Most Transplanted Fetal Nerve Cells in Brain of Huntington’s Patients Do Not Thrive, Study Says
While transplanted fetal nerve cells can survive long term in the brain of a Huntington’s disease (HD) patient, only a specific subset called interneurons thrive, according to a study.
Projection neurons — a particular type of nerve cell commonly lost in Huntington’s — were rarely detected, probably due to inflammation, the authors said.
The study, “Outcome of cell suspension allografts in a patient with Huntington’s disease,” was published in Annals of Neurology.
Transplanting fetal neural cells into the brain as a potential therapeutic strategy for Huntington’s began more than 20 years ago. These cells can be expanded in culture and maintained as stem cells or differentiated into various types of nerve cells.
Seven small, open-label trials of neural transplants have been conducted worldwide, assessing the therapy’s safety and tolerability in people with Huntington’s, as well as its feasibility.
In the current study, the researchers presented an analysis of the brain tissue of one of five patients with mild Huntington’s disease enrolled in the NEST-UK multicenter trial (ISRCTN36485475), where patients were transplanted with cells from the fetal striatum — a brain region responsible for motor coordination.
In the NEST-UK trial, Huntington’s patients were randomly assigned to receive a fetal neural cell transplant. Neural tissue from human fetuses was obtained, following ethics and consent procedures, from cases in which the mother elected to end her pregnancy.
The patient selected was diagnosed with Huntington’s at 37 years old and underwent a transplant, without complications, of neural cells into both sides of the brain.
After this patient died in 2015, an assessment of his clinical history showed no obvious changes after the transplant in disease course. This data was gathered through clinical examination and positron-emission tomography (PET) — an imaging technique that uses small amounts of radioactive materials, called radiotracers, along with a special camera and computer to help evaluate organ and tissue function.
The patient’s brain was processed 37.3 hours after death for analysis. Transplantation grafts were easily identifiable within the brain and were enriched in interneurons — nerve cells that influence the activity of other cells within a limited, localized brain region.
Projection neurons, which are another type of nerve cell, were rarely detected. In the brain’s striatum, the main projection neurons are called medium spiny neurons (MSNs), which are normally lost in Huntington’s.
The postmortem analysis revealed a strong response of the patient’s microglia — the immune cells of the central nervous system — surrounding the transplant. Microglia cells release pro- and anti-inflammatory signals in response to changes in the brain’s microenvironment.
The researchers also detected aggregates of the mutant form of the huntingtin protein (mHTT) within the transplanted tissue and in the surrounding cells. Cells from the immune system infiltrated within the grafted tissue also contained this protein. Both events may have contributed to poor graft survival.
“This study again highlights that fetal striatal allografts can survive long-term in the human HD brain. However, while interneurons within them survive, projection neurons degenerate, and this is all associated with inflammation around and in the transplant, as well as the expression of mHtt pathology at the graft site,” the researchers wrote.
“The relevance and mechanistic consequences of these observations awaits clarification but raises questions as to whether cell-based approaches for repairing the HD brain can ultimately repair the dysfunctional networks seen in this condition,” they concluded.