FDA approval for CRISPR/Cas9-based therapy for SCD – an accomplishment for science, not for majority of the patients.

The news of the FDA approving the world's first CRISPR/Cas9-based therapy for SCD is all over the internet. This is my opinion on what this achievement means for science and the majority of patients dealing with SCD.
FDA approval for CRISPR/Cas9-based therapy for SCD – an accomplishment for science, not for majority of the patients.

In a landmark development, the US Food and Drug Administration (FDA) has approved the world’s first CRISPR/Cas9-based therapy for Sickle Cell Disease (SCD). Named ‘Casgevy’, the innovative gene therapy was approved on December 8th for treatment in patients 12 years or older. I recently wrote about this revolutionary development on my blog and I suggest checking it out to get a quick primer on SCD and CRISPR/Cas9. This article focuses only on my opinion on this issue.

A great achievement!

As a biologist, especially after using CRISPR/Cas9 to make my life in the lab easier, I was ecstatic after reading the news. After all, it is a technique that was named 'breakthrough of the year' in 2015 by Science, and a little over eight years after their seminal paper, it won Jennifer Doudna and Emmanuelle Charpentier, a much-deserved Nobel Prize. And here we are, just about a decade after that paper, and only a couple years after the Noble Prize, with an approved therapy for humans. The celerity is remarkable, and it's not just me who thinks so. "It’s so exciting to see how fast, and frankly how safely and effectively, this therapy is being rolled out in humans," remarked Prof. Doudna on the approval of Casgevy.

Although my tryst with this revolutionary gene-editing technique is limited to making innocuous mutations in laboratory bacteria, the technique itself can have far-reaching implications. But to have arguably the most important drug regulatory authority in the world approve such therapy for use in humans, including children older than 12 years old, is a stupendous achievement for a technique that received plenty of bad press and widespread condemnation, even by the scientific community, when a Chinese scientist used it to edit human embryos, resulting in what the press called - CRISPR babies.

An achievement for the technique or the patients?

Perhaps it might seem obvious what I am trying to come to. It is a truly remarkable achievement for the technique, considering the CRISPR babies debacle happened a mere half a decade ago. It is amazing how something went from being a sin, leading to a jail term for the said Chinese scientist, in about five years. However, to be fair, Casgevy only involves editing adult stem cells unlike editing embryos and carrying them to term. However, we could be witnessing the beginning of a new surge in gene-editing-based therapies for various genetic disorders. An outstanding achievement from our, the scientists', perspective but is it great news for the patients, or rather, the majority of patients?

Of course, it would be harsh, not to mention insanely stupid, for me to say that this doesn't help the patients at all. However, some startling figures sound a little bothersome. The therapy has been priced at an eye-watering $2.2 million. "We believe the price of medicine to reflect the value that it brings, and the value that this brings is a one-time therapy for potentially a lifetime of cure," Vertex (The manufacturer of Casgevy) CEO said in an interview with CNBC. This is not an unsubstantiated claim either as the company has estimated that the cost of managing SCD over a lifetime for someone with recurrent pain crises is between $4 million and $6 million. While studies where the authors have no competing financial interest have claimed a more modest estimate of $1.7 million, it is still in the same ballpark.

However, it is not known if that would be enough to convince the health insurance providers managing the affairs of about 100,000 SCD patients in the US, of which, 16,000 have so far been declared eligible for the therapy. The last part of the previous sentence is what makes this concern even more serious. It has been suggested that more than 80% of SCD patients worldwide reside in Sub-Saharan Africa. I wish to take away nothing from those hopeful 16,000 Americans who deserve a healthy life but, at the same time, I can't help but think about the irrelevance of this development to the majority of the patients who don't even have access to basic healthcare.

Dr Kenny Lin quotes the example of hydroxyurea, a drug used to manage symptoms of SCD, in his recent blog. Despite being approved by the FDA in 1998, the drug remains unavailable to most patients. A recent proposal to provide hydroxyurea therapy to SCD patients in Sub-Saharan Africa has a modest budget of $100 million, not even close to meeting the cost of gene therapy for eligible patients.

Despite the overall tone suggesting otherwise, I am optimistic that rapid technological advances will help bring the price tag to a manageable level. Until then, I concur with Teonna Woolford, CEO of the Sickle Cell Reproductive Health Education Directive, "Approval does not mean access".

So, what about the side effects?

I have presented my work at quite a few conferences and this has been everyone's favourite question to ask - What about 'off-targeting'? Remind you, I just use CRISPR/Cas9 to make mutations in lab bacteria, so it is obvious that such a question is bound to be asked when we are talking about editing human cells.

Off-targeting refers to unintended edits made by an active Cas9 protein. These are not just hard to predict, but considering our limited knowledge of the human genome, it's even harder to speculate on the biological consequence of such edits. Unfortunately, just like any other CRISPR/Cas9-based method, Casgevy is not immune to off-targeting. The FDA panel, however, considered it a minor risk and believed that the clinical benefit shouldn't overshadow such theoretical concerns. Although I believe it is scientifically imprudent to regard it as a theoretical concern, it is worthwhile to not let the perfect be the enemy of the good. The therapy has been designed to minimize the off-targeting but the chance of it happening, however miniscule it may be, is still there.

As I mentioned earlier, the relatively rapid approval of this innovative therapy is amazing. This has also led to some sceptics asking about the long-term effects of the treatment. These concerns, partially arising from the aforementioned off-targeting, assume validity based on the lack of any long-term data on the efficacy of Casgevy. Does the curative effect last forever? A layman might answer yes, but an apt scientific response would be – we don't know. A follow-up of patients given Casgevy for 10-15 years, or even a lifetime, would provide necessary data to make a definitive statement but the truth is such data doesn't exist, at least for now.

Another problem is with the basic process of stem cell transplant itself. This is a necessary process whereby the faulty stem cells are eliminated by a heavy dose of chemotherapy, before their replacement by gene-edited stem cells. A risk of hair loss, infertility, secondary infections, and cancers, are genuine concerns that accompany chemotherapy. It might be unfair to count this as a limitation of Casgevy itself, rather it is a side effect of our current practices of stem cell replacement. However, until newer and safer ways of grafting editing cells are introduced, any potential gene therapy will come with a heightened chance of such unwanted consequences.

What's the bottom line?

Although I may have sounded very negative about this historic advancement in medical science, this news came to me as a delightful surprise. I have been a proponent of genetic engineering, not because that is what I studied and trained in, but because of the immense potential it holds. About a decade ago, I was involved in a fierce debate in my classroom over the proposed move by the Indian government to allow the farming of Bt-Brinjal, a pest-resistant variety of eggplant. I had high hopes, not to mention strong opinions, but much to my chagrin, the proposal was ultimately scrapped. Fast forward to now, the FDA has approved a CRISPR/Cas9-based therapy for a human disease. I believe this opens the floodgates for therapies for correcting other genetic disorders. There are some limitations and genuine concerns but if you are a person suffering from the debilitating pain crises caused by SCD and you have the means to afford the therapy, those concerns would hardly matter. I hope scientific advances will allow such therapies to become more accessible in the future. Until then, this is a win for the CRISPR/Cas9 technology, not for the majority of victims of SCD.

Please let me know what you think about the issue in the comments. The opinions I have expressed are personal and do not reflect the views of my employers. My opinions may be ill-informed for I am not an expert. The cover image is by , and was downloaded from Flickr. 

Please sign in or register for FREE

If you are a registered user on Research Communities by Springer Nature, please sign in