A Study of PBFT02 in Patients With Frontotemporal Dementia and Progranulin Mutations (FTD-GRN) (upliFT-D)

This is an interventional treatment trial for Frontotemporal Dementia focused on measuring frontotemporal dementia, Progranulin Mutations, FTD-GRN, Gene Therapy, Dementia Gene Therapy, AAV1, Fronto-temporal Dementia Read More

Inclusion Criteria:

1. Documented to be a pathogenic GRN mutation carrier
2. Clinical diagnosis of frontotemporal dementia
3. Have a reliable informant / caregiver (and back-up informant / caregiver) who personally speaks with or sees the subject at least weekly
4. Living in the community (i.e., not in a nursing home); assisted living may be permitted at the discretion of the investigator

Exclusion Criteria:

1. Classification of the GRN mutation as "not pathogenic," "likely benign variant," "benign variant," or "pathogenic nature unclear"
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. Presence of untreated hypothyroidism (thyroid stimulating hormone [TSH] > ULN and free T4 < LLN)
10. eGFR ≤ 30 ml/min (as calculated using the CKD-EPI equation)
11. Alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 2 × ULN, or total bilirubin > ULN)
12. Respiratory failure that requires supplemental oxygen
13. Inability to provide full consent or the lack of a legally authorized caregiver with adequate contact who can provide consent
14. Any contraindication to MRI or lumbar puncture (LP) (eg, local infection, history of thrombocytopenia, coagulopathy)
15. Any contraindication to the ICM administration procedure
16. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, LP, and/or MRI (e.g., fever, hypoxia, tachycardia, or evidence of active infection)
17. Immunocompromised status
18. Peripheral axonal sensory neuropathy
19. Receipt of a vaccine within 14 days of dosing
20. A positive test result for human immunodeficiency virus (HIV), human T cell leukemia virus (HTLV) type 1 or type 2, or Hepatitis B or C; a Mycobacterium tuberculosis positive test within 1 year of or determined at screening
21. Malignant neoplasia (except localized skin cancer) or a documented history of hereditary cancer syndrome
22. 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
23. Current or recent history of clinically significant suicidal ideation within the past 6 months
24. 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
25. Women who are breastfeeding
26. For sexually active men, 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
27. 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
28. Any acute illness requiring hospitalization within 30 days of enrollment

29. Failure to meet the protocol-specified coagulation test criteria:

    • Platelet count over 100,000 per uL
    • INR less than 1.5
    • aPTT less than 40 seconds
30. Use of anticoagulants in the 2 weeks prior to screening, or anticipated use of anticoagulants during the study. Antiplatelet therapies may be acceptable
31. Hypersensitivity or contraindications to corticosteroid use
32. Known or suspected intolerance or hypersensitivity to PBFT02 or any of its ingredients or to closely related compounds