PHILADELPHIA—Passage Bio Inc., a genetic medicines company focused on developing therapies for rare central nervous system (CNS) disorders, has published data supporting development of its gene therapy PBFTO2 for patients with frontotemporal dementia caused by mutations in the granulin gene (FTD-GRN). Passage Bio plans to initiate a Phase 1/2 trial in humans next year, with the goal of offering a transformative therapy to patients with this disease, which has no treatment options.

FTD is one of the more common causes of early-onset (midlife) dementia, causing impairment in behavior, language and executive function, and occurs at similar frequency to Alzheimer’s disease in patients younger than 65 years.

In preclinical work published online in the peer-reviewed scientific journal Annals of Clinical and Translational Neurology (ACTN), researchers found that a single administration of an optimized adeno-associated virus (AAV) containing the GRN gene resulted in elevated levels of progranulin (PGRN) in the brain and cerebral spinal fluid (CSF), reduced lysosomal storage lesions, normalized lysosomal enzyme expression, and corrected microgliosis in a mouse model of progranulin deficiency.

This shows that a single injection of AAV-granulin gene therapy into the CNS reverses frontotemporal dementia pathology caused by granulin mutations and is well tolerated. The study was conducted by the University of Pennsylvania’s (UPenn) gene therapy program, which supports further development of Passage Bio’s PBFT02.

The use of this approach with PBFT02 may allow researchers at UPenn and Passage Bio to empirically determine the levels of brain progranulin required to overcome this deficiency.

“We are planning to conduct a Phase 1/2 clinical trial beginning in the first half of 2021 in humans,” Bruce Goldsmith, Passage Bio CEO, tells DDN.

“There are currently no disease-modifying therapies for FTD patients. Their only option is supportive care and treatments aimed at temporarily reducing their behavioral, cognitive and movement symptoms,” he continues. “Our ultimate goal is to change this situation by developing a therapy that will be transformative for patients with FTD-GRN. FTD is one of the more common causes of early onset dementia; about 5 to 10 percent of FTD, which is about 3,000 to 6,000 patients in the U.S., is caused by a granulin gene mutation.”

“Our priority focus is first conducting a clinical study of PBFT02 in FTD-GRN,” Goldsmith adds. “There has been significant preclinical study of PBFT02, showing potential promise of this therapy for the GRN population. However, this does not preclude future study of PBFT02 for the broader FTD population.”

The upcoming study “entails using a device to directly inject PBFT02 into the intra-cisterna magna (ICM) region of the brain, which is a fluid-filled space behind the cerebellum,” Goldsmith explains. “The ICM route of administration has been shown to provide improved bio-distribution and transduction compared to the systemic (IV) administration in non-human primates, and also lower dose levels are expected to achieve the same protein expression.

“The ICM approach we are implementing was developed by the UPenn team and utilizes a combination of MRI and fluoroscopic imaging to guide injection. We have worked with the team there to develop a guide and training for use in our clinical studies.”

According to Goldsmith, the Phase 1/2 trial will be “a multi-center, open label, single-arm, dose escalation study to assess the safety and tolerability of a single dose of PBFT02 delivered into the ICM of adult subjects with frontotemporal dementia and heterozygous mutations in the granulin precursor gene.” Expected enrollment for the trial is nine patients.

To identify a vector capable of achieving optimal expression levels of GRN, the preclinical study evaluated three AAV serotypes (1, 5, and hu68) in non-human primates, as noted in the ACTN article. Following a single ICM injection of the AAV-GRN vectors, all non-human primates, regardless of AAV serotype, showed increased PGRN levels in the CSF. The injections were also well tolerated across serotypes.

However, a single administration of an optimized AAV1-GRN vector (PBFT02) showed the greatest CSF expression levels, reaching more than 50-fold the normal expression level, according to the published article. AAV1 also appeared to demonstrate extensive transduction of the ependymal cells that line the ventricles of the brain and are involved in the production of CSF.

“These findings suggest that the highly transduced ependymal cells achieved with AAV1 could be the primary source of PGRN in the CSF, which also could make it the ideal choice for GRN gene therapy,” stated Dr. James Wilson, director of the Gene Therapy Program at the University of Pennsylvania and chief scientific advisor of Passage Bio. “Of course, more study is needed, which is why we look forward to Passage Bio’s clinical development of PBFT02 for patients with FTD-GRN.”