Nervous System Diseases Program

Program Head: Jeffrey Macklis, MD

Goal: develop a model of neurological cellular repair

The complexity of the nervous system is mind boggling. In addition to the brain and spinal cord, it includes all of our sensory organs, each of which contains numerous different types of cells, and a myriad of different kinds of connections. This makes attempting to treat, let alone cure nervous system diseases perhaps the most difficult task confronting modern medicine, with more than 600 disorders affecting some 50 million Americans. But scientists do know that the onset of the vast majority of these diseases is triggered by the degeneration or injury of specific neuronal cell types. Thus cell-based therapy holds much promise for the development of future treatments.

Research suggests that it may be possible to repair many forms of nervous system damage by transplanting neural cells, or by activating stem cells that exist within a patient's nervous system. In the case of Parkinson's disease - which is caused by a shortage of dopamine - there is encouraging evidence from trials in patients that transplantation of dopamine-producing neurons may be beneficial, although more research is needed in order to optimize this treatment and eliminate unwanted side affects. Other recent findings support the idea of replacing dead or injured brain and spinal motor neurons by inducing stem cells to reform the neurons lost in conditions such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI).

Investigators at HSCI have established a model of cellular repair and protection for patients with nervous system diseases and this program is sub-divided into five different types of nervous system disorders: Parkinson's disease, motor system disorders, retinal disease, hearing disorders, and glial-based disorders. Researchers involved in this program represent multiple institutions including Massachusetts General Hospital, Harvard Medical School, McLean Hospital, Dana-Farber Cancer Institute, Massachusetts Eye and Ear Infirmary, Beth Israel Deaconess Medical Center, and Harvard University. Although geographically spread out, the program as a whole, brings together a wide range of expertise in basic stem cell and developmental biology as well as clinical applications. Their underlying aims are similar as they are all working on issues including identifying and fate mapping particular neural stem cells, understanding the molecular development of these cells, and learning how to use them for cellular therapy.

The program is initially focusing on ALS, a devastating and rapidly fatal disease. There are four key criteria that make this disease a good prototype:

• there are two specific types of nerve cells involved - corticospinal motor neurons (CSMN) and spinal motor neurons (SMN);
• these nerve cells are located in specific areas of the nervous system;
• there are no effective alternative treatments, so stem cell biology is the only approach that can offer help at this time;
• there's a possibility that a very small number of even imprecisely wired replacement motor neurons could provide clinically important treatment and life-changing function.

This is intended to develop a model that can later be used in approaching other diseases. Identifying precursor cell populations, understanding how to direct their development and deriving ALS human ES cell lines will advance the possibility of cellular repair throughout the nervous system.

The steps the Nervous Systems Diseases Program will take toward its goals include:

Identification of corticospinal motor neuron stem cells and their genetics
Novel types of engineered animal models provide a method of marking and tracking progenitor and stem cells as they mature. Understanding which cells become particular types of mature neuronal cells will enable researchers to draw a map of CSMN circuitry development. With this map and the identification of the signals used for CSMN maturity, human ES cells and/or neural precursor cells can be directed through the exact stages necessary to form functional CSMN for therapy.

Elucidating the molecular development of CSMN
Researchers are employing a variety of methods to identify genes that may play important roles, either independently or in concert with others, in the development of CSMN. The function of CSMN-specific genes is studied by either introducing them into an animal model, by techniques such as in utero electroporation and viral infection, or by shutting down their function with RNAi, a technique that interferes with a gene's machinery. Once functionally relevant genes have been elucidated and verified, direct relationships and programs of gene expression can be defined and applied to developing CSMN in a petri dish.

Many genes in development are shared and/or redundant; there are back-up pathways and multiple signals with different functions stemming from the same gene. It has been reasoned that some of the signals that control development of CSMN may also define the development of spinal motor neurons in the spinal cord, the second neuronal type that degenerates in ALS. Findings from these studies will allow researchers to explore the meaning of cross-talk between neuronal systems, especially in the context of disease progression, and may lead to the ability to repair the entire corticospinal circuitry.

Using cells to repair CSMN for therapy
Understanding the molecular and genetic controls over the development, connectivity, and survival of CSMN from early neural precursors and stem cells will enable researchers to investigate the normal development of how progenitor cells form CSMN and the signals that later define their maturation. With the proper signals identified, researchers will be able to direct the steps which ES cells or neural precursor cells must follow for transplantation. These signals will also enable researchers to stimulate existing neural precursors through the proper steps of maturation, which would eliminate the need for transplantation.

The knowledge gained from understanding the process of molecular development of CSMN will provide scientists with the tools for inducing and directing ES cells (both mouse and human) and neuronal precursors and stem cells to undergo neurogenesis (the birth of new neurons). Managing the development of ES cells will allow researchers to grow specific CSMN cells for therapeutic transplantation. In a similar approach, stimulating and controlling the development of adult neuronal precursors that already reside within a patient may produce new forms of therapy without transplantation.

Nervous System Diseases Lead Investigators

There are at least 50 researchers working together in the program.