10-Month-Old Boy Makes History as World’s First Patient Treated with Personalized CRISPR Therapy

Abstract

A boy who turned 10 months old in June has become the world’s first patient to be treated with a personalized CRISPR therapy designed to make a correction directly to the genome.

KJ Muldoon was born with severe carbamoyl phosphate synthetase 1 (CPS1) deficiency. He was too young and vulnerable to receive a liver transplant. And with each passing day, KJ’s risk for neurological damage or death increased.

Rebecca Ahrens-Nicklas, MD, PhD, director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at Children’s Hospital of Philadelphia, approached KJ’s father Kyle Muldoon and his partner, Nicole Muldoon, with the idea of a personalized CRISPR therapy that could correct KJ’s individual disease-causing mutation—something that had never before been done in humans.

Ahrens-Nicklas, who is also an assistant professor of pediatrics at the University of Pennsylvania’s Perelman School of Medicine, has focused her research on developing a gene-editing therapy for phenylketonuria, in an ongoing collaboration with her former doctoral classmate Kiran Musunuru, MD, PhD, cardiologist and professor of translational research at Penn Perelman.

Musunuru is first author, and co-corresponding author with Ahrens-Nicklas, of a study published in the New England Journal of Medicine detailing KJ’s treatment. “We anticipate that rapid deployment of patient-specific gene-editing therapies will become routine for many genetic diseases,” the study’s 45 authors predicted.¹

Musunuru also presented the work in a plenary session at the American Society for Gene and Cell Therapy (ASGCT) in New Orleans.

“We need a patient-first approach for any variant in any patient, whomever, wherever they are. Each and every patient deserves a fair shot at this,” Musunuru told the ASGCT crowd.²

Musunuru’s research team was able to determine how to correct one of KJ’s genetic changes within a few weeks. KJ had two truncating CPS1 variants, referred to as Q335X on the paternal allele and E714X on the maternal allele. He underwent whole-genome sequencing to uncover the mutation.

Upon submission of the U.S. Food and Drug Administration’s application to treat KJ, the agency granted approval in just 1 week. KJ received the first dose of a customized lipid nanoparticle (LNP)-delivered, bespoke base-editing therapy by intravenous infusion between the age of 6 and 7 months. To maximize benefit while optimizing safety, two additional infusions were administered at rising doses at 7 and 8 months of age.

Within 7 weeks after infusion day, KJ was able to tolerate increased dietary protein and receive half the starting dose of his nitrogen-scavenger medication.

KJ’s successful treatment resulted from collaboration between multiple academic and industry partners, including the Innovative Genomics Institute at University of California, Berkeley; Mass General Brigham Gene and Cell Therapy Institute; Danaher; and Acuitas Therapeutics.

Danaher-owned companies Aldevron and Integrated DNA Technologies manufactured KJ’s personalized therapy, which required a new guide RNA sequence, mRNA-encoded base editor, custom off-target safety services, and clinically validated LNP formulation, in 6 months, a speed that was three times faster than the standard timeline for gene-editing drug products. The effort was aligned with the mission of the Danaher-Innovative Genomics Institute Beacon for CRISPR Cures program.

“Years and years of progress in gene editing and collaboration between researchers and clinicians made this moment possible, and while KJ is just one patient, we hope he is the first of many to benefit from a methodology that can be scaled to fit an individual patient’s needs,” Ahrens-Nicklas said.³

DANON DISEASE PATIENT DIES IN ROCKET GENE THERAPY TRIAL

Rocket Pharmaceuticals has acknowledged the death of a patient in a pivotal trial assessing its Danon disease gene therapy candidate RP-A501, a study that the U.S. Food and Drug Administration has placed on clinical hold.

The patient, whose age was not disclosed, suffered an unexpected serious adverse event that involved clinical complications related to a capillary leak syndrome (CLS), following dosing with RP-A501 in early May, Rocket’s CEO Gaurav Shah, MD, told analysts on a conference call.

“We are heartbroken by this loss and are fully committed to our mission to develop gene therapies that address the underlying cause of devastating diseases like Danon. We are immensely grateful for the patients and families who participate in this important research,” Shah said.⁴

Shah said Rocket is investigating the cause of the event, which has prompted the company to voluntarily pause further dosing in the pivotal Phase II study (NCT06092034). During the conference call, Shah said the patient experienced signs of CLS about a week after receiving RP-A501 in early May.

RP-A501 consists of a recombinant adeno-associated serotype 9 (AAV9) capsid containing a full-length, wild-type version of the human LAMP2B transgene (AAV9.LAMP2B), which, when inserted into heart cells harboring mutations in the endogenous LAMP2 gene, is designed to fully restore cardiac function at its root.

RP-A501 is a single-dose treatment administered as an intravenous infusion. In preclinical and clinical studies, AAV9.LAM2B has been shown to target cardiac cells (cardiomyocytes) and deliver the functional LAMP2B gene to heart tissue, which ultimately leads to improved cardiac structure and function in patients. In 2023, the FDA granted RP-A501 its regenerative medicine advanced therapy designation, while the European Medicines Agency granted PRIority MEdicines eligibility to the gene therapy candidate.

