ETHICS for LUNCH: Parental Request for Experimental Therapy for a Child

1. ETHICS for LUNCH: Parental Request for Experimental Therapy for a Child J.M. Lorenz, MD February 16, 2006

2. Timmy is a 6 month old infant who was well until ~ 3 mo of age when parents noted loss of tone and movement in his lower extremities. A diagnosis of Spinal Muscular Atrophy-Type 1 (SMA) was made by a pediatric neurologist. Subsequently, the diagnosis was genetically confirmed. THE CASE

3. Spinal Muscular Atophy–Type I(aka Werdnig-Hoffamann disease) • Progressive neurodegenerative disorder affecting anterior horn cells • No known specific therapy • All children with SMA become quadriplegic • Mental status remains completely normal • In the past, average life span was two years; more recently with more aggressive care at least some children with the disease are now surviving to school age.

4. Condition at presentation to MSCHONY: Severely hypotonia with little movement of the upper extremities and absent deep tendon reflexes Cranial nerves function intact Breathing is diaphragmatic, but without respiratory distress Able to breast feed. THE CASE

5. QUESTION The bone marrow transplantation specialists (Dr. K) requested an ethics consultation regarding whether it ethical to offer a stem cell transplant, a highly experimental therapy, to a baby with SMA-type 1.

6. RELEVANT ISSUES ?

7. RELEVANT ETHICAL PRINCIPLES • Beneficence • Best interest standard • Parental autonomy • Distributive Justice

8. Stem cell transplant for SMA: BENEFIT ? • Stem cell transplantation as a therapy for SMA is based on the theory that pleuripotential cells can replace the damaged anterior motor neurons • There are no in vitro, animal, or human data regarding stem cell transplantation for SMA • Stem cell transplantation has been successful and resulted in clinical benefit in several neurologic diseases • This demonstrates the possibility of stem cell reaching the central nervous system, but the defective cells in these diseases are not anterior horn cells as in SMA

9. Stem cell transplant for SMA: BENEFIT ? • The closest analogous condition in adults is amyotrophic lateral sclerosis (ALS) • Results of stem cell transplants in animal models of ALS have been mixed • At a recent conference, investigators who had performed stem cells transplants in human adults with ALS were criticized for doing so with insufficient preclinical research • The scientists with expertise in SMA, whom the parents have contacted, are evenly spilt as to whether this procedure should be performed.

10. Stem cell transplant for SMA: BENEFIT IN THIS CASE ? • The benefit is “indefinable” • The availability of cord blood with a perfect HLA match in this case makes the likelihood of engraftment high • It is unknown whether the transplant will alter the course of the disease; at best, however, Dr. K believes that it may slow or halt the progression of the disease, but not result in recovery of lost function • Were the transplant to be performed • extensive pre and post neurological and pulmonary function testing will be performed • If and when the child expires, autopsy permission will be sought to confirm CNS engraftment.

11. Stem cell transplant for SMA: RISKS • Timmy is eligible for the lowest risk IRB approved immunosuppression protocol for nonmalignant diseases • Experience with this protocol has shown little serious toxicity from the immunosuppression drugs • The perfect HLA match in this case considerably reduces risk of graft versus host disease: the risk of lethal graft versus host disease is no greater than 10%.

12. The Family • Timmy’s parents proactive, well informed, and medically sophisticated • Stored cord blood is available from a previous child, who is a perfect HLA match with Timmy • The have consulted neurologists, geneticists, stem cell biologists, the SMA Foundation, numerous internet sites, and parents of children with SMA • They have had extensive counseling regarding prognosis and care required for children with SMA, as well as the risk and experimental nature of stem cell transplantation for SMA • After careful consideration, the parents are united in their desire for the stem cell transplant

13. SUMMARY: RELEVANT ISSUES • 1. The child’s prognosis without treatment is very guarded, but survival for some period of years is possible. • 2. Judgment of quality of that survival is very subjective and, therefore, the purview of the parents • 3. The basis for performing stem cell transplantation is purely theoretical, without any in vitro, animal or human data. • 4. The procedure carries a risk of death that may be as high as 10% with the lowest risk immunosupression protocol

14. SUMMARY: RELEVANT ISSUES • 5. Engraftment is likely, but the likelihood of any clinical benefit to the child is unquantifiable. • 6. The basis of the decision should first and foremost be Timmy’s best interest. • 7. The family seems to be well informed and have Timmy’s best interest of at heart. • 8. The results of this stem cell transplant may provide important information that could benefit patients in the future.

15. COMMITTEE OPINION • Stem cell transplantation, with the informed parental consent, is an ethically acceptable option in this case • Consideration of Timmy’s best interest and parental understanding of the disease, its prognosis, the care the child will require, the real risk of death, and the unknown benefits of and the experimental nature of stem cell transplantation are absolutely essential to this decision • Given the experimental nature of the procedure, care should be taken to learn as much as possible from this experience if it is undertaken.

16. RESOLUTION At a subsequent meeting with the parents very shortly after the initial consultation, the Director of the Bone Marrow Transplant Center related the issues and concerns that had been raised by the Ethics Committee. At that time the parent decided against stem cell transplantation.