mycophenolic-acid and Neuronal-Ceroid-Lipofuscinoses

Abstract Juvenile Neuronal Ceroid Lipofuscinosis is a lysosomal storage disease characterized pathologically by intracellular accumulation of autofluorescent storage material and neurodegeneration. Caused by mutations in the CLN3 gene on chromosome 16p12, the precise functions of the encoded protein remain unclear. Yet, recent preclinical discovery has established new therapeutic targets in development, including immunosuppressants, anti-inflammatories, and gene replacement therapies. Development of robust clinical trial endpoints appropriate for this poly-symptomatic disease, clinical trial design optimized for small samples, and adequate and efficient participant recruitment are challenges that lay ahead.

Topics: Aminopyridines; Anti-Inflammatory Agents; Genetic Therapy; Humans; Immunosuppressive Agents; Membrane Glycoproteins; Molecular Chaperones; Mycophenolic Acid; Neuronal Ceroid-Lipofuscinoses; Prednisone

Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model.. HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression.. Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease.. This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders.

Topics: Child; Child, Preschool; Dexamethasone; Drug Administration Schedule; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Mycophenolic Acid; Neural Stem Cells; Neuronal Ceroid-Lipofuscinoses; Neurosurgical Procedures; Stem Cell Transplantation; Stereotaxic Techniques; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Tripeptidyl-Peptidase 1

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) presents with progressive vision loss at 4-7 years of age. Blindness results within 2 years, followed by inexorable neurologic decline and death. There is no treatment or cure. Neuroinflammation is postulated to play a role in the neurodegeneration. The JNCL mouse model demonstrated decreased neuroinflammation and improved motor skills with immunosuppression. Based on this work, a short-term human clinical trial of mycophenolate mofetil has begun, however longer term effects, and whether immunosuppression modulates vision loss, have not been studied. We report a JNCL patient treated with immunosuppressive therapy in whom visual function was comprehensively characterized over 2 years.

Topics: Child; Dark Adaptation; DNA Mutational Analysis; Electroretinography; Female; Humans; Immunosuppressive Agents; Membrane Glycoproteins; Molecular Chaperones; Mycophenolic Acid; Neuronal Ceroid-Lipofuscinoses; Photic Stimulation; Retinal Degeneration; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity

Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and in the Cln3-/- mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3-/- mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease.

Topics: Animals; Autoantibodies; Blotting, Western; Brain; Cell Count; Disease Models, Animal; Immunohistochemistry; Immunosuppression Therapy; Immunosuppressive Agents; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones; Motor Skills; Mycophenolic Acid; Neuronal Ceroid-Lipofuscinoses; Neurons