Going Boldly

I recently watched Star Trek IV: The Voyage Home, the movie where the crew of the USS Enterprise travels back in time from the 23^rd century to retrieve a pair of humpback whales in order to save the Earth. The plot summary sounds stupid, but it’s my favorite Star Trek.

Dr. Leonard “Bones” McCoy is in rare form during this trip to the San Francisco Bay Area circa 1986. As he seeks to rescue fellow crewmember Pavel Chekov from a hospital, he offers a 23rd century take on what was then the state of the art medical technology. When he sees an elderly woman awaiting dialysis, he asks, “Is this the Dark ages?” An elevator discussion between two doctors about a chemotherapy patient leads Bones to cry out that “it sounds like the goddam Spanish Inquisition.” And when he confronts a surgeon who is about to drill holes in Chekov’s head to relieve pressure from a brain hemorrhage, he yells, “Put away your butcher knives and let me save this patient before it is too late.”

I thought of McCoy when I read a recent study published in Nature Medicine that reported that researchers at University College London, the KK Women’s and Children’s Hospital, and National University Health System in Singapore were able to prevent the fatal neurodegenerative condition Gaucher disease in mice treated with fetal gene therapy. It suggests that such an approach might be able to cure genetic neurodegenerative diseases before birth.

Gaucher disease is an inherited genetic metabolic disorder that results from a deficiency of the enzyme glucocerebrosidase, or GCase. GCase is needed to break down fatty metabolic waste called glucocerebrosides. Because people with the condition cannot break glucocerebrosides down, it accumulates in cells throughout their bodies. Over time, these waste fragments build up in the spleen, liver, bone marrow, and nervous system, causing bone disease, anemia, fatigue, eye problems, seizures, and in some cases brain damage.

The milder form of the disease does not involve the brain and can be treated with enzyme replacement therapy. But the acute childhood form is lethal, affects the brain, and is untreatable because the enzyme replacement therapy does not cross the blood-brain barrier.

The researchers delivered genetic material to code for the deficient enzyme using a viral vector injected into the brains of fetal mice with neuropathic Gaucher disease. The mice treated in utero with the gene therapy suffered less brain degeneration and survived longer than untreated mice. The treated mice lived for at least 18 weeks after birth compared to 15 days for untreated mice and had no signs of neurodegeneration, were fertile, and fully mobile. The treated mice were also better able to break down the metabolic waste involved in Gaucher and expressed the gene encoding the enzyme that is deficient in the disease.

“Being able to provide therapy at the earliest possible opportunity is vital in treating the brain which has a limited capacity to regenerate,” said senior author, Ahad Rahim of the UCL School of Pharmacy.

Based on the results in mice, a team from Singapore performed the test in non-human primates at the early stages of pregnancy when a clinical diagnosis of genetic conditions can be made, and when the immune system is more responsive to gene therapy.

Using macaques, the researchers showed that the delivery of viral vectors to the developing brain is feasible with an established clinical approach that resulted in the distribution of the transgene to the developing brain.

“Macaques and humans share a very similar neurological, immunological and physiological developmental time-line in the womb, making them accurate models for pre-clinical investigations before clinical trials can proceed,” said Associate Professor Jerry Chan, Senior Consultant, Department of Reproductive Medicine, KK Women’s and Children’s Hospital. “This new approach will bring hope, not only for Gaucher disease, but also for other inborn errors of metabolism that can potentially be treated using fetal gene therapy.”

The research team is working to develop a gene therapy for Gaucher disease with Apollo Therapeutics, a translational research collaboration between Imperial College London, University College London, the University of Cambridge, AstraZeneca, GlaxoSmithKline, and Johnson & Johnson Innovation.

Granted treating mice and monkeys is quite a long way off from having a viable approach that can be used to treat unborn children. The long-term efficacy and durability of fetal gene therapy is also not yet established. There’s also a practical challenge of identifying patients in utero for such a therapy. But the promise is clear.  For neurodegenerative diseases that rob children of their lives in their earliest years, fetal gene therapy may offer a way to cure a disease before it can manifest the damage it causes.

Delivering such a therapy in the 23^rd century may simply require waving a cellphone-looking gizmo that flashes and whirs, but even by the standards of  McCoy, its pretty nifty. Fetal gene therapy may be years, rather than centuries, away. But like Star Trek itself, the Nature Medicine study offers a glimpse of where we may boldly go in the future.

July 18, 2018