Lorenzo’s Oil and the Rehabilitation of Gene Therapy

Gene therapy strategies

Obviously, replacing a mutated ABCD1 gene with a healthier version in affected children would be the gold standard treatment option. Since you have a brain delivery system already available with HSCs, what if you could put a corrected ABCD1 gene into those stem cells, then allow the cells to migrate via those normal pathways into the brain? What would be the first step?

Anyone contemplating gene therapy manipulations begins with the choice of molecular transport vehicles. These are normally genetically re-engineered viruses fashioned into benign vectors, each capable of delivering corrected genes to the patient.

Many laboratories have used mouse gammaretroviruses as the vectors of choice. The big problem is that they will only transduce (supply the foreign gene) dividing cells. Since Jesse’s death, researchers have genetically engineered HIV-1 viruses to do the shuttling (Figure). Although they have been made replicatively defective, these viruses readily transduce nondividing cells. This property makes them the vector of first resort for many laboratories interested in gene replacement studies. Modified HIV-1 viruses are remarkably efficient at infecting HSCs. Once inside these cells, a certain percentage will express whatever foreign gene is on board, setting up a long-term presence of gene product in HSC lineages.

The question, however, remains: Would this work for patients suffering from ALD?

Seemingly simple—the introduction of the foreign gene into HSCs—the initial leg of this journey is a cautious one. If integration is successful, the next step is to determine what happens after transplantation. Once the cells stabilize in the patient, then one would start looking for clinical effects. That’s exactly what teams of researchers—some from Europe, some from the United States—have undertaken to do.

They were given permission to treat 2 ALD-affected boys, aged 7 and 7.5 years. The children had no matched donor available or cord blood for a ready sources of HSCs, which made them ideal candidates for a gene therapy trial. In the laboratory, autologous HSCs were transduced with an HIV-1 vector genetically engineered to express healthy ABCD1 genes. After myeloablative treatment, these HSCs were reintroduced into the patients.

The boys were followed up over the next 2 to 3 years. The researchers were looking not only to see whether the stem cells “took” but also to determine how many of them were expressing the corrected protein. To their excitement, the researchers found healthy ABCD1 proteins expressed in a wide variety of HSCs, including monocytes, T and B cells, granulocytes, and bone marrow progenitors. It wasn’t a great percentage, hovering between 9% and 14%. Would it be enough to produce a positive therapeutic outcome? The answer was yes! More than a year later, progressive cerebral demyelination in both boys stopped.

This was quite an achievement. Despite its relatively low level of correction, the boys’ brains were getting better—or at least stopped getting worse. The results are similar to those in ALD patients who have had the good fortune to find a donor source and subsequent transplantation. In a single stroke, a positive effect had been produced in patients with no such advantage. It had been done with a technology previously under a cloud, with a disease whose research efforts had been couched as negative high drama.

Perhaps we have come a long way after all, I thought. After hearing about the breakthrough—and recalling Lorenzo—it turned out to be a remarkably good day to be a scientist.