FAQ on the findings from the CRD-TMH-001 case report

What was the cause of death?

On October 4, 2022, we commenced an ‘N of 1’ clinical trial to test a mutation-specific CRISPR gene therapy approach for a DMD patient. The protocol began with suppressing the patient’s immune system to prepare his body to receive the therapy, which was delivered with a high dose adeno-associated viral vector (AAV) for body-wide distribution to his skeletal and cardiac muscles. 

Six days after receiving the therapy, the patient’s health began to rapidly decline, showing signs of cardiac and respiratory distress. The post-mortem findings from the study revealed that the patient’s lungs had sustained injury likely due to a strong immune reaction to the high dose AAV, and that unfortunately the gene therapy itself did not have a chance to do what it was designed to do. 

We knew going into the trial that this type of reaction to the vector was a risk for the patient, as the advanced stage of his condition meant that his body was weak and significantly compromised by the disease. But, at age 27, he was running out of time and options, and we, and he, felt that the potential benefit of the therapeutic outweighed the risk. 

How do you know that it was the AAV that triggered the adverse event and not the CRISPR gene editing therapy itself?

The timing of the patient’s passing (6 days following treatment), combined with a lack of expression of Cas9 in his body, suggests that the therapy was not yet activated in his tissues, and therefore, no mechanism of action took place. 

What does this mean for older, more advanced patients with DMD? 

Injecting the amount of virus needed to deliver gene therapies to hard-to-reach, systemic areas of the body (like muscle, which is body-wide) is known to trigger an immune response, which is why immune suppression is performed prior to treatment. For patients who are older and weaker, it is harder for the body to fight through the immune response to the toxic nature of high-dose AAV.

What have we learned from the case report?

Scientists have already learned a lot from studying what happened, including the potential for severe immune reactions to viral vectors at higher doses that can manifest as respiratory and cardiac complications. We also discovered that the body-wide distribution pattern of the gene therapy differed to what was observed in our preclinical studies in mice. This informs us that dosing of gene therapies need to be carefully considered for patients where the target tissue has undergone significant wasting.  

Perhaps the most significant learning is that ‘first generation’ vectors such as AAV9 delivered at high-doses required for body-wide reach to muscles can exert a strong toxic effect. Therefore, clinical trial participants need to be sufficiently healthy to receive this form of therapy, particularly to combat the initial acute immune reaction that occurs within the first week of the treatment. We hope that our data shared so far will contribute to the body of knowledge on how to best and safely dose gene therapy for neuromuscular disease patients.

Can you describe the CRISPR therapeutic in detail – how was it designed to work?

The potential therapeutic was designed to help the patient make the muscle protein (full-length dystrophin) that his body is missing. Known as CRISPR transactivation, the therapy was designed to upregulate an alternate form (brain isoform) of the dystrophin protein with the goal of stabilizing symptom progression of Duchenne muscular dystrophy.

This is the first time that this new CRISPR approach has been studied in human, so it’s particularly disappointing that the vector triggered such a strong immune response and the patient never had a chance to potentially benefit from the treatment. 

What were the steps to ensuring that the drug was safe for a first-in-human trial?

Several years of research, led by scientists and clinicians with expertise on developing therapies for rare neuromuscular diseases, preceded the approval of our investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA). The potential therapeutic was studied thoroughly and showed safety and efficacy in preclinical and IND-enabling studies.

Will Cure Rare Disease continue? 

We are more committed than ever to solving critical challenges in drug development for rare and ultra rare diseases. 

Cure Rare Disease remains committed to the many rare and ultra rare disease families who are left behind by the way drugs are traditionally developed – for larger patient populations with widespread commercial viability. We’ve shown that our framework can bring a potential therapeutic to clinical study. This framework combines collaborative science with innovative funding models to develop potential therapies for smaller patient populations who need effective treatments now. We’ll continue to break down barriers – and, particularly, the financial hurdles the rare disease community faces. We must develop new models of reimbursement to make the system more equitable.

We’re also firmly committed to the 20 families who are relying on therapies currently in our pipeline. Those programs will continue, taking into account what we learned from this case, with alternative vectors. 

Based upon these findings, will Cure Rare Disease adjust any potential therapies in its pipeline?

We will be using next-generation vectors for the additional programs in our pipeline, and we continue to explore and invest in research on alternative delivery methods, including more muscle-targeted viral vectors as well as nonviral delivery methods, for gene therapies. The vector used to deliver this potential therapy was the best available at the time, but the technology has already improved, and we have better options to consider now.

Will Cure Rare Disease have an age threshold for treatment, given that Terry’s age and condition likely played a role in his death?

We will follow the guidance of clinicians in determining whether future trial participants are healthy enough for treatment. 

Is this a setback for CRISPR? AAVs?

Our study shows that the CRISPR gene therapy did not have a chance to be activated; so, unfortunately, we did not learn anything about the safety or efficacy of the therapeutic itself. 

Regarding the AAV, there have been other deaths and severe adverse events from AAV delivery. The field is continually improving and investing in the future. Our hope is that delivery methods as well as our understanding of the body’s response to viral vectors continue to improve.