Could an In Vivo Gene Therapy Strategy be Effective in Treating Fanconi Anemia?

In a pre-clinical study, researchers demonstrate a novel gene therapy treatment approach for Fanconi anemia patients.

The Findings

Researchers at Children's Hospital of Philadelphia demonstrated a novel gene therapy treatment strategy for patients with Fanconi anemia, a rare genetic disease resulting in loss of blood-forming stem cells in the bone marrow. In a pre-clinical study, the researchers successfully used in vivo lipid nanoparticles (LNP), a therapeutic cargo delivery system, to reach key areas directly in the bone marrow, and temporarily restore critical stem cell functions. Preliminary results showed this approach helped blood stem cells grow and recover, even under stressful conditions without a negative impact to the immune system.

Why It Matters

Loss of blood cell production is part of the diagnosis of Fanconi anemia, an inherited DNA repair disorder with prominent hematologic complications. Caused by a mutation in FA genes, the condition is a chronic disease that can affect many of the body's organ systems, such as heart, skin, and gastrointestinal. It is also associated with a heightened risk of cancer as patients enter their 20s and 30s. Regular, lifelong monitoring is necessary.

While ex vivo gene addition and repair therapies are being considered as treatment options, limitations include reaching these sensitive stem cells in their native bone marrow environment and correcting them in a meaningful way. Most of the self-renewal capacity — the ability of these repaired stem cells to help the patient — is lost when the cells are taken out of the patient and manipulated in a dish.

"Lipid nanoparticles can be considered safer and more effective for certain diseases compared to traditional gene therapy using viral delivery, as they reduce the risk of immune reactions and can be engineered to target specific cells," said senior author, Peter Kurre, MD, Director of the Comprehensive Bone Marrow Failure Center at CHOP.

Peter Kurre, MD

Who Conducted the Study

The proof-of-principle trial was a collaboration of CHOP investigators including Dr. Kurre; first author Omar Banda, PhD, a Postdoctoral Fellow; and Sarah Adams, Lead Research Technician, in the Kurre Lab Among the CHOP co-investigators were Stefano Rivella, PhD, the Kwame Ohene-Frempong Endowed Chair in Pediatric Hematology; and Mohamad-Gabriel Alameh, PhD, Senior Principal Scientist in the Department of Pathology and Laboratory Medicine.

How They Did It

Omar Banda, PhD

Using a pre-clinical model developed by Dr. Banda, the investigators explored in vivo protein replacement by mRNA delivery via LNP — the same drug delivery vehicles used in mRNA COVID-19 vaccines — aiming to achieve functional recovery of the Fanconi anemia DNA repair pathway in patients with FA. With intravenous or intrafemoral injections, the researchers demonstrated efficient in vivo LNP transfection.

Quick Thoughts

"We discovered that in the case of Fanconi anemia, these nanoparticles establish the foundation to help us advance toward a paradigm-shifting in vivo treatment for individuals with this rare disease," Dr. Kurre said.

What's Next

Having demonstrated that LNP can be delivered efficiently in vivo, this research sets the stage for a more direct, efficient, and permanent in vivo gene repair approach using LNP delivery for patients with FA and other bone marrow failure diseases.

"Our results suggest that mRNA-LNP-based protein replacement therapy holds promise for clinical translation," Dr. Kurre said. "Because CHOP has so much experience with LNP, I think the translation to humans will happen within the decade."

Where the Study Was Published

The study was featured in Molecular Therapy Nucleic Acids and funded in part by the Cell and Gene Therapy Collaborative at CHOP.