Enzyme Replacement Therapy For Infantile Onset Neuronal Ceroid Lipofuscinoses

Executive summary SBIR awardRNSThe neuronal ceroid lipofuscinosesNCLsare lysosomal storage diseasesLSDswith a prevalence of approximatelyto nine per million populationtoperlive birthsThe infantile onset form termed CLNdisease is characterized by progressive intellectual and motor deteriorationseizuresloss of visionand early deathThis is caused by mutations in the CLNgenewhich codes for the lysosomal enzyme palmitoyl protein thioesterasePPTresulting in a reduction or absence of enzyme activityCLNdisease usually presents betweenandmonths of age and there arechildren with this form identified each year andknown children with CLNin the USwith likely many more undiagnosedThere is no treatment availableCollaborations PharmaceuticalsIncis working with DrJonathan Cooper and colleagues at the Washington University of StLouisWUSTLto test an enzyme replacement therapy for human recombinant PPTby combined intracerebroventricular and intrathecal dosing in PPTknockout miceAimProduction and Characterization of rhPPTWe will produce sufficient quantities of rhPPTand characterize the enzyme activity AimIntracerebroventricular and intrathecal administration of rhPPTWith the recent finding of significant spinal cord pathology that precedes brain pathology in Clnmiceand that therapeutically targeting this region improves the pathology and extends lifespan and motor performancewe propose treating Clnmice with monthly doses of rhPPTby either ICV or IT injections alone or by a combination of these routes and test for their effectsif anyon enzyme activitygait abnormalities and histopathologyIf we are successful in demonstrating that a combination of intracerebroventricular and intrathecal delivery of rhPPTcan improve the neuropathologymotor performance and restore enzyme activityin Phase II we will pursue efficacy studies in a larger animal model and perform IND enabling toxicologyimmunotoxicologyAn effective enzyme replacement for PPTrelated NCL would become the standard of care as no treatment is currently availableFurtherthe development of an ERT would be complimentary to any efforts to develop gene therapy for this diseaseOur potential return on investment for this treatment would be obtaining the FDA rare pediatric disease priority review voucherProgress to dateWe have initiated Aimto make additional enzymeenough for large animal studiesusing CHO DGcells and have set up our lab at Collaborations Pharmaceuticals Incto do cell culture and protein development for rare diseasesWe have initiated Aimto perform the in vivo studies at WUSTLTo date there have been no major technicaladministrativeor commercial challengesWe have also initiated discussions with clinical research organizations and contract manufacturing organizationse gCalvert labs and MassBiologicsto obtain quotes for future toxicology studies and making proteinrespectivelyI Corps TeamCEO PIDrSean Ekins is the CEO of Collaborations PharmaceuticalsIncCPIand also the PI of this grantHe brings more thanyears of preclinical Drug Metabolism and PharmacokineticsDMPKtoxicologyand drug discovery research in large pharmaceuticalbiotechnologyinformatics software and several start up virtual drug companies and other companiese gCollaborative Drug DiscoveryHe has obtained funding for andgtNIH DOD grants as the PI and has worked extensively on drug discoveryAs CEO of CPI since founding it inhe has been responsibility for the scientific success of research projectsworking closely with collaborators to develop projectsproviding project managementscientific marketing and commercializationCPI have been awardedgrants to date from the NIH and DODHe is therefore actively involved in several grants and collaborative projects working on drug discovery for rare and neglected diseasesHis goal is to industrialize drug discovery for rare diseases and demonstrate that treatments can be developed cost effectively by anyonePI Senior ScientistDrAna Puhl Rubio is the senior scientist working closely on this grant at CPI and collaborating with the team at Washington University of StLouisShe brings extensive knowledge and technical expertise in protein expression and purificationbiochemistry and biophysical techniques relevant to drug discovery and translational researchShe has completedPostdocsmade many proteins and solvedprotein structuresShe has also attended numerous business classes and courses for life science PhDsBusiness Advisory Board memberIndustry expertAndrea BarryBAMSis the President of Eleventh Hour IncShe has overyears of successful leadership and management experience in sales and marketingwith a focus on startups and visionary product releasesMDLScitegicAccelrysVertical i and CDDAndrea has been very closely involved with CPI since it was founded as a member of the board and she has provided business guidanceconsulting and coaching to the CEOEach team member is committed to the time requirements of the program Narrative Recombinant human palmitoyl protein thioeseraserhPPTcan be used as a treatment for PPTdeficient Neuronal Ceroid LipofuscinosesBatten Diseasetermed CLNThe rationale for enzyme replacement therapy is that lysosomal enzymesincluding PPTare taken up into cells via the classical mannosephosphate receptor pathway and can reduce the substrate burden and delay or stabilize disease progressionDelivery of various lysosomal enzymes to the cerebrospinal fluid has shown positive results in large animal models of other neurodegenerative lysosomal storage diseases and is advancing to clinical trials in several casesWe intend to synthesize and evaluate the efficacy of combined intracerebrovascular and intrathecal rhPPTto ultimately develop a treatment for CLNThis I Corps application would allow our experienced team to plan for the commercialization needs in preparation of a Phase II SBIR