Baby KJ's Story - a remarkable success of the customized CRISPR gene editing treatment

This morning, FDA conducted a roundtable discussion on cell and gene therapies. The roundtable invited 23 panel members from the academic and industry and was attended by FDA commissionner Dr Marty Makary and FDA CBER director Dr. Vinay Prasad. At the second half of the roundtable discussion, HHS secretary, RF Kennedy Jr, NIH director, Dr Jay Bhattacharya, and CMS Administrator, Dr Mehmet Oz all gave commentary speeches. The overall tone of the roundtable is very positive and the government agencies are very supportive to the cell and gene therapy (including xenotransplantation) development. The panel suggests various ways to support the cell & gene therapies. Renewing the pediatric priority review voucher program, Reduction of CMC requirements, continued support of flexible trial design and accelerated approval, and more reliance on post approval requirements and real-world evidence (RWE) were highlighted as key tools for the agency to reduce the number of programs caught in the

clinical “valley of death”. See the articles reported by FierceBiotech "'Not a horse and pony show': at FDA cell and gene roundtable, officials look for ways to cut red tape". and by BioSpace "RFK Jr. Joins Deputies in Voicing Support for Regulatory Flexibility for Cell and Gene Therapies".

During the roundtable discussions, the baby KJ's case was mentioned multiple times. It is worth discussing the baby KJ's story.

KJ Muldoon is a 10-month-old infant who became the first person in the world to receive a personalized CRISPR-based gene-editing therapy, marking a significant milestone in the treatment of rare genetic diseases.

Diagnosis and Condition

Shortly after birth, KJ was diagnosed with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare and life-threatening genetic disorder that impairs the body's ability to eliminate ammonia. This condition can lead to toxic ammonia buildup, causing severe neurological damage or death in infancy. 

Development of Personalized Therapy

With conventional treatments offering limited hope, a multidisciplinary team from the Children's Hospital of Philadelphia (CHOP) and Penn Medicine embarked on an unprecedented effort to develop a customized gene-editing therapy tailored specifically to KJ's unique genetic mutations. Within six months, researchers identified two truncating variants in the CPS1 gene and designed a bespoke CRISPR-based therapy using base editing technology. This approach allowed precise correction of the faulty DNA without cutting the genetic code. 

Treatment and Outcome

KJ received multiple infusions of the experimental therapy, delivered directly to his liver using lipid nanoparticles carrying the gene-editing components. The treatment aimed to correct the genetic defect responsible for his condition. Following the therapy, KJ showed significant improvement, including better tolerance to dietary protein and reduced dependence on supportive medications. After spending over 300 days in the hospital, he was discharged and returned home with his family.

Significance and Future Implications

KJ's case represents a groundbreaking advancement in personalized medicine and gene-editing therapies. It demonstrates the potential of customized CRISPR treatments to address ultra-rare genetic disorders by rapidly developing individualized therapies. While long-term outcomes and scalability remain areas for further research, this success story offers hope for treating other rare diseases through similar personalized approaches. 

For more detailed information, you can watch the FDA roundtable discussion on cell and gene therapies where KJ's case was mentioned: FDA Roundtable Discussion.

Impact of Baby's KJ's Case on Clinical Trial Design of Gene Therapies

Baby KJ's story was extensively discussed in a follow-up podcast "FDA Direct Ep. 7: This Week at the FDA!" by FDA commissioner Dr Makary and CBER director Dr Prasad. Their discussion of Baby KJ's story extended to the clinical trial designs for gene therapy studies and ultra rare diseases. 

The FDA's approach to clinical trial designs for gene therapy studies emphasizes flexibility and a nuanced understanding of the specific condition and therapy. Here are the key points:

• Flexible Trial Designs: The FDA acknowledges that a "one-size-fits-all" approach is not suitable. They adapt trial designs based on the specific condition, its frequency, severity, and the uniqueness of the therapy.
• "N of 1" Trials for Rare Diseases: For extremely rare and dire conditions, a single-patient ("N of 1") trial can be sufficient for approval, especially when there is a plausible mechanism of action and clear biological markers demonstrating effectiveness. An example highlighted is the rapid approval of a custom-tailored gene editing treatment for Baby KJ's rare condition.
• Plausible Mechanism Pathway: A strong, scientifically sound mechanism of action can support approval, even without extensive large-scale trials, if it suggests safety and effectiveness through extrapolated data.
• Challenges with Slowly Deteriorating Conditions: For conditions with slow and variable deterioration, relying on anecdotal evidence from "N of 1" studies without clear biological correlates is more difficult, as it's harder to distinguish treatment effects from the natural disease progression.
• Surrogate Endpoints: The FDA accepts the use of surrogate endpoints, such as tumor shrinkage in cancer, as indicators of a drug's activity.
• Industry Desire for Predictability: The industry seeks greater predictability regarding FDA expectations for endpoints, control arms, and when randomization is necessary. Improved communication and transparency are suggested to address this.
• Concerns with International Trial Data: There are concerns about relying solely on clinical trial data from certain countries, particularly if the majority of participants are from a single foreign country, for U.S. regulatory decisions.
• Re-evaluation of Trial Requirements: The FDA is open to re-evaluating requirements, such as the need for two clinical trials versus one for new drug approvals, to potentially streamline the process.

