EU-funded researchers have developed innovative genetic reprogramming techniques to replace and repair brain cells, opening up novel therapeutic pathways to combat debilitating disorders such as Parkinson’s and Huntington’s disease.
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Although the precise causes of many neurodegenerative diseases, such as Parkinsons, Huntingtons and Alzheimers are not known, all have serious, chronic and debilitating effects.
In the case of Parkinson’s, the brain cells responsible for producing the chemical messenger dopamine gradually die. Because dopamine regulates movement, Parkinsons patients suffer progressively worsening motor control, trembling and stiffness. An estimated seven to 10 million people worldwide suffer from the condition.
The EUs IN-BRAIN project, funded by the European Research Council, published the first proof-of-concept study showing that glial cells, resident non-neuronal cells in the central nervous system, can be converted into neurons directly in the brain using novel methods to reprogramme gene expression. Ongoing research suggests that other cells, such as skin cells, can also be reprogrammed in this way, potentially enabling the replacement of brain cells affected by different neurodegenerative diseases as well as by traumatic brain injury or stroke.
This is really transformative in the field of brain repair. If we learn to create new neurons in a controlled way in the brain, it opens up possibilities to replace neurons lost to disease and to repair brain circuitry, says principal investigator Malin Parmar, a developmental neurobiologist at Lund University in Sweden.
Our research has the potential to dramatically improve the healthcare of Parkinson’s patients in particular. These novel cell-based therapies could ultimately be used in all early-stage patients as a first-line therapy, Parmar says.
Lund University pioneered cell therapies for Parkinsons disease as far back as the 1980s, when researchers transplanted foetal dopamine cells into patients brains, showing that it is possible to replace lost neurons with new and healthy cells. Transplantation with foetal dopamine cells faces both practical and ethical challenges, however. Hence, the subsequent discovery of pluripotent stem cells different types of mature cells that can be reprogrammed has set the stage for todays promising avenues of research.
Giving cells a new goal in life
Scientists are focusing in particular on the development of reprogramming techniques using innovative transcription factors. These protein molecules can be used to turn on or off different genes in targeted cells, generating a desired behaviour and, in effect, transforming the cell type. Parmar and her team have summarised this process accessibly and entertainingly in the ERCcOMICS strip A Cells Life.
The finding that somatic cells like skin cells can be reprogrammed into pluripotent stem cells expanded the availability of scalable cell sources. Moreover, it challenged the dogma that mature cells are fixed and cannot be changed into something else. This concept then opened up other reprogramming methods, like the one we use to convert skin cells or glia to neurons, Parmar explains.
The IN-BRAIN projects results show that reprogramming cells directly in the brain is feasible with current technology. The approach could be particularly suitable as a therapy for diseases that cause a defined loss of specific types of neurons such as Parkinsons, Huntingtons, Alzheimers, and potentially some forms of cell damage caused by stroke.
Parmar and her team are currently conducting ongoing research focused on generating more clinically relevant models to determine more precisely how glial cells turn into neurons inside the brain. This is a key step before the results can start to be translated into clinical applications and novel therapies for patients.
Although more research and trials are needed, the approach could initially provide effective early therapy for people diagnosed with Parkinsons by rebuilding damaged brain circuitry. This in turn would eliminate the need for current therapies using medications that often cause severe side effects and reduce patients quality of life.
In the future, it is probable that such cell therapies will significantly lessen the need for patients to use drug therapies and, subsequently, invasive therapies to treat the side effects. This would also reduce patient morbidity and mortality and provide opportunities for an extended active life, thereby reducing the burden on healthcare systems and lowering the economic impact of disease, Parmar says.