Tay-Sachs and Sandhoff diseases, genetic disorders affecting the brain, have no effective treatment and are generally fatal during the first years of life. Scientists estimated that the replacement of cells affected by those that are genetically in good health could slow down or stop neuronal degeneration that causes symptoms. But the approach was prey to problems, including poor transplant in the brain and a graft response to the host in which the transplanted cells attack healthy tissues.
Now, Stanford Medicine’s researchers have developed a way to replace more than half of the most seriously affected cells, called microglia, with non -general precursor cells in mice. In animals with a form of Sandhoff’s disease, the approach helped them to live longer and considerably reduced the behavioral and motors of the disease.
If the approach can be translated for use in humans, it could offer hope for families of children with these rare diseases. Because it is not necessary to use a patient’s own cells, the approach could one day offer the possibility of “standard” therapy which would be faster and cheaper than tailor -made genetic engineering for each case.
Using a specific sequence of steps, we were able to make almost 100% incorporation of genetically healthy cells in the brain of mice while avoiding both rejection and transplant disease against the host, which is much better than previous approaches. In addition, we were amazed at the way this therapy worked. The mice survived during the experience, showed an improvement in motor function and have found normal mouse behavior such as exploration of open spaces. The difference between the animals treated and witnesses was dramatic. “”
Marius Wernig, MD, PhD
Werig, a program manager at the Stanford and regenerative medicine biology biology institute, is the main research author, which will be published on August 6 Nature. The former postdoctoral scholar Marius Mader, MD, is the main author of the study.
Devastating inherited diseases
Tay-Sachs, which affects approximately 1 in 3,700 newborns of Jewish origin Ashkénaze, and Sandhoff, which is much less widespread, belong to a class inherited from diseases called Lysosomal storage disorders. Although rare, many are devastating, especially those that mainly affect the brain. Affected infants often develop normally during the first weeks or months of life, but quickly regress as their neurons degenerate.
Babies born with these disorders have mutations in genes for enzymes essential to the function of lysosomes – cell recycling compartments responsible for breaking protein, carbohydrates and fat molecules which no longer needed lipids in smaller construction blocks for reuse. If lysosomes are unable to operate, these molecules accumulate at dangerous levels in the cell.
But there is a mystery.
“Although the symptoms of these diseases are due to the degeneration of neurons, the lysosomal enzymes levels in neighboring immune cells called microglies are sometimes a thousand times higher than in neurons,” said Wernig, the scientist of Dr Salim and Mrs. Mary Shelby. So why do neurons die if the microglies are more seriously affected?
One of the many functions of microglia is to swallow up and break down dead cells or pathogens into the brain. “They are like professional cleaners,” said Wertig. “Therefore, they have a much greater need for these degradation enzymes than other cells. The researchers wondered if the restoration of the lysosomal enzymes with microglia could somehow help neurons.
Past attempts to correct the genetic deficiency of microglia in lysosomal storage disorders involved a hematopoietic stem cell transplant (often called bone marrow transplant) to restart the patient’s immune system, including microglia in the brain. In this type of transplantation, the person’s immune system is first eliminated with drugs (a step called preconditioning), then precursors of genetically healthy immune cells are introduced intravenously in the hope that they will settle in the patient and begin to do the missing protein.
But bringing healthy cells into the brain is difficult because the body narrowly restricts access to the central nervous system. The other possible complications of a transplant on a body scale include the elimination of donation cells by all remaining immune cells or, conversely, graft disease against the potentially fatal host.
Research from the Werig Laboratory in 2022 has shown that it is possible to obtain a 90% transplant of donor cells by destroying the immune system of the receiver animal and treating them with a drug to kill existing microglies, giving hematopoietic stem cells given a competitive growth advantage. But the technique still required toxic preconditioning and rested on genetically identical donation cells to prevent graft against the host.
“A hematopoietic stem cell transplant is an approximate procedure to go through,” said Wertig. “This is not something you want to do to your patients unless there is no other option. »»
A targeted transplant procedure
In this study, Mader and Weernig tested if they could develop a brain -specific transplantation procedure which would avoid toxic preconditioning and the body’s effects of a hematopoietic stem cell transplant. To this end, they coupled the impoverished drug treatment of microglies with the irradiation of the brain to create a space so that the new cells to occupy. They then injected microglia precursor cells-a more specialized subset of hematopoietic stem cells-a donor animal not genetically paired in the brain. Finally, they administered two drugs to block the activation of immune cells, moreover, in the body that would otherwise kill unparalleled data.
This delicate stages tango led to an effective transplant of given cells, which nestled in the brain and turned into a microglia without migrating to the rest of the body or being attacked by the immune system of the receiver animal.
Cell transplants lasted: more than 85% of microglial brain cells were derived from the cells given eight months after transplantation. Untreated mice with a version of Sandhoff’s disease lived a 135-day median and no animal lived beyond 155 days. On the other hand, five of the animals treated with the transplant therapy of microglies specific to the brain lived up to 250 days, when the experience was interrupted.
Although the mice treated with long lifes have finally developed posterior legs paralysis, they have shown normal exploration behaviors in a large open pen and greater muscle force and coordination than witness animals.
A more in -depth study of the relationship between the given microglia and their neural neighbors has revealed something intriguing: the missing lysosomal enzyme is now manufactured by microglia in the indigenous animal neurons. Although the reason is not yet known, Werig and Mader suspect that microglies are packaging and secreting the enzyme in space between cells, where it is imported into neurons.
“This could be an important and unrecognized role for microglia: providing lysosomal factors to the environment, including neurons,” said Wernig.
Researchers are optimistic, their approach could be translated by humans because each individual step – irradiation, the administration of drugs used to destroy existing microglia and the application of drugs to prevent the immune attack of given cells – is already used to deal with other conditions.
“We have solved three big problems with this study,” said Wertig. “We have carried out an effective and limited transplantation of the brain without systemic toxic toxic, we were able to use non-general cells that do not require genetic engineering to make the missing lysosomal enzyme, and we have avoided immune rejection and graft-to-hotel disease. We are very happy. »»
Researchers also think that therapy could be widely applicable.
“It is possible that these lysosomal storage diseases are only an accelerated version of much more common neurodegenerative diseases such as Alzheimer’s or Parkinson,” said Weernig. “If this is the case, this therapy could be very relevant not only for a small subset of children, but for many, many more people. »»
The study was funded by the California Institute for Regenerative Medicine, the German Research Foundation, the New York Stem Cell Foundation, the Robert J. Kleberg Jr. and the Helen C. Kleberg Foundation and the Wu Tsai Neurosciences Institute.