Rocket is focusing its investigation on its recent introduction of a novel immune suppression agent to the pre-treatment regimen that had been implemented to mitigate complement activation observed in some patients. The agent was specific to its AAV9-Danon program, Rocket said.

Rocket disclosed on the call that the patient who died had received a marketed C3 complement inhibitor as a part of an amended immunosuppression protocol that was enacted following at least two cases of thrombotic microangiopathy during the trial.

The C3 inhibitor was given pre- and post-RP-A501 treatment in combination with the enhanced prophylactic immunosuppressive regimen of sirolimus, rituximab (marketed as Rituxan® by Genentech, a member of the Roche Group, and Biogen), and prednisone. A second patient also received the modified immunosuppression regimen, including the C3 inhibitor, and also exhibited early signs of CLS but had a reduced course of the C3 inhibitor, which according to Rocket further supports its hypothesis that the compound played a role in the development of CLS.

“BELIEVE IN AMERICAN SOLUTIONS,” CELL, GENE THERAPY LEADERS URGE FDA, NIH, HHS OFFICIALS AT ROUNDTABLE

Leaders from the world of cell and gene therapy, including molecular geneticists, immunotherapists, physicians, nonprofit directors, and patient advocates, shared their personal stories and policy recommendations with leaders of the U.S. Food and Drug Administration (FDA) in an extraordinary roundtable.

During the 90-min roundtable, FDA leaders heard from more than a dozen leading experts in the cell and gene therapy community. Many praised the FDA for its role in expediting therapies, especially the recent work around a cure for “Baby KJ,” the infant treated in Philadelphia with a bespoke base editor for an ultra-rare, potentially fatal genetic disorder.

Others raised warning flags about regulatory overreach, the threat of offshoring advanced therapeutics development to China, and the brain drain of young talent.

Opening the roundtable discussion was Terrence Flotte, MD, dean of UMass Chan Medical School and editor-in-chief of Human Gene Therapy. Speaking in his role as the new president of the American Society of Cell and Gene Therapy, Flotte discussed recent progress in gene therapy, citing the success of Novartis’ Zolgensma® (onasemnogene abeparvovec-xioi) for spinal muscular atrophy.

“With sufficient organization and federal support and partnership with the FDA, I believe it will be possible by 2030 to treat at least 1,000 patients with personalized genetic treatments. This would save billions in costs to manage their symptoms,” said genome editing pioneer David R. Liu, PhD, Liu, the Richard Merkin Professor, director of the Merkin Institute of Transformative Technologies in Healthcare, and vice chair of the faculty at the Broad Institute of MIT and Harvard.⁵

Liu—who is also the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute investigator—called for a national infrastructure for interventional genetics that would address five priorities: Rapid response diagnosis and therapeutic development centers to identify and optimize gene-editing agents and their delivery vehicles; small-scale, fast turnaround chemistry, manufacturing, and controls capabilities; cell, rodent, nonhuman primate, or virtual toxicology platforms; streamlined regulatory pathways for N-of-few trials; and shared public–private platforms for all of the above and for sharing clinical outcomes.

Several speakers raised concerns about the growing competitive threat from China. Rather than regulate early-stage cell and gene therapy trials, the FDA should instead regulate autologous products such as hemopoietic cells under local independent review board supervision, suggested immunotherapy pioneer Carl June, MD, director of the Center for Cellular Immunotherapies and Parker Institute for Cancer Immunotherapy at the University of Pennsylvania Perelman School of Medicine.

Fyodor Urnov, PhD, director of technology and translation at the Innovative Genomics Institute and a professor at the University of California, Berkeley, praised the public–private partnership that produced the bespoke gene-editing treatment for baby KJ: “We can give American children like Baby KJ a remarkable future. We need to believe in American solutions.”⁵

Attending the roundtable were FDA Commissioner Martin A. Makary, MD, and Vinayak (Vinay) Kashyap Prasad, MD, Director of the Center for Biologics Evaluation and Research. They were joined for the closing session by Jayanta (Jay) Bhattacharya, MD, PhD, Director of the U.S. National Institutes of Health (NIH); Mehmet Oz, MD, administrator for the Centers for Medicare & Medicaid Services; and Robert F. Kennedy, Jr., Secretary of the U.S. Department of Health and Human Services (HHS).

REGENXBIO SIGNS UP TO $250M ROYALTY MONETIZATION AGREEMENT

REGENXBIO has closed on a nondilutive, limited recourse royalty bond agreement of up to $250 million with Healthcare Royalty (HCRx). The agreement is designed to monetize select anticipated royalties and milestones and provides the adeno-associated virus-based gene therapy developer with both immediate and expected future, nondilutive capital.

REGENXBIO said it received $150 million at closing, which is expected to extend its cash runway into early 2027.

“This capital infusion positions us well to accelerate commercial preparations and continue extending our longstanding leadership in rare and retinal gene therapies,” said Mitchell Chan, Chief Financial Officer of REGENXBIO. “This strategic financing brings future potential funds forward and extends our runway beyond multiple meaningful milestones.”⁶

Those milestones, he said, include potential approval by the U.S. Food and Drug Administration of RGX-121 for Mucopolysaccharidosis type II (MPS II), topline data readout and Biologics License Application submission for RGX-202 for Duchenne muscular dystrophy, and topline data readouts for two pivotal studies of subretinal ABBV-RGX-314 for wet age-related macular degeneration.

