Stem Cell Treatment For Cerebral Palsy:
Cerebral palsy (CP) is a non progressive encephalopathy with clinical syndrome of restricted movement and posture with diverse etiologies. Its development could be attributed to prenatal, perinatal or post natal factors. Evidence suggests that prenatal factors result in 70-80% of cases of cerebral palsy. Cerebral palsy (CP) is known to affect 2/1000 live-born children. The symptoms of CP vary in terms of severity. The main symptoms include muscle spasticity, muscle weakness, uncontrolled movements, impaired mobility, speech impairment and/or challenges in eating, dressing, bathing, etc depending on the area of the brain affected.
Movement dysfunction is often accompanied by visual impairment, hearing loss, osteoporosis, learning disabilities, cognition impairment, behavioral issues and seizures. Risk factors for cerebral palsy include prenatal anemia, improper nutrition, infections, premature delivery, etc. Hypoxia and ischemia are the major risk factors prenatally and during delivery.
The conventional treatments available currently for CP are physical and behavioral therapy, Hyperbaric oxygen therapy (HBOT), Botulinum A toxin injection, surgical treatments, assistive devices, and medical management of associated conditions play a supportive role.
Unmet medical needs
The prevalence of CP is increasing due to decrease in mortality of low birth weight infants and increase in the rate of CP in these children. Hence, establishing a standard therapeutic approach is the focus of researchers and clinicians all over the world. Although the available treatment options are helpful in managing the symptoms to some extent, none of them repair the underlying damaged brain. There are no definitive treatment options to accelerate the development of cerebral palsy patients.
Role of Stem Cell Treatment For Cerebral Palsy
One of the common causes of cerebral palsy is hypoxic ischemia. The underlying neuropathology of CP mainly includes periventricular leukomalcia (PVL). It consists of diffuse cerebral white matter injury with or without focal necrosis. In PVL, there is also loss of pre-myelinating oligodendrocytes (pre-OLs) along with astrogliosis and microglial infiltration. The loss of pre-OLs lead to disruption in the production of mature OLs which further leads to disturbance in myelination followed by neuronal dysfunctions.
In CP, another contributing factor is the microglial activation which instigates the secretion of tumor necrosis factor alpha (TNF-?), interferon gamma (INF- ?), Interleukin -1 beta (IL-1?), superoxide radicals, nitrogen species, glutamates, adenosine exerting a toxic effect on neurons and oligodendrocytes. Stem cell therapy regulates these cellular mechanisms. Stem cells migrate and home onto the damaged areas and initiate repair process. They exert an anti-inflammatory effect by reducing the levels of TNF-?,IL-1?, IL-1?, IL-6 and increasing levels of IL-10; therefore, enhancing the endogenous brain repair. Stem cells also restore the damaged myelin by replacing lost OLs and pre-OLs.
Various preclinical studies have demonstrated the potential of
stem cell therapy in cerebral palsy.
Administration of these cells in animal models have led to survival, homing and differentiation into neurons, oligodendrocytes, astrocytes, etc. The homing property of these cells was confirmed by Chen et al, who transplanted magnetically labeled mesenchymal stem cells in a model of perinatal brain injury and found that these cells migrate to lesion sites and proliferate.
Woodbury et al. have demonstrated the differentiation of bone marrow cells into neurons in adult rats. Similarly, studies have shown that umbilical cord blood stem cells proliferate into neural cells via Sonic hedgehog (Shh) signaling pathway. Park et al reported differentiation of clonal neural stem cells (NSCs) into neurons and oligodendrocytes.
Titomanlio et al implanted neurosphere-derived precursors in neonatal mouse models which migrated to the lesion site and differentiated into oligodendrocyte and neurons and triggered reduction in lesion size along with improvement in memory performance. Transplantation of umbilical cord blood cells in rat models have shown to improve sensorimotor deficits along with other neurological functions. Other cells such as multipotent progenitor cells (MPCs) and oligodendrocyte precursor cells were also found to be efficacious in rat models.
Not many human clinical studies have been performed till date in CP. Few researchers have reported a positive outcome of intravenous and intrathecal administration of cord blood (CB) cells Li et al reported a case of intravenous autologous BMSCs transplantation, wherein improvements were observed after 6 months. Similarly, other studies involving intrathecal autologous BMSCs have 115 also demonstrated motor and functional improvements.
Seledtsov et al carried out a controlled study injecting a cell suspension from immature nervous and haematopoietic tissues. Their findings suggested that cell therapy was an effective, safe and immunologically justified method of therapy for patients with cerebral palsy. Chen et al and Luan et al administered neural stem cell like cells and neural progenitor cells respectively. They reported these cells to be safe and efficacious.