The overarching theme from recent FDA discussions is a shift towards a more flexible, common-sense, and scientifically driven approach to gene therapy regulation, prioritizing patient needs and scientific plausibility, especially for rare and life-threatening conditions.

References:

• World's first patient treated with CRISPR gene editing therapy at CHOP returns home
• First Personalized CRISPR Gene Editing Therapy Patient Baby KJ Discharged 
• Gene editing helped a desperately ill baby thrive. Scientists say it could someday treat millions

• A Baby Receives the First Customized CRISPR Treatment
• A Gene-Editing Breakthrough Saves Infant With Rare Disease

Industry-Sponsored N-of-1 Trials in Orphan Drug Development

N-of-1 clinical trial is often mentioned as one of the approaches to address the challenging issues in orphan drug development. at one point, FDA rolled out more guidance on 'N of 1' gene therapies including the guidance on "Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases". AHRQ had a publication "Design and Implementation of N-of-1 Trials: A User’s Guide". Recent "baby KJ's story" was touted by the FDA as a success story for individualized treatment for a N-of-1 disease condition "FDA Cell & Gene Therapy Roundtable: Putting Every Patient Within Reach of Innovation". Nature magazine had an article "A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases"

We would like to check the reality to see how many drugs or biological products were approved by the US FDA based on the evidence from N-of-1 clinical trials. 

We identified a few ultra-rare disease cases in the past decade where industry or institutional sponsors conducted single-patient (“N-of-1”) trials of experimental therapies. Notably, no drug or biologic approved in the last 10 years appears to have relied on N-of-1 clinical trial data for its FDA approval. The only FDA approval historically based in part on N-of-1 evidence was danazol for hereditary angioedema in the 1980s. Below we summarize key examples of N-of-1 trials involving drugs/biologics and rare indications:

Drug/ Biologic	Orphan Indication	Sponsor (Company/Institution)	N-of-1 Trial Design & Results	Regulatory Outcome
Milasen (custom ASO)	CLN7 Batten disease (Infantile neuronal ceroid lipofuscinosis)	Boston Children’s Hospital (Timothy Yu’s lab)	Single-patient, customized antisense oligonucleotide. FDA cleared an IND for Mila in late 2017, and she received serial intrathecal doses. Her seizure frequency fell dramatically (from ~30/day to <10/day) and her neurologic decline stabilized during treatment.	Investigational (IND only; no FDA marketing approval)
Custom ASO for A-T (no trade name)	Ataxia-Telangiectasia	Boston Children’s Hospital / A-T Children’s Project (Dr. Yu)	Personalized splice-modulating ASO for one AT patient. FDA granted an IND in 2020 for an N-of-1 trial. The child began receiving the ASO (via intrathecal delivery) later in 2020; detailed clinical outcomes have not yet been published.	Investigational (IND only; ongoing treatment)
CRD‑TMH‑001 (CRISPR-based gene therapy)	Duchenne muscular dystrophy (specific exon 1/promoter mutation)	Cure Rare Disease (nonprofit biotech)	Single-patient CRISPR/Cas9 gene-editing therapy. FDA cleared an IND in August 2022 for a one-person trial. The only enrolled patient (the sponsor’s founder’s brother) was dosed but later died (cause under review). As a result, efficacy remains unknown.	Investigational (IND only; trial suspended)
Danazol	Hereditary angioedema	Original developer (Searle/Pfizer)	Historical example: A multi-crossover N-of-1 trial (9 patients, 47 treatment periods) was reported in 1976. This small trial of danazol demonstrated reversal of HAE symptoms and formed part of the FDA approval record.	Approved (for HAE; orphan indication) https://www.fda.gov/media/87621/download section 5.2.4

Each case is discussed in more detail below.

