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; SONALA-001). 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. We also have data that support that ALA SDT is safe and well-tolerated in adult patients with recurrent glioblastoma multiforme, and leads to targeted oxidative stress and accompanying apoptosis in tumor tissue, in the absence of a thermal effect, similar to the animal model results. SONALA-001 is Orphan Drug designated for the treatment of all malignant gliomas and an Investigational New Drug (IND) application was cleared to proceed by the FDA. The goal of this R01 is to execute a Phase 2 clinical trial to provide safety and efficacy data for subsequent trials of ALA SDT in DIPG. As one of three clinical trial sites participating in this trial, the Ivy Brain Tumor Center will enroll 12 DIPG patients in up to 9 cohorts. This trial will be uncontrolled for ethical reasons. First, we will determine blood plasma PK of ALA metabolism and PpIX synthesis as this is the first intravenous (IV) formulation of ALA. Second, we will determine the maximum tolerated dose (MTD) or recommended Phase 2 dose of MRgFUS energy combined with IV ALA. Third, we will determine safety and efficacy of ALA SDT by following patients for up to 12 months. Successful completion of this trial will identify a safe dose 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 medi...