Fixing nature’s genetic mistakes in the womb

Tippi MacKenzie, MD. Photo buy Cindy Chew

Note:  Tippi MacKenzie, MD, is a Catalyst Program Awardee, who won for her work on in utero hematopoetic cell transplantation for treating alpha thalassemia major. She said the program’s process gave her the skills needed to move from lab to clinical trials. “Taking the leap to a clinical trial is huge. It involves a body of knowledge I don’t have,” MacKenzie said. “The Catalyst Program has provided that knowledge. Having the Catalyst team sort of hold your hand through the process has been great.” 

By Lisa M. Krieger via San Jose Mercury News 

By the time a baby is born with a catastrophic genetic disease, medical help is too little, too late.

UC San Francisco doctors are studying a bolder and better remedy, far earlier: repairing genes before birth, stopping disease before it starts.

Experts recently met on campus to plan how to best undertake this pioneering approach, called fetal gene therapy, as well as its potential pitfalls. Strategies will be discussed again at a Wednesday gathering.

“It would be a first in humans,” and a collaboration between leaders at a half dozen university medical centers, said Dr. Tippi MacKenzie, a pediatric and fetal surgeon who is leading the effort – still two to five years away — at UCSF’s Benioff Children’s Hospital.  “That’s one of the reasons we’re treading so carefully.”

“Treating the fetus could prevent illness and sustain a pregnancy,” she said.

No trials are currently planned. But the goal is to safely cure some of nature’s most rare and deadly mistakes, such as lysosomal storage disorders, spinal muscular atrophy, Duchenne muscular dystrophy, cystic fibrosis, and thalassemias. The technique may also one day be used to correct genes causing severe neurodevelopment delay.

It’s possible because of fast-moving advances in three key fields: fetal surgery, gene therapy and prenatal screening, which detects dangerous fetal genes in the mother’s blood.

Currently, parents have only two emotionally wrenching choices. One is caring for a child with a chronic, debilitating and often fatal disease. The other is abortion.

Fetal gene therapy offers a third option.

But it poses an ethical challenge: There are two patients, the healthy mother and the sick child. So care must be taken to ensure that the gene therapy doesn’t enter the mother’s bloodstream, hurt her in some still-unforeseen way or coerce her to agree to treatment.

“Any advance in fetal therapy, however welcome for good and important reasons, poses a risk of increasing pressure on pregnant women to sacrifice their own interests and autonomy…with women being subject to civil commitment or even criminal charges for failing to optimize the health of their fetuses,” said bioethicist Alta Charo of the University of Wisconsin, now a fellow at Stanford University.

Fetal gene therapy is not an effort to build “designer babies,” improving or enhancing the fetus. Rather, it is focused on preventing death from disease.

This makes it very different from the genetic alteration undertaken by a Chinese scientist in twin girls last year, to global condemnation. The Chinese experiment changed the basic reproductive genetic code, so a trait would be passed on to future generations. Moreover, it was not medically necessary to save the babies’ lives.

Instead, fetal surgeons envision fixing non-heritable genes at precise anatomic sites. Fetuses would be five to six months old, weighing nearly two pounds and measuring almost a foot. And the procedure would only fix rare disorders caused by an error in a single gene.

Genetic fixes to fetal disease graphic
Source: UCSF Center for Maternal-Fetal Precision Medicine

“These diseases have onset before birth — by birth, there’s already damage,” said surgeon MacKenzie.

There are other advantages to fixing fetuses. Their young immune systems tolerate changes that an older immune system would reject.  And they have fast-growing populations of cells, so any benefit would burgeon.

UCSF doctors have performed hundreds of successful fetal surgeries since the 1990s to correct structural problems, such as spina bifida.

But the fledgling field of gene therapy fell into disrepute in 1999 after 18-year-old Jesse Gelsinger died during an experimental treatment for metabolic liver disease. Later, children who got gene therapy for an immunodeficiency developed cancer. Those twin tragedies halted the momentum.

Since then techniques have improved, and gene therapy has rebounded. Billions of dollars have been invested in research to fix faulty genes. The procedure has been federally approved for treating diseases such as retinal blindness and hemophilia in children and adults.

Fetal testing in animals has also shown it can be done safely and effectively. And last year UCSF successfully transplanted a mother’s stem cells into her sick fetus, leading to the birth of an infant with a normally fatal fetal condition. 

Emboldened by these achievements, researchers now aim to move gene therapy earlier in the human lifespan — into the womb, where its potential is the greatest.

“If we offer people hope that we might be able to intervene, it changes the dynamics of whether we think a pregnancy is viable,” said Barbara Koenig, who leads UCSF’s Bioethics Program.

The first human trials would be cautious, said experts, focusing on life-threatening disorders with no other therapeutic options.

The healthy genetic material would be delivered by a long needle injected into the mother’s belly, penetrating the umbilical cord.

Different strategies would be tested.

One approach could use short strands of chemically-modified nucleotides that bind to genetic material – increasing or decreasing the proteins that are linked to disease.

Another would enlist the use of a benign virus that’s been loaded with healthy genes, using a gene-editing tool like CRISPR. It would infect sick cells, then replace a missing or defective gene with the good gene. Or it would repair a mutation.

A third approach is not to edit the gene, but instead use CRISPR to increase or decrease the gene’s activity.

The research is welcomed by parents of children with muscular dystrophy, caused by a mutation in the gene that makes the protein dystrophin.

“Ensuring dystrophin is present during brain development may be beneficial,”  said Eric Camino of Parent Project Muscular Dystrophy, “although we need to better understand how the absence of dystrophin impacts brain development before we could justify such early intervention.”

Fetal gene therapy’s safety and accuracy must be proven in clinical trials, said Arthur Caplan, professor of medical ethics at New York University’s Langone Medical Center. He said it is critical that gene edits don’t go off target, such as altering an unintended site of an unborn baby’s DNA.

There are concerns that the gene-carrying virus could infect the mother’s genetic makeup. There also is a very small procedural risk from the injection into the fetal umbilical cord.

“And any time you are doing an invention that requires going through the body of one person to get to the genes of a second person — even if the second person is a fetus — it is complicated,” said Koenig.

In many disease, the genetics are not yet fully understood, she added. Once it’s possible to cheaply and quickly screen the entire fetal genome, will there be the temptation to fix in the womb other later-in-life problems?

“What if you detect heightened susceptibility to certain cancers or heart disease or Alzheimer’s disease?” asked Koenig.

But these hurdles can be overcome, say doctors, raising the real possibility that clinical trials will soon be at hand — fundamentally and forever changing the practice of fetal and maternal care.

“Now that we have all these ways of looking into the womb,” said Koenig, “we now want to very responsibly figure out how to intervene at exactly the right point of time that will lead to the best outcome for the family.”

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