Genetically Engineered Cells Delivered Directly To The Brain

A therapeutic technique to transplant hematopoietic stem cells directly into the brain has been reported in a new study. This could represent a significant breakthrough in our approach to treating central nervous system diseases and neurodegenerative disorders.

Researchers, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the San Raffaele Telethon Institute for Gene Therapy, tested the technique in a mouse model to treat lysosomal storage disorders, a group of severe metabolic disorders that affect the central nervous system.

The findings are groundbreaking because, until now, it was thought that hematopoietic stem cells (HSCs) – whether from a healthy, matched donor or a patient’s own genetically-corrected cells – needed to be transplanted indirectly, through an intravenous line to the bloodstream. Therapeutic success has depended on those cells engrafting in a patient’s bone marrow, maturing and naturally circulating into the brain, at a very slow and inefficient rate.

Intracerebroventricular Delivery

But in children with lysosomal storage disorders, caused by enzyme imbalances that result in a dangerous build-up of lipids, carbohydrates or other materials in the body’s cells, time is of the essence to stop the disease’s progression.

“The main issue with the conventional HSC transplant strategy has been the length of time needed for the therapy to take effect in the brain. It can take up to a year for the genetically-engineered cell lineage to proliferate, spread and produce therapeutic effects in the brain. Oftentimes, patients don’t have the luxury of time to wait,”

says senior author Alessandra Biffi, MD, director of the gene therapy program at Dana-Farber/Boston Children’s. Biffi and her team wanted to find a faster, and more direct, way to transplant therapeutic HSCs into the brain.

In a mouse model of lysosomal storage disorders, Biffi’s team transplanted HSCs, which they had genetically engineered to correct the enzyme imbalance, directly into the brain. They found the direct approach jumpstarted the therapeutic benefits much faster than intravenous infusion alone.

They call their method, which infuses the cells into fluid-filled cavities in the brain called ventricles, “intracerebroventricular” delivery.

Myeloid Cells

Once the genetically-engineered HSCs are transplanted into the brain’s ventricles, the crucial enzyme they contain helps to metabolize the materials that were previously building up and causing tissue damage.

A new lineage of cells descended from the transplanted HSCs – a type of cell called a myeloid – begin to scavenge and consume the excess material that is responsible for neurodegeneration.

“There’s a positive impact from the presence of the new, metabolically-functional myeloid cells because they release signaling cytokines that counteract neuroinflammation, which if unchecked can trigger neuronal damage,”

Biffi says.

Importantly, the transplanted HSCs engraft in the mouse brains without migrating to other areas of the central nervous system. This essentially could create a chimera – a separate genetic profile within an organism – within the brain.

The ability to engineer a chimeric population of brain cells could open powerful new avenues to preventing or reversing neurodegenerative diseases like Parkinson’s, Alzheimer’s, ALS and more.

One-time Treatment Envisioned

Although transplanting HSCs directly into the human brain sounds invasive at first, Biffi explains that the procedure would not be overly complex in actuality.

“I envision this could be a one-time treatment accomplished via a catheter temporarily placed into the brain’s ventricles, under standard anesthesia,” Biffi says. “This would be in line with currently-used clinical procedures that enable access to the brain for treatment.”

Based on the promising results of their mouse studies, Biffi and her colleagues are moving forward with plans to develop the procedure for the clinic.

She says there is great potential for intracerebroventricular delivery of genetically-modified HSCs, alone or in combination with intravenous gene therapies. This approach would be a new tool for clinicians to treat a range of conditions that affect the brain or the entire nervous system.

Alessia Capotondo, Rita Milazzo, Jose M. Garcia-Manteiga, Eleonora Cavalca, Annita Montepeloso, Brian S. Garrison, Marco Peviani, Derrick J. Rossi, Alessandra Biffi
Intracerebroventricular delivery of hematopoietic progenitors results in rapid and robust engraftment of microglia-like cells
Science Advances 06 Dec 2017: Vol. 3, no. 12, e1701211 DOI: 10.1126/sciadv.1701211

Image: mouse brain that received a direct transplantation of hematopoietic stem cells, showing the transplanted cells (green) rapidly engrafted and giving rise to new cells (also green) that have widely distributed throughout the entire brain. Credit: Biffi lab / Dana-Farber/Boston Children’s Cancer and Blood Disorders Center