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Stem Cell Treatments For Inherited Genetic Diseases

Diagnosing genetic diseases before birth

There are a large number of inherited genetic diseases that can now be accurately diagnosed early in fetal life by examining fetal DNA obtained by chorionic villus sampling or amniocentesis. In most cases, the testing is done because the pregnant patient and their partner have been identified to be a carrier for this condition, or the condition is known due to family history. Treatment options depend on the specific condition. Some conditions are treatable with stem cell transplantation.

What is in utero hematopoietic stem cell transplantation?

In utero hematopoietic stem cell transplantation (IUHCT) was developed as a strategy to treat genetic diseases that addresses the challenges associated with postnatal transplantation. This is an alternative to traditional bone marrow transplant, which is done after birth. IUHCT is done during the pregnancy which offers a number of benefits, including limited rejection of donor cells and the possibility of a definitive cure for certain genetic conditions.

The fetal period is a unique time when the graft will not be rejected, therefore IUHCT could be applied to a wide variety of inherited defects (listed below). Animal research has demonstrated that injection of hematopoietic stem cells (the stem cells for blood) leads to long-term and successful growth of donor bone marrow stem cells. Research with human patients is ongoing, so far this strategy has only been applied successfully in a few human diseases.

Currently we are studying the application of this technology in patients carrying a fetus with alpha thalassemia major.

https://youtu.be/TXh1zfd21T8

Limitations of traditional postnatal bone marrow transplant

Successful bone marrow transplantation after birth is limited by several factors including a lack of an eligible donor, damage already done to the baby by the disease, rejection of the donor cells by the child’s immune system, and, in some cases, rejection of the baby’s tissue by the donor cells (graft-versus-host disease or GVHD).

Many of the problems associated with transplantation of stem cells after birth are related to the toxic treatment preparation and immune rejection. Transplantation before birth into a fetus whose immune system is not fully developed may overcome these problems.

Inherited Genetic Diseases Treatable with Stem Cells

Hemoglobinopathies

  • Alpha Thalassemia Major — The UCSF Fetal Treatment Center and UCSF Benioff Children's Hospital Oakland Thalassemia Center have established the first multidisciplinary center for Alpha Thalassemia Major. The program is designed to address the complex diagnostic, prenatal, intrauterine, and perinatal management issues affecting a family with an Alpha Thalassemia Major pregnancy. For more information please visit our page on Intrauterine Therapy for Alpha Thalassemia Major
  • Beta Thalassemia major
  • Sickle cell anemia

Immunodeficiency Diseases

  • Severe combined immunodeficiency syndrome
  • Bare lymphocyte syndrome
  • Chronic granulomatous disease
  • Wiskott-Aldrich syndrome
  • Infantile agranulocytosis (Kostman’s syndrome)
  • Lazy leukocyte syndrome (neutrophil actin deficiency)
  • Neutrophil membrane GP-180 deficiency
  • Agammaglobulinemia
  • X-linked lymphoproliferative syndrome
  • X-linked hyper-IgM syndrome

Inborn Errors of Metabolism

Mucopolysaccharidoses

  • Hurler’s and Hurler-Scheie disease (MPS-1) (a-iduronidase deficiency)
  • Hunter disease (MPS-II) (iduronate sulfatase deficiency)
  • Sanfillippo B (MPS-IIIB) (a-glycosaminidase deficiency)
  • Morquio (MPS-IV) (hexosamine-6-sulfatase deficiency)
  • Maroteaux-Lamy syndrome (MPS-VI) (arylsulfatase B deficiency)
  • Sly syndrome (MPS-VII) (b-glucuronidase deficiency)

Mucolipidoses

  • Fabry disease (a-galactosidase A deficiency)
  • Gaucher disease (glucocerebrosidase deficiency)
  • Krabbe disease (galactosylceramidase deficiency)
  • Metachromatic leukodystrophy (arylsulfatase A deficiency
  • Niemann-Pick disease (sphingomyelinase deficiency
  • Adrenal leukodystrophy
  • I-cell mucolipidosis II

Other Hematopoietic Diseases

  • Osteopetrosis
  • Diamond-Blackfan syndrome
  • Fanconi anemia

What is the outcome for a fetus with an inherited genetic disease?

