Recent scientific advances in the field of genome editing, which enables precise modifications to DNA, have greatly increased the potential to treat genetic diseases. Despite revolutionary progress in this area, treatment options remain limited. Several scientific challenges must be addressed before gene editing can be widely used in the clinic. For example, gene editing tools may cut in unintended areas in addition to the target site, and more research is necessary to understand how these errors affect patients.
Another key challenge is that many organs remain difficult to reach with gene therapies because we do not have adequate ways to deliver gene editing tools to all cells. While efficient delivery technologies exist for some targets, like liver cells, novel and specialized delivery methods designed for specific cell types and locations in the body are needed to ensure genome editing tools can reach sufficient numbers and types of somatic cells to modify DNA safely and effectively. Somatic cell gene therapies target non-reproductive cells, so the changes only affect the person who receives the gene therapy and are not passed down generation to generation.
To address these challenges, NIH launched the TARGETED (Targeted Genome Editor Delivery) Challenge, a multi-phase competition funded through the NIH Common Fund as part of the NIH Somatic Cell Genome Editing (SCGE) Program. SCGE was funded in 2018 to improve the efficacy and specificity of genome editing to help reduce the burden of common and rare diseases caused by genetic changes.
As part of the TARGETED Challenge, research teams will develop technologies for delivering genome editors to somatic cells. NIH will award up to $6 million in prize money across the challenge.
The Challenge is focused on finding delivery systems that can be programmed with biological or chemical tags that correspond to specific target cells and tissues. These tags would direct the delivery systems and the genome editing therapies to the target cells or tissues—like mail being delivered to different zip codes. Such programmable delivery systems would improve gene editing efficacy by targeting diseases at their source and would enhance safety by reducing undesired impacts on other tissues or cells. Ultimately, the development of safe and effective programmable delivery technologies for genome editors that are applicable to multiple diseases would help advance the application of gene editing therapies into the clinic.
The Challenge also is interested in gene editing delivery technologies that can cross the blood-brain barrier (BBB). The BBB protects the brain by blocking harmful substances from entering the fluid of the central nervous system. Unfortunately, it also blocks the uptake of many therapeutics, hindering treatments for brain diseases. While viruses are one of the few approaches that can be used as delivery systems to cross the BBB, they are expensive and difficult to make. Therefore, there is a pressing need for effective non-viral technologies to deliver genome editing machinery across the BBB to a substantial proportion of clinically relevant brain cell types. Such technologies could have broad implications for the treatment of many neurogenetic diseases.
Solutions to both target areas would not only provide proof-of-concept for the delivery of genome editing therapeutics, but they could be adapted to deliver other types of therapies to treat common and rare diseases in general.
The first phase of the Challenge began on May 15, 2023 and will run until October 5, 2023. More information about the Challenge is available on the TARGETED Genome Editor Delivery Challenge website.
“National Institutes of Health launch TARGETED Challenge,” NIH Common Fund, May 15, 2023
TARGETED Genome Editor Delivery Challenge (NIH Common Fund)
Somatic Cell Genome Editing Program (NIH Common Fund)
NIH Support: The SCGE program is led by the NIH Common Fund, the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS). The Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the National Heart, Lung, and Blood Institute (NHLBI) are also contributors to this Challenge.
Posted on by Dr. Francis Collins
Recently, CBS’s “60 Minutes” highlighted the story of Jennelle Stephenson, a brave young woman with sickle cell disease (SCD). Jennelle now appears potentially cured of this devastating condition, thanks to an experimental gene therapy being tested at the NIH Clinical Center in Bethesda, MD. As groundbreaking as this research may be, it’s among a variety of innovative strategies now being tried to cure SCD and other genetic diseases that have long seemed out of reach.
One particularly exciting approach involves using gene editing to increase levels of fetal hemoglobin (HbF) in the red blood cells of people with SCD. Shortly after birth, babies usually stop producing HbF, and switch over to the adult form of hemoglobin. But rare individuals continue to make high levels of HbF throughout their lives. This is referred to as hereditary persistence of fetal hemoglobin (HPFH). (My own postdoctoral research in the early 1980s discovered some of the naturally occurring DNA mutations that lead to this condition.)
Individuals with HPFH are entirely healthy. Strikingly, rare individuals with SCD who also have HPFH have an extremely mild version of sickle cell disease—essentially the presence of significant quantities of HbF provides protection against sickling. So, researchers have been exploring ways to boost HbF in everyone with SCD—and gene editing may provide an effective, long-lasting way to do this.
Clinical trials of this approach are already underway. And new findings reported in Nature Medicine show it may be possible to make the desired edits even more efficiently, raising the possibility that a single infusion of gene-edited cells might be able to cure SCD .
