Disease Team Therapy Planning I
Spina bifida is a devastating birth defect that causes lifelong lower extremity paralysis. It is one of the most common birth defects in the United States. Spina bifida can affect physical, educational, social, and psychological development, and most patients require many operations throughout life. The societal costs associated with this disease are staggering: the average total lifetime cost to the State of California ranges from $532,000 to well above several million dollars per child born with spina bifida, and these figures do not include the indirect medical costs, pain and suffering, and lost productivity of unpaid caregivers. The most severe form of spina bifida, myelomeningocele or MMC, occurs when normal fetal development is interrupted anywhere from the brain to the end of the spinal cord, and the tissue surrounding the developing spinal cord does not close properly. As a result, the nerves do not develop as they should. Results of the recently completed nationwide Management of Myelomeningocele Study strongly suggest that prenatal repair of MMC is safe and effective in improving brain function and preventing hydrocephalus (fluid in the brain), thus decreasing postnatal ventricular shunting (drains). However, improvements in bladder and bowel function and lower extremity paralysis remained limited. We are thus left with an unsolved problem that profoundly impacts patients, their caregivers, and society. This Disease Team grant proposes investigation of an innovative stem cell-based therapy for MMC. Because of the unique immunologic conditions of the fetal environment, stem cell therapy offers the potential to cure this debilitating defect. Specifically, we hypothesize that neural crest stem cells delivered via a bioengineered nanofibrous scaffold placed on the defect will correct the damage to the developing spinal cord, promote neural regeneration and improve the adverse effects of MMC. A clinical trial using stem cell-seeded bioscaffolds to treat fetal MMC will be conducted by our multidisciplinary Disease Team, which is made up of experts in pediatric and fetal surgery, neuroanatomy and neurobiology, spinal cord injury, bioengineering, stem cell science, and nanotechnology. Successful use of stem cell therapy for spina bifida would provide a more effective treatment for this disease to a larger proportion of affected patients, and our investigation and optimization of this treatment approach could pave the way for many other clinical applications of stem cell-seeded bioscaffolds.
Statement of Benefit to California:
California’s 5-year statewide rate for spina bifida (myelomeningocele, MMC) was 6.8 per 10,000 live births between 1999 and 2003. Hispanics, who make up approximately 37% of the State’s population, experienced higher rates of spina bifida and other neural tube defects than any other single racial/ethnic population. This 5-year rate was significantly higher than the Healthy People 2010 target of 3 per 10,000 births, based on an objective to reduce the occurrence of spina bifida in the State. Economic and social costs associated with spina bifida are significant. Average total lifetime cost to California is approximately $532,000 per child born with spina bifida. For many children, the cost may be well above several million dollars, and these figures do not account for indirect medical costs, pain and suffering and lost time of unpaid caregivers. Spina bifida is the most disabling birth defect compatible with life and affects children in essentially all aspects of their lives. There are interventions that improve function, but none are curative and many are temporary or minimally effective. Interventions beyond prevention that mitigate the negative consequences of spina bifida are necessary to improve the lives of affected individuals. The great promise of fetal therapy for spina bifida is that the earliest possible intervention—in the womb—will reduce the need for shunting and the adverse impacts on learning and adaptation and will correct the lower body paralysis that these individuals suffer from birth. Results from the recently completed NIH Management of Myelomeningocele Study showed that prenatal spina bifida repair is beneficial. Babies who underwent fetal intervention experienced fewer neurological problems, were less likely to have a shunt, and were more likely to have a normally positioned brainstem and better leg motor function compared with those treated after birth. The trial represented the first attempt to prevent the consequences of the disease rather than treating the problems after they arise. The results suggest, for the very first time, that the paralysis associated with spina bifida might be cured. This proposal presents an innovative stem cell based therapy that may eliminate the distal neurologic dysfunction of spina bifida. In summary, the cost of this lifelong birth defect is staggering to California and the toll taken on the quality of life of affected children and their caretakers is profound. A curative treatment would relieve the State of the tremendous cost burden of the disease and will be life-changing for individuals with spina bifida. The proposed clinical trial will enroll patients across California. Scientific findings and biomedical materials from our studies will be publicly available to State non-profit and academic organizations. Intellectual property will be developed under the CIRM guidelines to benefit California.