Progress in gene therapy: a promise that could come to pass?

We often write about the excesses and over-promising of human genetics, but here are two stories on something genetics seems to have gotten right.  Successful gene therapy stories both, they represent, to us, a use of money and expertise that fulfills the promises of the field and actually changes lives.

Both reports are in the July 11 issue of Science.  The first (paywalled, but here's one summary and here's another) describes gene therapy for MLD, metachromatic leukodystrophy, an inherited neurological disease caused by deficiency in an enzyme that is required for maintenance of the myelin sheath, the protective lipid layer around nerve fibers.

The disorder is caused by variants in the ARSA gene, as described in the paper:

ARSA deficiency causes accumulation of the enzyme substrate, sulfatide, in oligodendrocytes, microglia and certain neurons of the Central Nervous System (CNS), and in Schwann cells and macrophages of the Peripheral Nervous System (PNS). This build-up of sulfatide leads to widespread demyelination and neuro-degeneration, which is ultimately manifested in patients as severe progressive motor and cognitive impairment.

Without myelin, nerves in the central and peripheral nervous systems eventually cease to function properly.  MLD becomes progressively worse and patients usually die not many years after onset.  Incidence is from 1 in 40,000 to 1 in 160,000 worldwide, with some populations having much higher rates.  

Researchers used a lentivirus to introduce the corrected form of the gene into cells, first demonstrating proof-of-principle in their mouse model of MLD in which they showed that disease could be both prevented and corrected.  They report that transferring the strategy to people was a challenge, and one major potential set-back is leukemia as a consequence of the treatment, although they have altered the method for introducing the virus into cells in an effort to circumvent this.

They have now treated 9 patients with early-onset MLD, and report the outcome for the first three patients after 24 months for one and 18 months for the other two. The children's cognitive and motor skills development is currently age-appropriate, they have no signs of demyelination and no signs of leukemia. That's very encouraging.

The other report is of gene therapy in children with Wiskott-Aldrich syndrome, an immunodeficiency disorder caused by mutations in the WASp gene, which codes for a protein that regulates the cytoskeleton of the cell.  The platelets of affected children are small and function improperly, and children are at high risk of autoimmune disorders and malignancies.

Researchers used the same method of introducing the functioning version of the gene into patients and report results after 20-32 months of follow-up, and again, they are encouraging.  The patients now have healthy immune systems and no signs of leukemia.

This is good news for people with these disorders, but it's also good news for the field of gene therapy.  The field has held great promise for decades, but the challenge has been to develop methods for safely introducing genes into the cells where they are needed.  It sounds as though progress has been made.

Engineering: Where science really works
Science as an exploration of the unknown has to juggle various aspects of its agenda.  These include the difficulties of the problems themselves, technological limitations, costs, and of course various professional and other vested interests. Sometimes 'we like sheep' follow fads and current thinking without really considering what we're doing.  When nature is complex, or causation unclear or highly complicated, we often falter.  And we sometimes wish that things were actually simple, even when we know very well that's incorrect.

But one thing that can be said about human beings: we are great at technology.  Technology tends to work.  So when a cause really is known, and there is a clear objective, there's a good chance we can figure out how to achieve it.  We are terrific at engineering solutions for known problems. That's the case with strong genetic causation of a disease.  The objective is to intervene to prevent or treat the disease.

The challenge may be great, but we have a way of getting there eventually with technological advances.  The two examples we see in the current literature seem hopeful in that sense.  They also constitute what we think are unexceptionably good ways to invest health-related funds.

This won't change the fact that Nature is not compelled to yield easily to us, even in engineering.  Nor is there any reason that success in engineering will guarantee that the rest of science will yield to what are essentially engineering approaches that, as is these days so often basically the case.

But it is gratifying that many times we are able to solve problems, once we have properly identified them.