Many genetic diseases affect cells in multiple organs, leading to a wide range of outcomes. Depending on the diagnosis, outcomes may range from death or severe life-long impairment to survival and treatment after birth with minimal impact. Even in the same condition within a family can affect some family members more severely than others. A good example is sickle cell disease: some children have very mild disease and do not need any treatment and others have very severe disease that requires frequent treatment.

Your genetic counselor will help explain the specific prognosis for your fetus’s diagnosis. Information about the consequences of each of these many conditions can be found on reliable websites, support groups, and publications devoted specifically to that diagnosis. We have provided links to some of these resources below.

How serious is the inherited genetic disease in my fetus?

For you to make the best decision, you will need accurate and complete information about your fetus’s condition. In addition, you will want to know if there are associated defects, or if this problem is part of a cluster of problems (syndrome). Testing includes:

  • Genetic testing of fetal material either from the placenta, or from the amniotic fluid, or obtained directly from the fetus. This is the most important part of this evaluation.
  • Examination of family history and DNA from the parents and other family members.
  • Imaging of the fetus by transvaginal or transabdominal ultrasound or magnetic resonance imaging (MRI).
  • In considering possible fetal therapy, it is very important to know the age of the fetus. This is most accurately determined by early ultrasound.

When all the information is available, you will want to discuss it with a knowledgeable genetic counselor or perinatal geneticist. If appropriate, you may be referred to specialists for that particular inherited genetic disease.

What are my choices during this pregnancy?

The most important consideration is the accuracy of the diagnosis along with genetic counseling about the consequences of the condition. If after comprehensive genetic counseling, you choose to continue the pregnancy, you will start planning the proper time and place of delivery for optimal care after birth.

For inherited diseases that cause trouble at birth and require immediate treatment, the place of delivery will be the most important consideration. You may choose to deliver in a center that has special expertise in treating that particular diagnosis.

Babies with some types of conditions will need support in an intensive care nursery, and may require transfusion with blood, dialysis to cleanse the blood, or even postnatal hematopoietic stem cell transplantation. In some cases, the disease may make the baby vulnerable to infection and thus require special precautions. For some rare diseases, there are only a few centers specialized in the treatment of that disease.

Fetal intervention before birth

In some types of genetic diagnoses, intervention before birth may be considered. The reasons to consider intervention before, rather than after, birth are:

  1. The genetic disease causes ongoing damage to the fetus that can be prevented by earlier treatment; and
  2. The disease will require hematopoietic stem cell transplantation and this may be improved when performed before birth.

The potential advantage of stem cell transplantation in utero is to take advantage of fetal immunologic immaturity or tolerance, thus avoiding the need for immunosuppression or myeloablation (destroying some of the bone marrow in order to make room for new donor bone marrow). Some disadvantages are the risk of the procedure itself, which requires injecting the donor cells into the very small fetal abdomen or bloodstream. There is also the risk of causing infection or of the transplant not working. All these factors must be carefully considered before deciding whether to attempt this novel therapy currently under study.

What will happen after birth?

Management after birth will depend on the nature of the inherited genetic condition. In many cases, the baby may require specialized therapy only available at tertiary care centers. For many diseases, hematopoietic stem cell transplantation, usually in the form of a bone marrow transplant, will be planned after birth. Often, repeated testing and careful follow-up are necessary to protect the baby until the transplant is performed.

Even when stem cell transplantation has been performed before birth, careful follow-up after birth will be necessary. In some cases, transplantation of stem cells from the same donor may be repeated after birth, taking advantage of the potential that the prenatal transplantation has established immunologic tolerance to those donor cells.

For many of the inherited genetic diseases, it is helpful for families to connect with other families caring for babies or children with similar challenges.

Support Groups & Other Resources

  • Explore Stem Cells — contains over 50 expert articles about the basics of stem cells and stem cell therapy.
  • March of Dimes — Researchers, volunteers, educators, outreach workers and advocates working together to give all babies a fighting chance
  • Birth Defect Research for Children — a parent networking service that connects families who have children with the same birth defects
  • Kids Health — doctor-approved health information about children from before birth through adolescence
  • CDC - Birth Defects — Dept. of Health & Human Services, Centers for Disease Control and Prevention
  • NIH - Office of Rare Diseases — National Inst. of Health - Office of Rare Diseases
  • North American Fetal Therapy Network — NAFTNet (the North American Fetal Therapy Network) is a voluntary association of medical centers in the United States and Canada with established expertise in fetal surgery and other forms of multidisciplinary care for complex disorders of the fetus.