A step forward in treating serious genetic disorders prenatally

(Press-News.org) Injecting medicine into the amniotic fluid staves off progression of spinal muscular atrophy in utero. 

Evidence is mounting that clinicians can treat serious genetic disorders prenatally by injecting medicine into the amniotic fluid, thus preventing damage that begins in utero.  

A UC San Francisco-led study found that delivering medicine for spinal muscular atrophy (SMA) via the amniotic fluid was safe, and it helped prevent damage to nerve cells in the spinal cord, a part of the central nervous system that is responsible for movement. One experiment was done in mice with SMA — a neurodegenerative disease that causes muscular weakness, atrophy, and death if untreated. Another followed in sheep that did not have the disease, to demonstrate that the method is safe. 

The therapy used molecules called antisense oligonucleotides, or ASOs, that can alter the expression of genes through interactions with RNA, which creates proteins. ASOs are currently given to babies and children with diseases that affect the nervous system, including SMA.  

“Children with severe forms of SMA can have irreversible damage by the time they are born, and we wanted to see how we could treat as early as possible, in the least invasive way,” said Tippi MacKenzie, MD, a fetal and pediatric surgeon at UCSF Benioff Children’s Hospitals and a senior author of the study, which appears in Science Translational Medicine.  

Previous research has shown that SMA can be diagnosed before birth, and that expression of the genes involved in the disorder can be manipulated prenatally. This is the first research on treatment for SMA via amniotic fluid — a less invasive method than the other possible route via the umbilical vein. 

One step closer to clinical trial 

The researchers found that mice treated prenatally with ASOs fared better in terms of survival, motor function and motor neuron numbers than mice that were treated only after birth or were not treated. In sheep, they confirmed the safety of the treatment and its ability to reach the spinal cord and other organs in therapeutic concentrations via the amniotic fluid.  

“This suggests we may be able to use amniotic fluid to deliver therapeutic RNA molecules for other severe, early-onset diseases that affect different areas of the body,” MacKenzie said. 

This is the first study to test the safety of prenatal administration of therapeutic ASOs in large animals, as well as how the medicine distributes throughout their bodies when injected. Previous studies have looked at intra-amniotic injection of ASOs in mice with Angelman and Usher syndromes.  

To apply for FDA approval of a new drug application, researchers must show that the therapy corrects disease — as happened with the mice in this study — and that the ASOs were distributed throughout the body with acceptable levels of toxicity— as happened with the sheep.  

“With these results, we are one step closer to testing prenatally in humans an existing treatment for those diagnosed with the disease,” MacKenzie said.  

An inverse amniocentesis 

If eventually approved, the procedure would be given during pregnancy, much like amniocentesis, in which amniotic fluid is collected to test for genetic or chromosomal abnormalities, said first author Beltran Borges, MD, a UCSF post-doctoral scholar and aspiring pediatric neurologist in MacKenzie’s lab.  

“This is sort of an inverse amniocentesis,” Borges said. “Once translated to the clinic, it could be an outpatient procedure.” 

The researchers were tickled to see through fluorescence that, when the medicine was injected into the amniotic fluid, the fetuses swallowed and inhaled it, which then distributed it to other parts of the body including the lungs, intestines, brain, spinal cord — and even the nose hairs.  

 “It is remarkable that you can inject something in the amniotic fluid and let it sit there, and over time a fetus swallows it or sniffs it in, and it gets to the brain and elsewhere,” Borges said. “There are likely other routes of entry as well, including through the bloodstream.” 

The project was special because it brought different research efforts together, MacKenzie said. The sheep study was led by UCSF with significant help from UC Davis; the mouse research was done by colleagues at Johns Hopkins School of Medicine and Cold Spring Harbor Laboratory in New York. Scientists at Ionis and Biogen provided critical guidance, reagents, and experimental support. 

“It takes a lot of trust and effort to put studies from three different labs and industry collaborators together,” MacKenzie said. “This type of multi-disciplinary collaboration — it’s the most rewarding way to do science.”  


Authors: UCSF authors are Beltran Borges, MD, Maria T. Clarke, BS, Akos Herzeg, MD, PhD, Tony Lum, MD, Fareha Moulana Zada, BS, Marco Cordero, BS, Nalin Gupta, MD, PhD, and Tippi C. MacKenzie, MD, PhD. For all authors, see the paper.  

Funding: This work was supported by Biogen, the National Institutes of Health (R35NS122306, GM42699), the UCSF Center for Maternal-Fetal Precision Medicine, and the St. Giles Foundation. For all funding, see the paper. 

 

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