Milasen for Batten Disease (CLN7)

• Drug & Sponsor: Milasen is a one-off antisense oligonucleotide (ASO) developed at Boston Children’s Hospital by Dr. Timothy Yu’s team. It was designed for an 8‑year-old patient (“Mila”) with a unique retrotransposon mutation in the CLN7 gene causing Batten disease.
• N-of-1 Design & Results: After rapid sequencing and preclinical work, the FDA granted an IND to trial milasen in late 2017. Mila then received intrathecal milasen injections every 3 months under an N-of-1 protocol. Over ~9 months of treatment, Mila’s seizure frequency fell from ~30/day to under 10/day, and her neurological decline notably stabilized. No significant adverse effects were reported, and her condition improved in several clinical measures. These results were published in the New England Journal of Medicine (2019).
• Regulatory Outcome: Milasen remains an investigational therapy given under an IND. It was not submitted for FDA marketing approval (and Mila later died in early 2021). Thus, no FDA approval was sought or granted for milasen.

Customized ASO for Ataxia-Telangiectasia

• Drug & Sponsor: A patient-specific splice-switching ASO (unnamed) was developed by Dr. Yu’s group (supported by the A-T Children’s Project) for a young girl with ataxia-telangiectasia (AT). The ASO was tailored to correct her particular ATM gene splicing defect.
• N-of-1 Design & Results: The FDA granted IND approval for this one-off ASO treatment in 2020actionforat.org. The affected child began receiving the ASO via intrathecal infusion that year, under a single-patient trial protocol. (To our knowledge, no detailed efficacy data from this N-of-1 trial have yet been published.)
• Regulatory Outcome: This custom AT therapy is in the investigational stage (IND only). No FDA marketing approval has been sought or obtained.

CRD‑TMH‑001: CRISPR Therapy for Duchenne Muscular Dystrophy

• Drug & Sponsor: CRD‑TMH‑001 is a one-time, custom CRISPR/Cas9 gene-editing therapy developed by Cure Rare Disease (a nonprofit “n=1” biotech) to target a specific exon 1/promoter mutation in the DMD gene. Cure Rare Disease’s founder (motivated by his brother’s illness) sponsored the program.
• N-of-1 Design & Results: In mid-2022, the FDA cleared a first-in-human IND for CRD-TMH-001. The trial was explicitly a single-patient study: one eligible DMD patient (age 27, the sponsor’s brother) was treated. The therapy was infused intrathecally as planned. Tragically, the patient died several months later; a causality review is ongoing. To date, no efficacy data (or definitive safety findings) from this N-of-1 trial have been published.
• Regulatory Outcome: CRD-TMH-001 remains purely investigational under the IND. No further patients have been treated and no FDA approval has been pursued.

Historical FDA Approval: Danazol for Hereditary Angioedema

• Drug & Indication: Danazol is a synthetic steroid used to prevent attacks of hereditary angioedema (HAE), a rare genetic edema disorder.
• N-of-1 Trial Evidence: In 1976, a classic FDA review noted that the approval of danazol for HAE was supported in part by an N-of-1 multiple-crossover trial of nine patients (47 treatment periods). In that study, each subject alternated between danazol and placebo in random sequence, demonstrating clear reversal of clinical and biochemical abnormalities on danazol. This case was cited in section 5.2.4 of the FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications
• Regulatory Outcome: Danazol was approved for HAE prevention (an orphan indication) and remains an approved drug (marketed as DANOCRINE). This case shows that the FDA has historically accepted single-subject crossover data in rare diseases. However, it is an older example; no similar approvals based on N-of-1 data have emerged in the past decade. The N-of-1 study of Danazol in HAE was published in New England Journal of Medicine in 1976 "Treatment of Hereditary Angioedema with Danazol — Reversal of Clinical and Biochemical Abnormalities"

Summary

In summary, we found only a handful of “N-of-1” clinical trials over the past 10 years involving investigational drugs for very rare diseases. These include two custom antisense oligonucleotides (Mila’s milasen for Batten disease, and an ASO for one AT patient) and one CRISPR gene therapy for Duchenne MD. All were “approved” only under individual INDs and have shown promising signals but remain experimental; none has led to FDA marketing approval. Apart from the historical example of danazol (approved via N-of-1 data in the 1970s), our searches of FDA databases, ClinicalTrials.gov, and published literature did not identify any new orphan drugs approved based on N-of-1 trial evidence. Thus, while N-of-1 trials are an emerging tool for ultra-rare diseases, they have not yet changed the landscape of FDA approvals in the last decade.