Scientists develop gene delivery ‘trucks’ that could treat brain diseases

Scores of researchers have produced new tools that can deliver genes and selectively activate them in hundreds of different cell types in the brain and spinal cord, a breakthrough that scientists hope advances them toward developing targeted therapies to treat neurodegenerative diseases such as ALS, Parkinson’s disease and Alzheimer’s. The discoveries, made through the National Institutes of Health’s BRAIN initiative, show with unprecedented clarity and precision how neural cells work together, but also how diseases disrupt their tight choreography. The insight offers the promise that doctors may one day treat diseases by manipulating dysfunctional cells. “Looking ahead, with sustained investment, the advances we can achieve in understanding consciousness — and in repairing neurological and neuropsychiatric disorders — will be nothing short of life-changing,” Gord Fishell, a professor of neurobiology at Harvard Medical School and one of the scientists involved in the discoveries, said in an interview for the BRAIN webpage. “This will revolutionize both our grasp of how the brain works and our ability to treat currently intractable conditions.” Neurodegenerative diseases afflict more than 9 million Americans. NIH launched the multibillion-dollar BRAIN initiative 12 years ago to improve understanding of the brain and central nervous system and to speed the discovery of cures for related disorders. The advancement of the gene delivery systems, the result of several years’ work by more than 300 U.S. and international scientists, was described in eight papers published Wednesday in the journals Cell, Neuron, Cell Reports, Cell Genomics and Cell Reports Methods. Advertisement John Ngai, who directs the BRAIN program, compared the new tools to a truck delivering genetic packages to specific cell neighborhoods in the brain. The vehicles in these experiments were actually adeno-associated viruses, which can penetrate cells but do not cause disease and can be made to target specific tissues. The cargo the viruses carried included switches called enhancers and promoters, sequences of DNA that regulate the amount of a gene that is transcribed into RNA, and ultimately how much of a protein is produced. Promoters act as an on-off switch for the process, while enhancers speed it up. “If you think about the brain as the marvelous computer that it is — 86 billion neurons and about as many nonneural cells making trillions of connections — if you want to know how a computer works, you need a parts list,” Ngai said. “You need to know what the components are, what their properties are, how many you’ve got of each. But, most importantly, you not only need to know how they wire together, but you need to know the logic of information flowing from one part to another.” Fishell, who is also a member at the Broad Institute of MIT and Harvard, said many brain conditions amount to problems in the precisely calibrated rhythm of the different brain cells. Advertisement “If you think of a symphony, people are playing notes, and those notes rise and fall in rhythm, and you have many notes being played in a very complex way,” Fishell said. “The analogy I’ve given is: Are you really going to fix the symphony by picking up a piccolo and just playing notes? It will sound horrible. “What you want to do is take the rhythms that are naturally there and increase or decrease the rhythms to get them to the correct pace.” Although much of the work was done in model organisms such as mice, rats and nonhuman primates, some was done in lab dishes using human brain tissue removed during some epilepsy surgeries and other procedures. The tools present an attractive alternative to the time-consuming work of making transgenic mice, which scientists use to model human diseases and to study the function of specific genes. The ability to reach only specific cells also offers a powerful mechanism for treating disease. Too often, treatments go to cells that need it but also to cells that don’t. “You give it everywhere and all sorts of things can go wrong,” said Bosiljka Tasic, director of molecular genetics at the Allen Institute for Brain Science in Seattle and one of the scientists involved in the new discoveries. Advertisement In some cases, this lack of precision can lead to a treatment worsening the disease. On the other hand, targeting very specific cells for treatment can be highly effective, explained Avery Hunker, a scientist at the Allen Institute. “We’ve been looking at using some of our tools to just affect cells that are damaged in Parkinson’s disease, and we find that this strategy is very effective, at least in mice,” Hunker said. “It has huge translational potential.” The delivery systems described in the new papers provide scientists with experimental access to specific cells in the brain circuits that help us take in and respond to vast amounts of information in daily life: faces we see, a breeze we feel on the skin, a memory triggered by the smell of an apple pie cooking. Other brain circuits drive the autonomic nervous system, which regulates vital bodily functions carried out without any conscious effort, such as breathing, heart rate, blood pressure and digestion. Advertisement “A circuit is really individual cells that talk to each other through various means; one is electrical impulses,” Tasic said. “So, basically, one cell will activate itself; it will fire this electrical impulse, and that impulse spreads to other cells that are connected to it.” Previously, when scientists wanted to study a particular brain circuit, they could track only one cell type at a time. But the new tools announced Wednesday allow researchers to observe the actions of multiple cell types in a particular circuit. Scientists can use the adeno-associated viruses to deliver fluorescent proteins to specific types of cells, lighting them up so that their actions can be observed. Ngai said the new delivery tools have been developed for broad use and will be made available to scientists through BRAIN-funded labs and through Addgene, a global nonprofit repository. The latest discoveries came from a branch of the BRAIN initiative called the Armamentarium that focused on developing molecular tools that would allow scientists to gain access to the different types of cells in the brain. Advertisement While the NIH could not put a price on the cost of the research that resulted in the eight papers, this branch of the BRAIN initiative is expected to represent a total investment of more than $50 million. Asked whether the BRAIN project will absorb any of the proposed $20 billion in cuts to the NIH budget, a spokesman said, “NIH does not comment on pending budgets or future funding decisions.” The rate of progress on the BRAIN project surprised some of the scientists.