In the early 1990s, Mike McCune and his colleagues thought they had found a way to give babies disposable HIV**: genetically modifying hematopoietic stem cells to inhibit the virus and then transplanting them into bone marrow. But this method has never made it to clinical trials.
This is not considered a good business plan," he explained, because companies make more money by giving these patients a lifetime of antiretrovirals than a one-time offer.
Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy, a process very similar to McCune's HIV**, is already on the market and was recently approved by the FDA as the first CRISPR-based method. This involves in vitro gene editing of blood stem cells for sickle cell disease (SCD) and then transplanted back into the patient. However, casgevy** is expensive, costing up to $2.2 million. At the same time, another in vitro gene against SCD, Lyfgenia, was $3.1 million. The high cost may limit access for patients in the United States, a gap that is difficult to bridge for the 79% of children with SCD in sub-Saharan Africa.
Now, McCune and others are looking to bring genes to the masses by developing methods that involve processing cells in vivo, which may cost much less than ex vivo cells. With only one injection, the in vivo method will use a vehicle to deliver the DNA-altering mechanism into the cells. In the case of SCD, the target will be hematopoietic stem cells, and these adjustments will induce them to produce healthy hemoglobin, McCune explained; For HIV, viral DNA can be cleaved within infected cells to prevent viral replication and transmission, as well as reinfection.
While existing in-vivo genes** for rare genetic diseases also have eye-watering price tags, McCune believes the cost will go down over time.
McCune, who is now the head of the Gates Society's HIV Frontiers program, is helping charities reach agreements with a number of private companies with the goal of making genes a reality for HIV and SCD. At least one biotech company, Excision Biotherapeutics, is pursuing a similar approach to HIV** independent of Gates.
The economics of HIV
In McCune's view, there will be a market and payers for disposable HIV**, both in the U.S. and in sub-Saharan Africa. He noted that the health care system currently pays tens of thousands of dollars a year per HIV patient in the U.S., and that money can be repurposed to cover ** costs. He added that in sub-Saharan Africa, the U.S. spends about $7 billion a year on antiretroviral** for the Emergency Plan for AIDS Relief (PEPFAR), which may be enough to cover a one-time cost.
He said there was no comparable payer for SCD**. "We have to work on this. I think this is going to become very important because the inequity of health care during COVID was highlighted and now that these millions of dollars are probably still not accessible to SCD patients, the inequity is going to become even more apparent. ”
Medical treatment is a step towards wider application in the body**
Gates & Guide Therapeutics, Bluebird Bio, Greenlight Biosciences, Intellia Therapeutics, CRISPR Therapeutics, ImmunoCore, BioNTech, Vir, Ensoma, Emmune, ADDITION works with companies such as Novartis, as well as non-profit organizations and academic laboratories, working on all aspects of genes in vivo**. The association also partnered with the National Institutes of Health, which pledged $100 million to the effort.
McCune said the agreement with the partners includes a non-exclusive right for Gates to ensure access to these technologies for people living with HIV and SCD in low- and middle-income countries.
Why are they giving us these rights? He asked. Part of the answer is, "The applications of this platform are varied and not limited to the realm of HIV and sickle cell disease, but into the more lucrative areas of disease that companies seem to be focusing on in the context of genetics," including cancer. "They're going to think it's a way to return on investment, and that could be huge," McCune said.
Intellia is a grantee of the Gates Society and is currently in the preclinical stage of developing CRISPR** sickle cell anemia (SCD) in vivo. "The benefits of a one-off** are undoubtedly available to patients around the globe," he said. "In addition, our technology platform is modular, so we want to apply it to multiple indications for diseases. From one investigational product to another (especially when targeting the same cell type and edit type), we usually only need to change the targeted region of the guide RNA, which is used to direct the CRISPR machinery into the gene of interest. ”
Similarly, Christine Silverstein, chief financial officer of Excision Biotherapeutics (which has not yet received funding from Gates), said the technology behind the company's CRISPR HIV** drug candidate, Fast Tracked EBT-101, could be applied to other chronic viral infectious diseases, including herpes and hepatitis B. Multiplex gene editing methods develop potential *** She said in a statement.
But success is never guaranteed. Despite the current excitement about CRISPR, barriers to its use remain, including safety concerns that cannot be ignored, and safety concerns have also emerged for other genes. Gates itself is hedging its bets while pushing for the development of HIV vaccines.
Reference** HIV Update.