in a person. The importance of a biomarker is that it can be used to measure the response to a treatment when used in a person. For instance, blood cholesterol is a proven biomarker for coronary heart disease: lowering blood cholesterol is directly related to decreasing chances of coronary heart disease and this biomarker has been successfully used in trials of medications for this disease.

Identifying a biomarker for MLIV is critical. While we might have other measures for improvement that we would like to see when a treatment is applied in people (motor measures, for instance), these can be difficult to quantify. A measurement of a chemical in the blood, however, that is distinct to MLIV and that changes when a treatment is applied would be a very significant indicator that a treatment has worked.

When MLIV patients provide blood samples to clinical investigators at MGH, these samples are used in a biomarker investigation study that is looking to find and validate this kind of biomarker.

Translational Research

Investigators have conducted MLIV research for many years in a basic science stage of research. Basic science research is primarily focused on answering the questions of “Why?” and “How?”.  Basic research seeks to answer why does the disease cause the many pathologies in the body and how does the mechanism of disease work?

The next step is to take the basic understanding of the disease and try to intervene to slow, stop or reverse the symptoms by applying treatments. To this end we have created several mouse models of MLIV which reproduce the disease quite splendidly. These mice have been used in laboratories around the world to study many aspects of the disease including motor dysfunction, brain disease, gastroenterological pathology, ocular disease, and more. They are also excellent models for testing potential treatments.

Regulatory Approval Process

After a potential therapy has been thoroughly demonstrated to alleviate disease in the animal models the regulatory phase of preclinical developments begins. Clinical trials must be reviewed and allowed to proceed by the FDA. This can be a lengthy and complicated process. The steps in FDA clinical trial approval include:

• Pre-Investigational New Drug (pre-IND and IND) meetings with FDA
• Toxicology studies in animals
• Producing the treatment (e.g. vector) using Good Manufacturing Practices (GMP)
• Investigational Drug Application (IND)

Clinical trials are typically done in three phases. However, treatment trials for very rare diseases such as MLIV are often conducted with a Phase I/II trial combined together where safety (the purpose of a Phase I trial) and efficacy (the purpose of a Phase II trial) are examined in the same Phase I/II trial. This is typically done due to the small number of patients available for the trials. Phase III verifies the treatment is safe and effective in a larger number of clinical trial subjects. Sufficient clinical research studies and biomarkers are vital to clinical trials to measure the efficacy of the treatment.

Success in therapy development depends on family involvement at all stages. Here are some of the key ways in which families drive treatment progress: