PROJECT SUMMARY Diffuse Intrinsic Pontine Gliomas (DIPG) are rare and deadly pediatric brain tumors. They are extremely aggressive tumors that are found in the pons, which controls many of the body's most vital functions such as breathing, blood pressure, and heart rate. There is no currently effective means of treatment for DIPG, and the median survival is 7-11 months after diagnosis. Thus, there is significant need for a method to effectively treat DIPG. To address this unmet need, SonALAsense is developing sonodynamic therapy (SDT), a non-invasive drug-device combination, to treat DIPG. SDT uses an MRI-Guided Focused Ultrasound (MRgFUS) device in combination with a drug called 5-aminolevulinic acid (ALA). Three independent laboratories have demonstrated the safety and efficacy of ALA SDT in animal glioma models where the animals were dosed first with ALA and then treated with MRgFUS at energies that do not raise brain temperature. MRgFUS activated Protoporphyrin IX (PpIX), a metabolite of ALA, created singlet oxygen that induced necrosis and apoptosis in the glioma in a process similar to photodynamic therapy. Activation of PpIX non-invasively caused regression of the gliomas and extended survival. The goal of this Direct to Phase II program is to provide safety and efficacy data on the best MRgFUS energy doses to use with 10 mg/kg intravenous (IV) ALA for subsequent clinical trials of ALA SDT in DIPG. This will be accomplished through the execution of 3 Aims. In Aim 1, we will develop sensitive assays to detect ALA and PpIX in small blood sample volumes. In Aim 2, we will determine blood plasma pharmacokinetics (PK) of ALA metabolism and PpIX synthesis following IV dosing as this is the first time an IV formulation of ALA will be used for therapeutic purposes in children, and it is important to understand possible differences in PK between pediatric and adult subjects. In Aim 3, we will determine the safety and efficacy of ALA SDT in DIPG patients using a single IV dose of ALA while using 3 ascending MRgFUS energy dose cohorts. This will help determine both the maximum tolerated energy dose in DIPG patients and the recommended Phase 2 dose of MRgFUS energy in combination with 10 mg/kg IV ALA. Successful completion of this proposal will inform a drug dose ranging study. Completion of these trials are critical to proceed to the next stage of clinical development, in which DIPG patients will receive SDT therapy on a monthly basis to attempt to maximize effects on survival of these patients using a safe IV dose of ALA in combination with an optimal dose of MRgFUS. The goal of this development program is to obtain the clinical data necessary for FDA marketing approval and to commercialize this combination therapy for DIPG patients who have no therapeutic options. ALA SDT has the potential to be the first successful treatment for DIPG and for the first time in medical history parents of children with DIPG would not only have hope that the life of t...