AFTD recently spoke with Passage Bio Chief Executive Officer William Chou, M.D., about his colleagues’ work to develop an effective therapeutic designed to treat FTD-GRN.

*Responses have been edited for clarity and length.

 

Can you share some background on Passage Bio’s approach to developing an FTD-focused therapeutic?

As we know, there are some forms of FTD that are driven by a genetic variant, and there is one form where some people with FTD have a deficiency in the granulin gene. With this deficiency, people end up not making enough of an important protein called progranulin, and this is a driver of the problems that arise in some people who have FTD. Our approach at Passage Bio is an adeno-associated virus (AAV) gene therapy that provides a functioning granulin gene to people, enabling them to produce their own progranulin. The hypothesis is that having a higher level of progranulin will be beneficial to people who are diagnosed with FTD caused by a GRN variant.

We deliver our therapy, PBFT02, through an intracisternal magna procedure – it’s a two-minute procedure that’s similar to a lumbar puncture or epidural. Because we administer it closer to the brain to maximize the amount of our AAV gene therapy that gets to the brain, we do it under computer tomography (CT) guidance. We are actively recruiting people to participate in our ongoing clinical trial in the U.S. and other countries.

AFTD Note: The GRN gene makes a protein called progranulin (PGRN). PGRN acts as a caretaker of brain nerve cells, or neurons. PGRN contributes to nerve cell development, survival, function, maintenance, and repair. PGRN also helps reduce inflammation. Though PGRN is not completely understood, we do know when PRGN levels are reduced (due to a pathogenic variant in one copy of the GRN gene), abnormal levels of TDP-43 accumulate, causing FTD.

What inspires you and your colleagues to work in the FTD and neurodegenerative disease space?

I’ve worked in several other gene therapy programs, and once you’ve been able to change a person’s life – either potentially curing them from cancer or making it so they don’t suffer any more debilitating symptoms – once you get that feeling of, “Wow, we can make such a profound impact on people,” you want more. That’s what gene therapies have the potential to do – they can make a dramatic change in a person’s life. It’s incredibly satisfying to be able to do that.

I trained in internal and geriatric medicine, so I’ve taken care of a lot of people with dementia, and I’ve helped a lot of families who’ve struggled with the medical, social, and emotional effects of taking care of a loved one with dementia. Personally, being able to make an impact on people with dementia and their families – particularly with a disease like FTD – it is very special to me.

There is one interaction burned in my memory from the AFTD Education Conference. I was speaking with a family member, a daughter of a person with FTD. Her dad had a genetic variant of FTD, and she had been tested and learned she had that genetic variant, though she is completely asymptomatic. The thing I remember most about this discussion was the urgency that I really felt from her – it was palpable, it was emotional. I felt it inside. When we finished the conference that day, I sent an email to everybody at Passage Bio wanting to share that story and convey her urgency, because we are in a race overall, but we are in a race for this woman. I could feel it for her – we need to get there quicky because she’s looking to us to get there. It makes what we do more meaningful.

What do you hope people will learn and understand about FTD?

For the general community, I think understanding that FTD is its own entity and that is different from other forms of dementia is really important because a lot of times, it’s the people affected and their families that bring something to the attention of physicians and they are the drivers of an earlier diagnosis. You can’t be diagnosed unless you go to the doctor and say, “Hey, something is different.” The subtle changes that happen in FTD may be different than what a person might expect with something like Alzheimer’s – it might not just be memory loss. Dementia might be changes in communication, it might be personality changes. Awareness of this is essential to accelerate diagnosis overall.

For the FTD community, I think it is vital that people diagnosed, their families and their treating physicians understand that treatments are being developed for FTD, but we can only successfully get them developed if people get genetic testing and get involved in the research. When I was in training more than 20 years ago, we counseled people who had neurodegenerative diseases like FTD to not get genetic testing. In medicine, we were taught to not do a test unless there is something you might potentially do with those results. And 20 years ago, there were no treatments being developed and there was nothing you could do with that information from a genetic test.

Here we are, 20 years later and it is 180 degrees different. We have multiple trials going on right now in investigational therapies for patients with certain genetic variants, and so people need to get tested, because there are potential life-changing interventions in development. But we need people to get involved so we can make more rapid progress so we can help people like the young woman I met at the Education Conference.

This year, AFTD is focused on making sure every FTD story counts. Why do you think it is important for people to share their stories?

Awareness of FTD and sharing FTD stories is important for both physicians and people impacted. From a physician standpoint, FTD is trickier to diagnose. The changes can be more subtle – it’s less common than other forms of dementia, and awareness is only going to help with diagnosis. For those who are affected, FTD can be a difficult disease to live with – sharing an experience is a way people can cope and awareness is going to help people and their families know there are others out there like them. I truly believe that stories are the most effective way to raise awareness because people remember stories, as stories often have an emotional component.

What are your hopes or visions for the future of FTD and the neurodegenerative disease landscape?

My real hope for FTD and other neurodegenerative diseases is that they’re someday seen as manageable, treatable illnesses with impactful therapeutic interventions available. In my career as a physician, I’ve seen multiple diagnoses go from being seen as fatal to now being diseases we can treat. As an example, when I was in medical training there were no effective treatments for HIV, and a diagnosis was akin to a death sentence. Now, HIV is a chronic disease that can be managed. We’ve gotten here through a lot of research and a lot of science.

Another example is sickle cell disease, which causes people to get debilitating pain crises, and face an earlier mortality. There had been decades without meaningful advancements in therapeutic options, and we now have an approved – and will hopefully soon have more than one approved – genetic therapy that can dramatically change a person’s life. It is a tidal wave, a sea change, in how people see both of those diseases.

There are hundreds of patients who’ve been treated with genetic medicines – we have multiple approved genetic therapies that are on the market right now, which means the data have been strenuously evaluated in the U.S. and Europe and the therapies have been deemed safe and effective.

The science is rapidly advancing in FTD and there are many genetic medicines showing great promise that we can get to the same level of impact in treatment, but we can only get there with people, clinicians, and family members getting involved – that means getting genetic testing and participating in research. There is tremendous power in genetic medicines. The science is catching up in neurodegenerative disease – so there is great hope for the future. The impact can be profound for people who face a diagnosis.

AFTD Note: Whether you have a personal or family history of FTD, or whether past misdiagnosis could potentially be masking one, AFTD strongly recommends that you consider genetic counseling as a first step to answering questions about your genetic status.

A genetic counselor can evaluate the likelihood that you or your family’s condition has a genetic cause and can help you think through the benefits and risks of genetic testing and ways to talk to family members about genetic testing, privacy concerns, and more. For individuals who are interested in genetic testing, the genetic counselor will discuss the risks and benefits of testing and identify the specific test that can ensure the most accurate results possible. For more information about genetic counseling, click here.

 

AFTD deeply appreciates Passage Bio’s continued support of our mission and their Gold-level sponsorship of the 2023 Education Conference. You can now view recorded sessions of this year’s event on AFTD’s YouTube channel.