Developing Insulin-like growth factor binding protein 2(IGFBP2)peptide fragment-based therapeutics to treat functional and behavioral deficits in Phelan-McDermid Syndrome.

ABSTRACTAlisBio is developing novel therapeutics based on Insulin like growth factor binding proteinIGFBPpeptide fragments to treat functional and behavioral deficits in Phelan McDermid SyndromePMSa monogenic form of autism spectrum disorderASDaccounting forof ASD diagnosesThe focus of this Phase I grant is to demonstrate that proprietary IGFBPmimetic peptide fragments reverse disease relevant cellularfunctional and behavioral deficits in a mouse model of PMSIncreasing prevalence of ASD diagnoses in the U Sposes an enormous personal and public health challengewith annual costs of care for children with ASD estimated to be $BDue to the immense etiological heterogeneitydevelopment of therapeutics for ASD is extremely challengingDrug development for etiologically defined subtypes of ASDsuch as PMScould be achievable and could pave the way for treatment of other forms of autismDevelopment of the first effective pharmacological treatment for PMS would therefore have a substantial impact for the management of PMS andpotentiallyASDThere are no existing disease modifying therapeutics for PMS or ASD on the market todayAn experimental treatment based on IGFI has shown some efficacy but suffers from significant drawbacks as a long term treatment optionThe established course of treatment for PMS and ASD today leverages regular therapiese gspeechphysicaloccupationalbehavioralto support developmental challenges and specific medicationse gADHDepilepsyanxietyto address the variety of specific clinical symptomsAlisBio s approach is valid and relies on key innovationsprevious research by the team showed that IGFBPs have a completely novel pharmacology producing their therapeutic effects via a unique mechanism of actionthe proposed research uses peptide fragments from the conserved sequences of the active IGFBPs that show high activity and potency and are well toleratedmaking them ideal therapeutic agentsandprevious research by the team showed that IGFBPand therefore the proprietary peptide fragmentsare superior to IGFI in its therapeutic like effects as well as enhancing synaptic plasticitywhich is the underlying deficit in PMSThe team on this STTR project has extensive published expertise on developing other peptides from preclinical testing to successful Phase II clinical trial dataas well as on investigating synaptic plasticity in neurodevelopmental disorders and ASDTheSpecific Aims of the proposed project areto determine the ability of proprietary IGFBPmimetic peptide fragments to rescue disease relevant cellular abnormalities in Shankdeficient mouse neuronsto determine the ability of proprietary IGFBPmimetic peptide fragments to rescue in vivo dendritic spine morphology and in vivo auditory LTP deficits in Shankdeficient miceandto determine the ability of proprietary IGFBPmimetic peptide fragments to rescue in vivo learningmemoryand vocalization quality measures in Shankdeficient miceSuccessful completion of this proposal will show that the proprietary IGFBPpeptide fragments rescue the cellularelectrophysiological and behavioral deficits in Shankdeficient miceThe Company will then advance the therapeutic to Phase II IND enabling studies and follow on clinical trials NARRATIVE Autism spectrum disordersASDpresent an enormous personal and public health challengewith the prevalence of diagnosis ofinchildren in the U Sand total annual costs of care of $BThere are no disease modifying pharmacological treatments for ASD that address core neurodevelopmental deficitsPhelan McDermid SyndromePMSis one of few etiologically defined forms of ASD accounting forof ASD diagnosesThis Phase I STTR application sets out to demonstrate that proprietary IGFBPmimetic peptide fragments reverse cellularelectrophysiological and behavioral phenotypes of a mouse model of PMSand due to their unique characteristics present a novel path to developing the first effective pharmacological treatment for PMS andpotentiallyASD