RARE Daily

Death in N-of-1 Trial Attributed to Immune Response to Vector

May 19, 2023

Terry Horgan, the brother of Cure Rare Disease Founder and President Rich Horgan, died from an innate immune response to the vector used in an experimental CRISPR gene therapy the company developed to treat his form of Duchenne muscular dystrophy.

The findings were made public in a case report from the clinical study published in the open access preprint server medRxiv.org. The paper has not been peer-reviewed, but the company said it is making the report available to the rare disease community while it submits the manuscript to a peer-reviewed journal.

“As we’ve communicated, the evidence in the report suggests that Terry had an adverse reaction to the viral vector used to deliver the potential CRISPR therapeutic, worsened by his age and the advanced stage of his condition,” wrote Rich Horgan, CEO of Cure Rare Disease in a letter to the rare disease community announcing the publication. “Unfortunately, we didn’t have an opportunity to learn whether the potential CRISPR therapeutic we developed for Terry was efficacious. We did, however, learn much that we can apply to our ongoing programs and share with the broader neuromuscular and gene therapy fields.”

Duchenne muscular dystrophy (DMD) is a rare disease caused by mutations in the gene that encodes for dystrophin, a protein critical for the normal function of muscle cells. These mutations, the majority of which are deletions, result in the lack of dystrophin protein and progressive loss of muscle function. Loss of strength and function typically first appears in pre-school age boys and worsens as they age. As the disease progresses, the severity of damage to skeletal and cardiac muscle often results in patients experiencing total loss of ambulation by their early teenage years and includes worsening cardiac and respiratory symptoms and loss of upper body function by the later teens. There is no cure for DMD and currently approved therapies provide limited benefit.

The experimental therapy was designed to help Terry Horgan 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.

In October 2022, Terry Horgan received an experimental CRISPR gene therapy as the only patient in a clinical study to evaluate a therapy tailored to treat the gene mutation underlying his Duchenne muscular dystrophy.

Prior to dosing, the protocol began with suppressing his immune system to prepare his body to receive the therapy, which was delivered with a high dose adeno-associated viral vector for body-wide distribution to his skeletal and cardiac muscles.

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

Cure Rare Disease said Terry was weak and significantly compromised by the disease. He was 27 and it was known that this type of reaction to the vector was a risk given his advanced disease. Nevertheless, he felt that the potential benefit of the therapeutic outweighed the risk.

Cure Rare Disease said scientists have learned 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. They also discovered that the body-wide distribution pattern of the gene therapy differed to what was observed in its preclinical studies in mice. The company said this indicates that dosing of gene therapies need to be carefully considered for patients where the target tissue has undergone significant wasting.

Finally, they said 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.

Based on the finding, Cure Rare Disease said it will be using next-generation vectors for the additional programs in its pipeline. It said it continues 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.

Photo: Rich Horgan, founder and president of Cure Rare Disease

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