Aug 11, 2023

Disclosures: Parhiz reports equity in and/or research support from BioNTech and Capstan Therapeutics. Rivella reports scientific advisory board and/or consulting roles with Bristol Myers Squibb, BVF Partners L.P., Cambridge Healthcare Research, Catenion, Celgene Corporation, CSL Vifor, Disc Medicine, ExpertConnect, First Manhattan Co., Forma Therapeutics, Ghost Tree Capital, GSK, Incyte, Ionis Pharmaceuticals, Keros Therapeutics, LifeSci Capital, MeiraGTx, Noble Insight, Protagonist Therapeutics, Rallybio LLC, Sanofi Aventis U.S., Slingshot Insights, Spexis AG, Techspert.io and venBio Select LLX. ADD TOPIC TO EMAIL ALERTS Receive an email when new articles are posted on Please provide your email address to receive an email when new articles are posted on . Please try again later. If you continue to have this issue please contact customerservice@slackinc.com . Back to Healio Researchers at Children’s Hospital of Philadelphia and Perelman School of Medicine at University of Pennsylvania developed an in vivo proof-of-concept model for the delivery of gene editing tools to treat blood disorders. This approach allows for the modification of diseased blood cells within the body. If translated into the clinic, this could increase access and reduce the cost of gene therapies for blood disorders, according to authors of a paper published in Science.. Current gene therapy approaches for hematologic conditions such as sickle cell disease and beta-thalassemia require conditioning treatments like chemotherapy to make room for the new, modified blood cells. This method is expensive and potentially risky, study authors contend. “What we are proposing is an example of in vivo cellular programming, or in vivo cellular engineering,” Hamideh Parhiz, PharmD, PhD, research assistant professor of medicine at Penn Medicine, told Healio. “Instead of an extensive ex vivo-plus-chemotherapy procedure, we are proposing that we can do a simple injection of targeted lipid nanoparticles encapsulating RNA-based medicine. We can target cells in vivo, and we can change the behavior and function of cells.” Parhiz and colleague Stefano Rivella, PhD, Kwame Ohene-Frempong endowed chair on sickle cell aneemia and professor of pediatrics at Children’s Hospital of Philadelphia, spoke with Healio about their innovation, how it may benefit patients with hematologic conditions, and the next steps in their research. Healio: What are the mechanisms of this in vivo approach to delivering gene-editing tools? Parhiz: The way cell therapy is being done now is to take cells out of the body, manipulate them in vitro, and then administer them back to the patient. This is an expensive and time-consuming procedure. To avoid all these steps, we decorate the surface of lipid nanoparticles with antibodies against specific cells. My team at University of Pennsylvania has [conducted] several proof-of-concept studies ... delivering RNA cargos to several cell types in vivo. In the current paper, we used a very similar platform technology and applied it to target hematopoietic stem cells. Stefano Rivella Rivella: I have been working in the field of gene therapy for a long time using lentiviral vectors. I was in the lab when one of the first lentiviral vectors was made for the treatment of beta-thalassemia, and I am familiar with this technology. One major issue is the requirement of myeloablation to put the cells back into the bone marrow of patients. Myeloablation is very toxic; one of the side effects is loss of fertility. And it will not be realistic to use this technology in countries where patients cannot afford $2 million to $3 million for these treatments. In these countries, the infrastructure to perform myeloablation and bone marrow transplants may not be available. Therefore, Hamideh and I were wondering how we could make things easier for the patient, as well as more affordable and accessible. Healio: How is this in vivo gene-editing approach being assessed, and how is it performing? Parhiz: Basically, we are claiming that we are targeting bone marrow hematopoietic stem cells. Initially, we did proof-of-concept studies in vitro, showing we were able to achieve mRNA delivery and translation. After, we did ex vivo analyses. We manipulated cells in vitro and then injected those in mice to see how we can track those cells in the body. Then we did two proof-of-concept studies: one was in vivo depletion of bone marrow stem cells. The other one was in vitro gene editing of sickle patient cells. Rivella: This technology is a tool to deliver genetic information. You can compare it to a vessel or an envelope that can deliver the message to the cells inside the body. This envelope is full of genetic information for bone marrow cells. To allow the envelope to reach the bone marrow stem cells, we used antibodies — which we call our “GPS” — which tells these envelopes where to go. The genetic information we deliver is provided as RNA molecules. RNA molecules are very versatile and can be used for multiple purposes. For instance, we have shown we can kill bone marrow stem cells delivering an mRNA that encodes for a protein called PUMA, which can induce the suicide of bone marrow hematopoietic stem cells. In this case, we could prevent the side effects of myeloablation, preserving the fertility of the patients. We also used this technology for gene editing — correcting, in vitro, mutations in sickle cells from patients. Our paper shows that it is possible to use this technology for these purposes, but it will require a lot of work before it can be used in humans. Healio: Is there anything else you would like to mention? Parhiz: This is an example of a platform technology with a lot of potential. We can deliver RNA to different cell types, affecting their function. My team did this with T cells and other cells before. Now, with Stefano’s team, we did this with bone marrow hematopoietic stem cells. However, theoretically, we can apply this to any specific cell type in the body. That will open a lot of new potential in terms of doing in vivo cell-specific engineering. For example, in T-cell targeting, we did in vivo [chimeric antigen receptor] T-cell therapy. Here, we modified bone marrow hematopoietic stem cells. The same technology can be used for several other applications that are now ongoing. Rivella: We are hopeful that in the future we can successfully apply this technology in treating many stem cell blood disorders. The sky is the limit. For more information: Hamideh Parhiz, PharmD, PhD, can be reached at Stemmler Hall, Perelman School of Medicine, 3450 Hamilton Walk, Philadelphia, PA 19104; email: hamideh.parhiz@pennmedicine.upenn.edu . Stefano Rivella, PhD, can be reached at Leonard and Madlyn Abramson Pediatric Research Center, 3615 Civic Center Blvd., Room 316B, Philadelphia, PA 19104; email: revillas@chop.edu . Read more about