Gene editing shows promise for Wiskott-Aldrich syndrome

The federal government recently approved a treatment for sickle cell disease that uses the same gene-editing technique researchers are exploring to treat Wiskott-Aldrich syndrome (WAS). WAS is a rare and serious primary immunodeficiency (PI) characterized by life-threatening bleeding problems and infectious complications.

The medical product for sickle cell disease will be the first on the market to use CRISPR-Cas9 gene editing technology, laying the groundwork for the Food and Drug Administration (FDA) to consider future gene editing treatments for other conditions like WAS.

During the Immune Deficiency Foundation (IDF) 2023 Conference, the PI community learned about multiple facets of gene editing and WAS from Dr. Matthew Porteus, a professor of pediatrics specializing in stem cell transplantation and regenerative medicine, hematology/oncology, and human gene therapy at Stanford Medicine Children's Health at Stanford University.

“What once we could only draw on the chalkboard in terms of genome engineering, we can now do in stem cells with high efficiency and specificity. We can really edit the DNA of a cell, almost like we can edit a document on our computer,” said Porteus, a pioneer in the gene editing field.

Currently, gene editing for WAS is still in the research stages and has not yet reached clinical trials. Porteus described how CRISPR gene editing works, how studies show it produces better results, such as more WAS protein cells, than traditional gene therapy, and how it poses challenges requiring scientists, investors, and the FDA to rethink strategies to bring it to market.

In gene editing, the experience for the patient is not that much different from that of gene therapy. As in traditional gene therapy, doctors collect hematopoietic stem cells from a patient, correct the cells, and infuse the corrected cells back into the patient.

In both traditional gene therapy and gene editing, the new version of the gene without the PI-causing variant is inserted into cells; however, where they are inserted is different. The difference is that in traditional gene therapy, the new copy is either added in a random place in the DNA or remains as a separate piece of DNA in the cell. In gene editing, the new copy is added to the DNA just upstream of where the variant copy is, making it more precise than traditional gene therapy.

“Instead of inserting it into the genome in a random fashion, we insert it exactly back into the gene itself, so that now the good copy of the gene is going to be used instead of the bad copy of the gene. But all the natural factors that regulate when, where, and how much the gene should be expressed are intact.

“The reason we want to target our genes exactly where we want is that for many of the primary immunodeficiency diseases, it's not just giving back to the genome a good copy of the gene, but we need that good copy expressed or utilized by the cells at just the right time and then just the right amount. There are a number of different diseases associated with primary immunodeficiencies where the regulated expression is absolutely essential,” said Porteus, adding that two of those PIs are WAS and X-linked severe combined immunodeficiency (SCID).

“By inserting the gene exactly where you want, you not only avoid the risks of genes being inserted in the wrong place in the genome, but you get enhanced efficacy as well.”

Researchers conducted studies in which they used the CRISPR system to insert different forms of the WAS gene into itself, and they examined how effective that was compared to using a traditional lentiviral gene therapy vector.

“What they showed, interestingly, is that you could get more WAS protein cells, so more cells expressing the protein using the gene-editing system than with the (gene therapy vector) system. So, it shows that it is just as effective inserting genes as it is as a lentiviral gene therapy vector,” said Porteus.

Researchers also examined how macrophages and platelets fared between the two systems. They found that, in the macrophages, the insertion frequency was higher using the genome editing system and that the macrophage function was better. Similarly, in the function of the platelets, there was more WAS protein using genome editing versus lentiviral delivery. Furthermore, with genome editing, the platelets were bigger and had better function.

“This again shows that by using genome editing to knock the good copy, the wild-type copy of the gene, into itself, we get, again, increased safety by avoiding random integrations and increased efficacy by getting more expression in the right cells to fully rescue function,” explained Porteus.

Before CRISPR gene editing enters clinical trials, researchers must make the technology more efficient and reduce the need for chemotherapy, said Porteus. In addition, drug companies must convince investors to support gene editing-based medicine for rare diseases, which can run in the millions for just one treatment.

“I think for those of us who are in academia, we need to continue to improve the technology to make it safer, more effective, and simpler. And we need to continue to develop that pipeline such that there's pressure on biotechs and entities to finally bring these to the clinic,” said Porteus.

“I think that biotech, pharma, and others really need to think about new business models for developing one-time cures for patients with rare diseases. It is possible that the current model of private companies that have shareholders in which the number one value is creating shareholder value in terms of money is not the right model for developing therapies for diseases like WAS and other rare diseases.”

Finally, the FDA also plays a crucial role in aiding the therapies’ success.

“The FDA is designed to protect patient safety, and it is designed, in my opinion, to regulate drugs that might treat hundreds of thousands, if not millions of people in the United States. This highly expensive pathway serves its purpose, but for rare diseases, it is burdensome and slows things down,” said Porteus.

“I think we need to collaborate with our FDA colleagues to streamline the process to initiate an IND (investigational new drug application), which is to test a drug in the first few patients and then streamline a process for getting it approved, so it can be given to as many patients as possible.

“I believe that if we defined a different regulatory pathway for diseases that are rare or ultra rare, this would be incredibly important.”

Organizations like IDF play a crucial role in helping make gene editing a reality for those who need it.

“Where patient advocates and patient organizations can do some of their best work is participating in developing safe but streamlined processes to get these therapies into rare patients and really pushing the regulatory agencies and even politicians to think about is the risk-benefit that the regulatory agencies now adopt really appropriate for these rare and devastating diseases?” said Porteus.

“Perhaps we need to help them understand that the bar needs to be moved a little bit or otherwise, these will just sit on the shelf or sit in publications and not be helping patients.”

Porteus hedged on predicting exactly how long it would take for gene editing for WAS to move to clinical trials but said he hoped it would be within one to three years. He looks forward to the day when the process can be broadly applied to many diseases. CRISPR gene editing shows promise for not only WAS, SCID, and sickle cell disease but also cancer, Alzheimer's disease, cystic fibrosis, and HIV, among others.

“I end with an optimistic take that we have the potential to impact the lives of millions of patients. And now the question is, can we execute on that promise?” said Porteus.