A Study of PBFT02 in Patients With Frontotemporal Dementia and Progranulin Mutations

Open to people ages 35-75

1. Documented to be a GRN mutation carrier
2. Clinical diagnosis of frontotemporal dementia
3. Plasma NfL level > 50 pg/mL
4. Have a reliable informant / caregiver (and back-up informant / caregiver) who personally speaks with or sees the subject at least weekly
5. CDR plus NACC FTLD global score of 0.5 or 1.0
6. Should be living in the community (ie, not in a nursing home); assisted living may be permitted at the discretion of the investigator

1. Biomarker evidence of Alzheimer's disease (AD).
2. Previous treatment with any gene therapy. Any other therapies with the potential to alter PGRN levels must be washed out for at least 5 half-lives prior to entry into this study
3. Homozygous GRN mutation carrier
4. Rosen-modified Hachinski Ischemic Scale score > 7
5. Known presence of a structural brain lesion (eg, tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic subject
6. Known presence of an AD-causing mutation in PSEN1, PSEN2 or APP based on genetic testing history (if performed)
7. Previous history of Korsakoff encephalopathy, severe alcohol or substance dependence (within 5 years of onset of dementia), except where onset of increased alcohol consumption occurs at the time of FTD disease onset
8. History of untreated vitamin B12 deficiency
9. Evidence through history or laboratory testing of unregulated hypothyroidism (thyroid stimulating hormone [TSH] > 150% of normal)
10. . Serum creatinine > 2 mg/dL
11. . Total bilirubin above the upper limit of normal
12. . Elevated hepatic enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 2 × upper limit of normal [ULN])
13. . Respiratory failure that requires supplemental oxygen
14. . Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent
15. . Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy)
16. . Any contraindication to the ICM administration procedure
17. . Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, LP, and/or MRI (Temperature > 38°C, oxygen saturation below 95% on room air or baseline oxygen requirement, heart rate or respiratory rate abnormal for age of the subject, abnormal blood pressure for age, evidence of infection)
18. . Immunocompromised patients
19. . Peripheral axonal sensory neuropathy
20. . Receipt of a vaccine within 14 days of dosing
21. . A positive test result for human immunodeficiency virus (HIV) or Hepatitis B or C; a Mycobacterium tuberculosis positive test within 1 year of or determined at screening
22. . Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome
23. . Any concurrent disease that, in the opinion of the investigator, may cause cognitive impairment unrelated to GRN mutations, including other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin deficiency
24. . Current or recent history of clinically significant suicidal ideation within the past 6 months
25. . For females of childbearing potential, a positive serum pregnancy test at the screening visit, a positive serum result on Day 1 prior to administration of the investigational product, or unwillingness to have additional pregnancy tests during the study. Females of childbearing potential must use a highly effective method of birth control or engage in abstinence until 90 days postdose
26. . Women who are breastfeeding
27. . For men of childbearing potential, unwillingness to use a medically accepted method of double-barrier contraception (such as a condom/diaphragm used with spermicide) or engage in abstinence from the date of screening until 90 days postdose
28. . Any condition (eg, history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk or would interfere with evaluation of the investigational product or interpretation of subject safety or study results
29. . Any acute illness requiring hospitalization within 30 days of enrollment
30. . Subjects who do not meet the protocol-specified coagulation test criteria
31. . Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study is exclusionary. Antiplatelet therapies may be acceptable
32. . Subjects with hypersensitivity or contraindications to corticosteroid use
33. . Subjects with known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds