Gene, Stem-Cell Therapies Emerge as Options for Fetal Care

By Will Boggs MD

July 14, 2020

NEW YORK (Reuters Health) - Fetal gene and stem-cell therapies are emerging as treatment options for select conditions, according to a new review.

"Fetal cellular and gene therapies are feasible and primed to become viable treatments for a number of conditions during the next decade," Dr. Amy E. O'Connell of Boston Children's Hospital and Harvard Medical School told Reuters Health by email. "Physicians should have a basic understanding of these treatments and be aware of the risks and benefits to patients."

Stem-cell transplant and gene therapy in utero might allow treatment and, ideally, cure of a wide range of genetic disorders. These therapies offer the possibility of curing a genetic disorder prior to birth or at least reduce damage and/or postnatal immunologic reactions to the missing gene product, which could radically change the approach to clinical care for these patients and reduce the financial burden for the patient and healthcare system.

Critical to any of these therapies is the prenatal diagnosis of the genetic condition, Dr. O'Connell and her colleagues note in their report in JAMA Pediatrics. This ultimately requires direct analysis of fetal DNA obtained through chorionic villous sampling or amniocentesis.

Ideal target disorders include those that result in severe morbidity and/or mortality and in which irreversible pathology begins before or shortly after birth and for which effective postnatal therapies do not exist, the authors say.

More than a dozen genetic disorders are amenable to fetal intervention, ranging from hemophilia A to Zellweger disease.

Theoretical advantages of fetal treatment include the ability to maximize the dose of stem cells or gene therapy per recipient weight, the tolerogenic fetal immune system, and cellular niche accessibility.

Stem cell-based therapies have successfully cured patients with immunodeficiencies, but congenital hemoglobinopathies, such as sickle cell disease and beta-thalassemia, have proven less responsive to such treatment.

Mesenchymal-stromal-cell therapy has shown promise in several experimental models of disease and may prove beneficial in osteogenesis imperfecta and for treating diseases with underlying inflammation prior to the development of established fibrosis.

Fetal gene therapy relies on vectors to deliver gene products, and active research is exploring viral vectors with specific tropisms for particular organs of interest, such as the liver and brain.

In vitro gene therapy could, for example, benefit patients with hemophilia A, even if not curative, by converting a severe, life-threatening disorder to a mild phenotype.

Ethical considerations will determine how best to proceed with next-generation fetal therapies, the authors say, and families will have to weigh the risks of fetal therapy against those of potential disease and disability. Clinicians and investigators should engage in shared decision-making, adhere to rigorous informed consent, and ensure the primacy of a pregnant woman's autonomy.

Fetal therapy is not without risks, the report notes. For in utero stem-cell transplant, the main risks are graft-versus-host disease, graft rejection, and graft failure. In prenatal gene therapy, the risks of therapy depend largely on the modality of gene correction.

Ongoing challenges include the need to improve our ability to identify diseases early enough to intervene and the need to develop tissue-specific vectors and delivery systems. Research should include not only safety and efficacy studies, but also evaluation of the socioeconomic burden and psychosocial effect of treatment on patients and families, Dr. O'Connell and her colleagues write.

"For fetal therapies, it's no longer a matter of 'if,' but 'when' stem-cell and gene therapy become available to treat medical conditions in utero," she said. "Recent advances in fetal diagnostics, surgical approaches, and maternal fetal management have made this a reality."

"There are many considerations that need to be undertaken for the fetus, the pregnant woman, and the family as a whole, and the medical community needs to be primed to support these families as the field progresses," she said.

"We continue to have some work to do to in order to translate our basic studies into human therapies, and the importance of critically assessing these therapies from an ethical standpoint cannot be emphasized enough," Dr. O'Connell said. "It will take a large collaborative effort by many specialized fields over the next ten years to successfully and safely bring fetal stem-cell and gene therapies into the clinical realm."

"Before testing interventions during pregnancy, biologically plausible benefits to suggest why it would be superior to conducting gene therapy in newborns should be clearly outlined," write Dr. Russell S. Kirby and colleagues of the University of South Florida, in Tampa, in a linked editorial.

"Informed consent is always important in medical care, and here it is paramount, given that it is impossible to medically or surgically treat the fetal patient without the thoroughfare of the mother," they note.

"Clinicians must bear in mind the experimental nature of these therapies at present and ensure that regulatory processes are adhered to and data on outcomes are systematically accumulated," the editorial concludes.

Dr. Simon N. Waddington of University College London, who has researched various aspects of fetal and neonatal gene therapy but was not involved in the review, told Reuters Health by email, "Gene therapy is becoming a clinical reality. Hemophilia B, an inherited genetic disease, appears to be curable, at least as far as we know so far (a decade out!). However, the field has so much to learn - it is very much work in progress."

SOURCE: and JAMA Pediatrics, online June 29, 2020.