Pioneering Progress: Insights from ASGCT 2025 on the Future of PMS Therapeutics
Last week I attended the annual meeting of the American Society of Gene and Cell Therapy in New Orleans. It’s the largest gene therapy meeting, with about 8,000 attendees, attracting patient advocates, academic investigators, and companies from around the world. Below are my take-aways from the meeting, including some insights about how new breakthroughs in gene therapy might be relevant to PMS.
Early diagnosis is key
The talks by Dr. Kiran Musunuru and Dr. Rebecca Ahrens-Nicklaus about baby KJ’s tailor-made gene editing therapy were among the highlights of ASGCT. Another inspiring talk was from Dr. Tippi MacKenzie, a fetal surgeon, who is treating genetic diseases even prior to birth. Key take-away: early diagnosis enables early intervention.
Gene-editing
CRISPR-Cas9 has, thus far, failed to convert into treatments for brain disorders. There are no FDA-approved CRISPR-based gene editing therapies for brain disorders.
The concerns I heard about the most at ASGCT are potential off-target effects with CRISPR and a lack of a clear regulatory pathway for CRISPR-based treatments for brain disorders. These concerns have, thus far, dampened industry enthusiasm for CRISPR-based treatments for brain disorders.
However, there are many diseases where there is early stage research to explore base editors, which combine DNA-modifying enzymes with Cas9, a DNA-targeting protein
For PMS patients with a single nucleotide mutation, the base editing approach might be feasible. This approach would necessitate (1) finding cohorts of PMS patients who have the exact same mutation, (2) creating discovery programs to explore the base editing approaches for those mutations*, and (3) finding companies who would be willing to advance those programs to clinical stage.
*Our colleagues at the Rett Syndrome Research Trust have invested $7 million in their MECP2 Editing Consortium, which provides us with a rough estimate of the potential cost for the CureSHANK Accelerator to undertake a gene editing discovery program.
Viral Vectors: Getting gene therapies into the brain
Viral vectors, such as the AAV9 viral vector being used in Jaguar Gene Therapy’s JAG201 gene replacement for PMS, continue to be the safest, most durable, and most-studied vectors to date. Other viral vectors include HIV/lentiviruses, which are beginning to be tested in more brain disorders (and already approved for administration into the brain in one disease, AADC deficiency).
There are a few concerns about viral vectors. One is the potential risk of immunogenicity (over-activating the immune system) if a very high dose of a viral vector is administered. Another is the inability to re-dose the patient with the same virus-based gene therapy, because the body’s immune system recognizes the viral capsid and mounts an attack against the capsid, both reducing the effectiveness of the gene therapy and potentially triggering immunogenicity. AAV vectors also have some limitations in the size of the payload they can carry. Because of these downsides, there’s interest in developing other approaches to getting gene therapies into the brain.
Bacteriophages (aka phages) are viruses that infect and kill bacteria. They do not infect human cells, making them less likely to provoke an immune response in humans. Because of the low likelihood of immunogenicity, phages are beginning to be explored for their potential use as gene therapy vectors. One researcher told me that phages are capable of crossing the blood-brain barrier and can carry a large payload (potentially even a large gene like SHANK3). The work on phage vectors is very early, and there are no clinical trials on phage vector gene therapies yet.
Synthetic vectors, such as nanoparticles, lipid-based vectors, and polymer-based vectors, seem to be one of the biggest areas of research interest. Synthetic vectors can overcome the blood brain barrier and may be able to carry a large payload, they’re less likely to cause immunogenicity, and they can be designed to target specific cell types. I’m not aware of any clinical trials of synthetic vectors in brain disorders yet.
Route of administration
Currently most gene-targeted treatments for brain disorders are delivered either directly into the brain via intracerebroventricular (ICV) or intra-cisterna magna (ICM) injection or intrathecal administration (lumbar injection). The route of administration is informed by the specific therapy. There are new approaches being developed that enable less invasive routes of administration.
Last week Capsida announced they have received IND approval from the FDA to begin a clinical trial of an IV-administered gene therapy for STXBP1 deficiency. It is a developmental disorder that shares some similarities with PMS. Normally an IV-administered gene therapy would present a strong risk of going to places in the body where it could cause harm (such as the liver). Capsida has a highly engineered AAV capsid that can cross the blood-brain barrier and is de-targeted from the liver and dorsal root ganglia. This will be an important trial for CureSHANK to follow.
Another company developing BBB-crossing gene therapies is Apertura, which has developed a transferrin receptor-targeting capsid. Their AAV capsid binds to the human transferrin receptor 1, the body’s natural way of shuttling iron into the brain. Apertura is currently developing transferrin receptor targeting capsids for Rett syndrome and Tuberous Sclerosis complex, two diseases that share similarities to PMS. Similar approaches for brain disorders are being developed at Biogen and Regeneron. The transferrin receptor approach has already received regulatory approval in Japan for JCR/Takeda’s blood-brain barrier penetrating drug for Hunter syndrome.
The future for PMS
The first patient has been dosed with Jaguar Gene Therapy’s JAG201. At ASGCT I was stopped by many researchers, patient advocates, and industry representatives who congratulated our community for achieving this major milestone. The road to approved therapeutics is fraught with innumerable challenges – just getting to this point is an accomplishment that cannot be overstated.
While, certainly, most of the talks at ASGCT focused on the successes, there were stories about failures at all the different stages of discovery and development. This drove home just how fortunate the PMS community is to be in a phase II clinical trial of a gene therapy.
PYC presented a summary of their work at ASGCT, which covered the same topics as the webinar with CureSHANK, PMSF and PYC on March 13, 2025. If all proceeds according to PYC’s plan, their ASO will be the next PMS gene therapy to go into clinical trial (anticipating the latter half of 2026).
While other gene therapy approaches could also be applicable to PMS, they would, at best, be several years away from clinical trials in PMS.
Thinking about how we get to life-transforming therapeutics for PMS as fast as possible, our task at hand is to enable the success of the companies that are already working on our disease. This includes Neuren, which is not developing a gene therapy for PMS, but whose NNZ2591 phase II trial has shown strong indicators of efficacy. These companies have already spent tens of millions of dollars to get where they are. If they are successful, it will establish PMS as a tractable disease, attracting more companies to invest in PMS.
There are two ways you can help:
1. CureSHANK will be launching the CureSHANK Accelerator to enhance discovery and development of new therapeutic strategies for PMS. If it’s important to you for there to be multiple treatment choices in PMS, please donate to CureSHANK to support the Accelerator.
2. If your child is between 12 and 36 months, please consider participating in the natural history study and/or the JAG201 trial. If you know families whose kids are under 3 years of age, please let them know about the trial. Families should reach out to the trials sites directly to learn more about participating in the natural history study or the trial.
• United States, New York
Seaver Autism Center at Mount Sinai
New York, New York, United States, 10029
Contact: Abby Siegel
Phone: 212-241-3072
Email: abigail.siegel@mssm.edu
Principal Investigator: Alex Kolevzon, MD
• United States, Illinois
Rush University
Chicago, Illinois, United States, 60612
Contact: Aimee Puz
Phone: 312-942-9841
Email: aimee_f_puz@rush.edu
Principal Investigator: Elizabeth B Kravis, MD
• United States, Massachusetts
Boston Children’s Hospital
Boston, Massachusetts, United States, 02115
Contact: Anna Cronin
Phone: 617-919-3499
Email: anna.cronin@childrens.harvard.edu
Principal Investigator: Siddharth Srivastava, MD