Pictured: Illustration of gloved hands using tools to manipulate a DNA double helix/iStock, MicrovOne

In the early 1990s, Mike McCune and his colleagues thought theyd found a path to a one-time HIV treatment for babies: genetically modifying hematopoietic stem cells to suppress the virus and then transplanting them into the bone marrow. But the treatment never made it to clinical trials.

It was not considered to be a good business plan, he explained, because companies would make more money by selling these patients antiretroviral therapies for a lifetime than to deliver a one-time treatment.

Vertex Pharmaceuticals and CRISPR Therapeutics Casgevy, which involves a process much like McCunes HIV treatmentex vivo gene editing of blood stem cells for the treatment of sickle cell disease (SCD) followed by transplantation back into the patientdid make it to market, having been recently approved by the FDA as the first CRISPR-based therapy. But Casgevy is pricy: it costs a whopping $2.2 million dollars. Its competitor Lyfgenia, another ex vivo gene therapy for SCD approved at the same time, carries a sticker price of $3.1 million. The high cost may limit access even for patients in the U.S., and will likely be a far more formidable barrier in sub-Saharan Africa, where 79% of babies with SCD are born.

Now McCune and others are looking to bring gene therapy to the masses by developing treatments that involve treating cells in vivo, which could be far less costly than the ex vivo variety. Requiring only a single injection, the in vivo approach would use vectors to deliver DNA-changing machinery into cells. In the case of SCD, the target would be blood-making stem cells and the tweaks would induce them to make healthy hemoglobin, McCune explained; for HIV, viral DNA could be snipped inside infected cells to prevent viral replication and spread, as well as reinfection.

While an existing in vivo gene therapies for rare genetic diseases also have eye-popping sticker prices, McCune argued that over time, costs will fall.

McCune, now head of the Gates Foundations HIV Frontiers program, is helping to forge agreements between the philanthropy and multiple private companies with the aim of making gene therapy an accessible reality as a treatment for both HIV and SCD. And at least one biotech, Excision BioTherapeutics, is pursuing a similar approach to HIV treatment independently of Gates.

As McCune sees it, there will be both a market and payers for a one-shot HIV treatment, both in the U.S. and in sub-Saharan Africa. He points out that the healthcare system is currently paying tens of thousands of dollars annually for each HIV patient in the U.S., money that could be redirected to paying for a cure. And in sub-Saharan Africa, he added, the U.S. is spending about $7 billion each year on antiretroviral treatment for people with HIV under a program called PEPFARfunding that could likely cover the cost of a one-shot treatment instead.

Theres no comparable payer for an SCD treatment, he said. We have to work on that. And I think thats going to become really important because the inequities of healthcare, so poignantly highlighted during COVID, are going to become even more glaringly obvious now that there are multimillion-dollar treatments that are likely to remain inaccessible to many people with SCD.

Gates has partnered with companies including Guide Therapeutics, bluebird bio, GreenLight Biosciences, Intellia Therapeutics, CRISPR Therapeutics, Immunocore, BioNTech, Vir, Ensoma, Emmune, Addition and Novartis, as well as nonprofits and academic labs, to work on aspects of in vivo gene therapy. The foundation has also partnered with the National Institutes of Health, which committed to kicking in $100 million toward the effort.

Agreements with partners, McCune said, include a non-exclusive right for the Gates Foundation to make sure that the technologies are available to people living with HIV and SCD in low- and middle-income countries. Why would they give us those rights? he asked. Part of the answer is that the applications of this platform are diverse, outside of the realm of HIV and sickle [cell disease] and into the realm of the more remunerative diseases that companies seem to focus on in the context of gene therapy, including cancer. They would see this as a pathway for return on investment, which [could] be huge, McCune said.

Intellia, a former Gates grantee, is in the preclinical stages of developing an in vivo CRISPR treatment for SCD, company spokesperson Ian Karp wrote in an email to BioSpace. The benefit of a one-time treatment certainly has applicability to patients across the globe, he said. Additionally, our technology platform is modular, such that we do hope to leverage it across multiple indications / diseases. Oftentimes the only change we need to make from one investigational product to the next (particularly when targeting the same cell type and edit type) is in the targeting region of the guide RNA which serves to direct the CRISPR machinery to the gene of interest.

Similarly, Christine Silverstein, chief financial officer at Excision BioTherapeutics (which has not received Gates funding), said that the technology behind the companys candidate CRISPR HIV treatment, the Fast Tracked EBT-101, may be applied to other chronic viral infectious diseases including herpes and hepatitis B. In fact, our work in HIV is setting the foundation for advancements of Excisions pipeline which unites next-generation CRISPR nucleases with a novel, multiplexed gene editing approach to develop potentially curative therapies, she said in a statement.

But success is by no means assured. Despite the current excitement over CRISPR, hurdles to its therapeutic use remain, including not-insignificant safety concerns, and safety issues have also cropped up with other gene therapies. The Gates Foundation itself is hedging its bets, working in parallel to drive the development of a therapeutic vaccine for HIV.

Still, McCune is dreaming big. Even for conditions where effective treatments exist, these sorts of in vivo treatments might be something that takes pills off the shelves and sets the course for a different kind of medicine.

Shawna Williams is a senior editor at BioSpace. She can be reached at shawna.williams@biospace.com or on LinkedIn.

Read more:
Could Treatments for HIV and Sickle Cell Open the Gene Therapy Floodgates? - BioSpace