Gene therapy for global health: A Q&A with Dr. Mike McCune

Since 2018, the foundation has made a series of investments that aim to discover gene-based cures for sickle cell disease (SCD) and HIV that can be delivered safely and accessibly in a “single shot.” This week, the foundation announced that it is providing funding for the pharmaceutical company Novartis to develop affordable, single-dose gene therapies for people most affected by these diseases in sub-Saharan Africa and other regions.

We spoke with Dr. Mike McCune, head of the foundation’s HIV Frontiers Program, to understand how these therapies will both push the scientific envelope and help ensure future access to treatment to those in need around the world.

First and foremost, there’s a huge unmet need. SCD is a major cause of death and disability in some of the world’s most under-resourced communities, from sub-Saharan Africa and India to Black communities in the United States. About 80 percent of the world’s SCD burden is in sub-Saharan Africa, where roughly 1,000 children are born with it every day, more than half of whom will likely die before age 5. While treatments are available, they’re still expensive and resource-intensive, and their effectiveness is far from ideal. Even in the U.S., life expectancy for people with SCD is just 43 years.

Second, SCD is a disease with a relatively simple and well-characterized cause: a single, inherited genetic mutation. Tremendous advances have already been made in reversing the disease, by genetically modifying blood-forming stem cells ex vivo. Ex vivo treatments require a patient’s cells to be removed from their body, altered in a lab, and then reinfused. This successful ongoing work allows us to focus on pushing the boundaries of in vivo delivery approaches.

Third, we expect that scientific and practical advances made in tackling in vivo gene therapies for SCD will be transferable to similar efforts against HIV, a disease for which the precise pathways for sustained, antiretroviral-free viral remission (or “cure”) have yet to be defined.

Gene therapy has the potential to end the global threats of SCD and HIV, but only if we can make it far more accessible than today’s gene-based treatments. Though these treatments are already helping people with cancer and rare genetic conditions, they’re expensive and require intensive hospital-based care. Even wealthy countries struggle to provide access to them.

We’re aiming for something very different: affordable gene-based cures that can be delivered in vivo—directly into the body—in a single treatment, ideally as a “shot in the arm” (see https://pubmed.ncbi.nlm.nih.gov/30982768/). It’s truly ambitious science by any standard. What’s most exciting, though, is that we’re harnessing that ambition to create practical and affordable treatments for the people who need them most.

Gene therapy is new territory for global health. To have the best chance of success, we really need to draw on the best research labs and networks. Novartis has some of the deepest expertise in gene therapy anywhere.

With foundation support, Novartis will establish a dedicated research team to carry out this work in labs at the Novartis Institutes for BioMedical Research (NIBR) and provide them with knowledge, resources, and senior leadership involvement from across the company. To have such a focused, well-backed team confronting a global health problem is a rarity in the industry.

In the initial three years, NIBR will focus on discovering new gene therapy candidates and will help the foundation assess candidates identified through our work with other grantees. With our grant funding, they’ll also plan for and conduct animal studies as well as other translational preclinical work. Depending on the pace of discovery, we may extend the collaboration beyond three years and start planning for clinical trials.

Like all of the foundation’s work, the collaboration is governed by our global access policies. The grant agreement includes specific provisions to ensure access to any resulting products, as assessed at each step in the discovery and development process. And, broadly speaking, advancing access in low- and middle-income countries is at the heart of our combined efforts.

The HIV Frontiers Program team has been supporting a continuum of research and planning that is needed to ultimately deliver safe, effective, and affordable gene-based cures for SCD and HIV. These efforts include basic research, technical innovation, preclinical and clinical development, and planning for global access to future cures.

To reach our aspirational goal of “single shot” cures, we recognize the need to invest in organizations that bring in complementary strengths and experience. For example, in October 2019, the foundation and the U.S. National Institutes of Health (NIH) announced a new collaboration focusing on critical research toward development of in vivo gene therapies for SCD and HIV to resource-limited parts of the world. At the same time, we have been supporting technical innovation and preclinical validation of new in vivo delivery technologies through grants to academic labs, not-for-profits such as Caring Cross, and biotechnology companies such as Guide Therapeutics, bluebird bio, GreenLight Biosciences, Intellia Therapeutics, CRISPR Therapeutics, Immunocore, and BioNTech. The Novartis grant represents another important addition to this body of work, enabling us to support a highly experienced multinational company as they select and validate the most promising candidate cures and move them into clinical studies. These activities will serve to bolster our collaborative efforts with the NIH, which has its own programs fostering groundbreaking research on SCD and HIV cures.

Additionally, we’re engaging with health experts, advocates, and country leaders to make sure that research is driven by local needs and with the full participation of communities. This is occurring in partnership with the NIH, which is supporting the development and enhancement of research infrastructure in countries in sub-Saharan Africa with a high prevalence of both HIV and SCD. Leadership for these efforts is being provided by African scientists and physicians in these countries. Importantly, we have worked over the past several years to establish a public-private partnership (the HIV Cure Africa Acceleration Partnership) to engage a multidisciplinary group comprised of professionals in the natural and social sciences, payers, regulators, community leaders, and people living with SCD and HIV to build models and programs that are practical and acceptable from the stakeholder perspective, thus improving the likelihood of success.

Much can be accomplished by scaling up existing interventions. Many, if not most, childhood SCD deaths, for example, could be prevented by improving screening and access to early interventions that are already standard in the U.S. After decades of slow progress, we’re finally seeing real movement on this front. In fact, Novartis is a key partner with Ghana and other countries working to improve SCD diagnosis and increase access to existing standards of care.

The foundation’s strategy reflects the unique strengths of private philanthropy: to enable organizations to take risks and give scientists the freedom to experiment without worrying about generating a profit. Even with full access to today’s best care, new and more cost-effective cures will ultimately be needed. Since the necessary investments are risky and it will be many years before these new treatments are available, we need to start the work now.

We’ve already seen some exciting, though early, proof-of-concept studies demonstrating the promise of ex vivo gene therapies for SCD. Meanwhile, delivery technologies for in vivo treatments are advancing rapidly. The U.S. Food and Drug Administration recently approved the first-ever in vivo gene therapies for patients with certain genetic disorders—interventions that use an adeno-associated virus to deliver the treatment directly to the body’s cells. Other technologies are also being studied in animals, including the use of other viruses and lipid nanoparticles as candidate delivery mechanisms.

Given the potential of this science, we want to keep researchers focused on the greatest unmet needs, including cures for SCD and HIV in resource-limited parts of the world where they are most prevalent. As COVID-19 has reminded us all, diseases are truly global issues, cutting across borders, income, and geographies. By encouraging industry, government, and other players to align now where the need is greatest, we can help ensure that the resulting innovations benefit all of humanity, not just a select few.