Sickle cell disease is caused by a specific point mutation in a gene that codes for the beta chain of hemoglobin. People with just one copy of this mutation have sickle cell trait and are generally healthy. But those who inherit two mutant copies of this gene suffer lifelong consequences of the presence of this abnormal protein. Their red blood cells—normally flexible and donut-shaped—assume the sickled shape that gives SCD its name. The sickled cells clump together and stick in small blood vessels, resulting in severe pain, anemia, stroke, pulmonary hypertension, organ failure, and far too often, early death.
Eleven years ago, a team led by Vijay Sankaran and Stuart Orkin at Boston Children’s Hospital and the Dana-Farber Cancer Institute discovered that a protein called BCL11A seemed to determine HbF levels . Subsequent work showed the protein actually works as a master mediator of the switch from fetal to adult hemoglobin, which normally occurs shortly after birth.
Five years ago, Orkin and Daniel Bauer identified a specific enhancer of BCL11A expression that could be an attractive target for gene editing . They could knock out the enhancer in the bone marrow, and BCL11A would not be produced, allowing HbF to stay switched on.
Because the BCL11A protein is required to turn off production of HbF in red cells. the researchers had another idea. They thought it might be possible to keep HbF on permanently by disrupting BCL11A in blood-forming hematopoietic stem cells (HSCs). The hope was that such a treatment might offer people with SCD a permanent supply of healthy red blood cells.
Fast-forward to the present, and researchers are now testing the ability of gene editing tools to cure the disease. A favorite editing system is CRISPR, which I’ve highlighted on my blog.
CRISPR is a highly precise gene-editing tool that relies on guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to correct the misspelling. The gene-editing treatment involves removing bone marrow from a patient, modifying the HSCs outside the body using CRISPR gene-editing tools, and then returning them back to the patient. Preclinical studies had shown that CRISPR can be effective in editing BCL11A to boost HbF production.
But questions lingered about the editing efficiency in HSCs versus more common, shorter-lived progenitor cells found in bone marrow samples. The efficiency greatly influences how long the edited cells might benefit patients. Bauer’s team saw room for improvement and, as the new study shows, they were right.
To produce lasting HbF production, it’s important to edit as many HSCs as possible. But it turns out that HSCs are more resistant to editing than other types of cells in bone marrow. With a series of adjustments to the gene-editing protocol, including use of an optimized version of the Cas9 protein, the researchers showed they could push the number of edited genes from about 80 percent to about 95 percent.
Their studies show that the most frequent Cas9 edits in HSCs are tiny insertions of a single DNA “letter.” With that slight edit to the BCL11A gene, HSCs reprogram themselves in a way that ensures long-term HbF production.
As a first test of their CRISPR-edited human HSCs, the researchers carried out the editing on HSCs derived from patients with SCD. Then they transferred the editing cells into immune-compromised mice. Four months later, the mice continued to produce red blood cells that produced high levels of HbF and resisted sickling. Bauer says they’re already taking steps to begin testing cells edited with their optimized protocol in a clinical trial.
What’s truly exciting is that the first U.S. human clinical trials of such a gene-editing approach for SCD are already underway, led by CRISPR Therapeutics/Vertex Pharmaceuticals and Sangamo Therapeutics/Sanofi. In January, CRISPR Therapeutics/Vertex Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had granted Fast Track Designation for their CRISPR-based treatment called CTX001 .
In that recent “60 Minutes” segment, I dared to suggest that we now have what looks like a cure for SCD. As shown by this new work and the clinical trials underway, we in fact may soon have multiple different strategies to provide cures for this devastating disease. And if this can work for sickle cell, a similar strategy might work for other genetic conditions that currently lack any effective treatment.
 Highly efficient therapeutic gene editing of human hematopoietic stem cells. Wu Y, Zeng J, Roscoe BP, Liu P, Yao Q, Lazzarotto CR, Clement K, Cole MA, Luk K, Baricordi C, Shen AH, Ren C, Esrick EB, Manis JP, Dorfman DM, Williams DA, Biffi A, Brugnara C, Biasco L, Brendel C, Pinello L, Tsai SQ, Wolfe SA, Bauer DE. Nat Med. 2019 Mar 25.
 Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH.Science. 2008 Dec 19;322(5909):1839-1842.
 An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, Shao Z, Canver MC, Smith EC, Pinello L, Sabo PJ, Vierstra J, Voit RA, Yuan GC, Porteus MH, Stamatoyannopoulos JA, Lettre G, Orkin SH. Science. 2013 Oct 11;342(6155):253-257.
 CRISPR Therapeutics and Vertex Announce FDA Fast Track Designation for CTX001 for the Treatment of Sickle Cell Disease, CRISPR Therapeutics News Release, Jan. 4, 2019.
Sickle Cell Disease (National Heart, Lung, and Blood Institute/NIH)
Cure Sickle Cell Initiative (NHLBI)
What are Genome Editing and CRISPR-Cas9? (National Library of Medicine/NIH)
Could Gene Therapy Cure Sickle Cell Anemia? (CBS News)
Daniel Bauer (Dana-Farber Cancer Institute, Boston)
Somatic Cell Genome Editing Program (Common Fund/NIH)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases