Feature

NIH initiative takes ‘multiple-shots’ approach toward cure for sickle cell disease

The NIH launched an initiative to coordinate and accelerate research into a cure for sickle cell disease.

W. Keith Hoots, MD, director of the blood diseases and resources division at the NHLBI, said the Cure Sickle Cell Initiative would make use of the most advanced basic science and genetic research from around the world. Specifically, the NHLBI aims to support both industry and academic research into cell and genetic therapies, clinical trials, comparisons of treatment methods, and data accrual.

In addition to the approximately $100 million the NIH spends on sickle cell disease research each year, the NHLBI has committed new funding to fuel these curative-focused strategies. A key goal of the initiative is to find a cure that could benefit patients who do not have access to bone marrow transplantation.

HemOnc Today spoke with Hoots about the challenges associated with sickle cell disease treatment, how this initiative came about and why it is important.

Question: Can you explain how this initiative came about?

Answer: One of my NIH colleagues approached Francis S. Collins, MD, PhD, the director of the NIH, after Congress passed the 21st Century Cures Act — the cancer moonshot — in late 2016. He said, “Why don’t we undertake a moonshot for sickle cell? It’s a single disease with a single genetic mutation of a nucleotide.” The thinking was that we could make very rapid progress because DNA researchers were developing genetic modifications with the potential to overcome the mutation in individuals with sickle cell disease. The main question was the feasibility, and whether it was worth it to push hard to get a genetic cure of one ilk or another.

Q : Could you talk about the process of gathering experts?

A : We created a workshop that included people with expertise in this space — people who have made efforts in the early preclinical phase to cure sickle cell. In addition, we looked for people with expertise in any genetic disease. We inquired about their thought processes and asked them what they could contribute and what we could do to augment their efforts.

Q : What are some specific strategies you’re hoping to explore with this initiative?

A: We plan to partner to provide resources for endeavors by the scientific community around the world in the public and private sector to identify therapeutic strategies. We also will include patient engagement in all of our efforts.

Q : Could you elaborate on the clinical aspects of what you’re hoping to accomplish?

A : Laying the groundwork for clinical research of potential curative strategies requires a multifaceted group of people and agencies. These include regulatory organizations like the FDA, investors, investigators in academia and, in several cases, private companies. We are engaging with all of them, as well as with the patient population, to try to see how we can enable what we call multiple shots on goal.

Q : Which genetic strategies will the initiative explore?

A : Essentially, it breaks down into two major and one developmental potential approaches. The first is gene transfer, where you take a correcting gene, put it into the target hematopoietic stem cells and put the modified cells back into the person with the disease. Such approaches might include genes that upregulate fetal hemoglobin, which is turned off over 6 months or so. We know that if you can keep fetal or reestablish fetal expression to a significant degree, you can mitigate a lot of the morbidities from sickle cell. Alternatively, if the defect is in the beta chain of hemoglobin, you can put in a gene that corrects the sickle cell disease mutation (at the single nucleotide in the sixth position in the beta chain)..

The second research strategy is gene editing. This includes zinc finger nucleases transcription activator-like effector nucleases (TALENs) and, more recently, CRISPR/Cas9 nucleases. In most cases, these nucleases break the DNA at a targeted location. Then DNA reassembles at the targeted site, sometimes editing out the mutant nucleotide and replacing it with a nucleotide that coded fetal normal hemoglobin: Hgb F or Hgb A. Rather than just giving a normal gene, you’re editing the DNA of the hematopoietic stem cell to try to partially correct the downstream protein, the hemoglobin that’s made from the gene.

The first two strategies are ready, or nearly ready (editing), for early-phase human trials.

A third approach, which is not necessarily ready for prime time, is to use small molecules such as nanoparticles to effect a change within a hematopoietic stem cell. Such an approach that could modify sickle genes without having to go through an autologous transplant would be a real coup in terms of improving the lives of many more people. But that is much further down the road.

Q : Is there a timeline for results?

A : Dr. Collins suggests a timeline of 5 years. It’s very aggressive, however we’re looking at accelerating these scientific advancements compared with the “usual” developmental path.

Q : Are you confident that you’re going to achieve a cure?

A : I’m confident that we’re going to do it for the first generation of people to receive it. What I’m less confident about is when it becomes widely available to the majority of people who want it. We’re working on that part, too. —by Rob Volansky

For more information:

W. Keith Hoots, MD, can be reached at 45 Center Drive, NIH, Bethesda, MD 20894.

Disclosure: Hoots reports no relevant financial disclosures.

The NIH launched an initiative to coordinate and accelerate research into a cure for sickle cell disease.

W. Keith Hoots, MD, director of the blood diseases and resources division at the NHLBI, said the Cure Sickle Cell Initiative would make use of the most advanced basic science and genetic research from around the world. Specifically, the NHLBI aims to support both industry and academic research into cell and genetic therapies, clinical trials, comparisons of treatment methods, and data accrual.

In addition to the approximately $100 million the NIH spends on sickle cell disease research each year, the NHLBI has committed new funding to fuel these curative-focused strategies. A key goal of the initiative is to find a cure that could benefit patients who do not have access to bone marrow transplantation.

HemOnc Today spoke with Hoots about the challenges associated with sickle cell disease treatment, how this initiative came about and why it is important.

Question: Can you explain how this initiative came about?

Answer: One of my NIH colleagues approached Francis S. Collins, MD, PhD, the director of the NIH, after Congress passed the 21st Century Cures Act — the cancer moonshot — in late 2016. He said, “Why don’t we undertake a moonshot for sickle cell? It’s a single disease with a single genetic mutation of a nucleotide.” The thinking was that we could make very rapid progress because DNA researchers were developing genetic modifications with the potential to overcome the mutation in individuals with sickle cell disease. The main question was the feasibility, and whether it was worth it to push hard to get a genetic cure of one ilk or another.

Q : Could you talk about the process of gathering experts?

A : We created a workshop that included people with expertise in this space — people who have made efforts in the early preclinical phase to cure sickle cell. In addition, we looked for people with expertise in any genetic disease. We inquired about their thought processes and asked them what they could contribute and what we could do to augment their efforts.

Q : What are some specific strategies you’re hoping to explore with this initiative?

A: We plan to partner to provide resources for endeavors by the scientific community around the world in the public and private sector to identify therapeutic strategies. We also will include patient engagement in all of our efforts.

PAGE BREAK

Q : Could you elaborate on the clinical aspects of what you’re hoping to accomplish?

A : Laying the groundwork for clinical research of potential curative strategies requires a multifaceted group of people and agencies. These include regulatory organizations like the FDA, investors, investigators in academia and, in several cases, private companies. We are engaging with all of them, as well as with the patient population, to try to see how we can enable what we call multiple shots on goal.

Q : Which genetic strategies will the initiative explore?

A : Essentially, it breaks down into two major and one developmental potential approaches. The first is gene transfer, where you take a correcting gene, put it into the target hematopoietic stem cells and put the modified cells back into the person with the disease. Such approaches might include genes that upregulate fetal hemoglobin, which is turned off over 6 months or so. We know that if you can keep fetal or reestablish fetal expression to a significant degree, you can mitigate a lot of the morbidities from sickle cell. Alternatively, if the defect is in the beta chain of hemoglobin, you can put in a gene that corrects the sickle cell disease mutation (at the single nucleotide in the sixth position in the beta chain)..

The second research strategy is gene editing. This includes zinc finger nucleases transcription activator-like effector nucleases (TALENs) and, more recently, CRISPR/Cas9 nucleases. In most cases, these nucleases break the DNA at a targeted location. Then DNA reassembles at the targeted site, sometimes editing out the mutant nucleotide and replacing it with a nucleotide that coded fetal normal hemoglobin: Hgb F or Hgb A. Rather than just giving a normal gene, you’re editing the DNA of the hematopoietic stem cell to try to partially correct the downstream protein, the hemoglobin that’s made from the gene.

The first two strategies are ready, or nearly ready (editing), for early-phase human trials.

A third approach, which is not necessarily ready for prime time, is to use small molecules such as nanoparticles to effect a change within a hematopoietic stem cell. Such an approach that could modify sickle genes without having to go through an autologous transplant would be a real coup in terms of improving the lives of many more people. But that is much further down the road.

PAGE BREAK

Q : Is there a timeline for results?

A : Dr. Collins suggests a timeline of 5 years. It’s very aggressive, however we’re looking at accelerating these scientific advancements compared with the “usual” developmental path.

Q : Are you confident that you’re going to achieve a cure?

A : I’m confident that we’re going to do it for the first generation of people to receive it. What I’m less confident about is when it becomes widely available to the majority of people who want it. We’re working on that part, too. —by Rob Volansky

For more information:

W. Keith Hoots, MD, can be reached at 45 Center Drive, NIH, Bethesda, MD 20894.

Disclosure: Hoots reports no relevant financial disclosures.

    See more from HemOnc Today's PharmAnalysis