Along with fueling late-stage activities, REGENXBIO said, the agreement will enable it to retain future potential nondilutive opportunities and potential long-term financial benefit from its NAV® licensees and MPS programs.

HCRx has agreed to provide REGENXBIO an up to $250 million bond in exchange for rights, up to the principal amount and accrued interest, to anticipated royalty payments from sales of Zolgensma® for spinal muscular atrophy, as well as royalty and certain milestones payments from RGX-121 and RGX-111 for MPS II and MPS I, respectively, under a partnership with Nippon Shinyaku, and NAV Technology Platform licensees Rocket Pharmaceuticals and Ultragenyx.

HCRx will receive quarterly interest payments derived solely from the royalty and milestone revenue received, less payments to REGENXBIO’s upstream licensors, and warrants to purchase up to 268,096 shares of the company’s common stock at $14.92 a share, a 100% premium to REGENXBIO’s 30-day weighted average price.

In addition to the $150 million received at closing, REGENXBIO could receive an additional $50 million by April 30, 2027, tied to achieving Zolgensma sales milestones, and $50 million more upon the mutual agreement of REGENXBIO and HCRx, which would further extend the company’s cash runway.

SPLICEBIO CLOSES $135M SERIES B FINANCING

SpliceBio has closed on a $135 million Series B financing whose proceeds will be used toward advancing the clinical development of its lead candidate SB-007, a gene therapy for Stargardt disease, including the ongoing interventional Phase I/II ASTRA trial (NCT06942572) and the observational POLARIS study (NCT06435000).

Proceeds will also be used to accelerate SpliceBio’s pipeline of adeno-associated viral (AAV) gene therapy programs in ophthalmology, neurology, and other undisclosed indications that apply the company’s Protein Splicing platform.

“This financing marks a pivotal milestone for SpliceBio as we advance the clinical development of SB-007 for Stargardt disease and continue to expand our pipeline across ophthalmology, neurology and beyond,” said Miquel Vila-Perelló, PhD, SpliceBio’s CEO and cofounder. “We are building a company positioned to lead the next wave of genetic medicines.”⁷

SpliceBio says it is expanding the scope of diseases that can be tackled through gene therapy by addressing a basic limitation of AAV vectors, namely their inability to deliver genes that exceed 4.7 kilobases.

SpliceBio’s Protein Splicing platform leverages a family of proprietary, engineered proteins called inteins, originally developed at Princeton University. The technology enables the splitting of the gene into two or more transgenes that are then delivered using dual AAV vectors. Once inside the cell, the DNA of each transgene is transcribed into messenger RNA and translated into protein. SpliceBio’s engineered inteins are designed to then assemble the full-length protein needed to treat the disease.

SB-007 is designed to address the underlying genetic cause of Stargardt disease by producing a functional copy of the full-length ABCA4 protein with the potential to treat all patients, regardless of their specific ABCA4 mutation. SB-007 is the first dual AAV gene therapy cleared by the U.S. Food and Drug Administration to enter clinical development for the disease and has also received regulatory clearance for clinical development from the United Kingdom’s Medicines and Healthcare products Regulatory Agency.

The Series B financing was co-led by new investors EQT Life Sciences and Sanofi Ventures, with participation from Roche Venture Fund, as well as all existing investors: New Enterprise Associates, UCB Ventures, Ysios Capital, Gilde Healthcare, Novartis Venture Fund, and Asabys Partners.

FDA GRANTS PLATFORM TECHNOLOGY DESIGNATION TO SAREPTA VIRAL VECTOR

The U.S. Food and Drug Administration (FDA) has granted its platform technology designation to the rAAVrh74 viral vector used by Sarepta Therapeutics in its investigational gene therapy SRP-9003 (bidridistrogene xeboparvovec) for the treatment of limb-girdle muscular dystrophy type 2E/R4.

“This is one of the first programs to receive platform technology designation and an important recognition by FDA of the reproducibility and adaptability of this technology across multiple therapeutic programs,” said Louise Rodino-Klapac, PhD, Sarepta’s Chief Scientific Officer and Head of Research & Development.⁸

SRP-9003 (bidridistrogene xeboparvovec) uses the AAVrh74 vector, designed for systemic and robust delivery to skeletal, diaphragm, and cardiac muscles. The gene therapy is intended to deliver a full-length beta-sarcoglycan transgene and uses the MHCK7 promoter, chosen for its ability to robustly express in the heart—a critical feature for patients with limb-girdle muscular dystrophy Type 2E/R4 (LGMD2E/R4), or beta-sarcoglycanopathy, many of whom die from pulmonary or cardiac complications.

SRP-9003 is being assessed in the Phase III EMERGENE trial (also called Study 9003-301, NCT06246513), a multinational, open-label study of the gene therapy in ambulatory and non-ambulatory participants ages 4 and older. EMERGENE’s primary endpoint is expression of beta-sarcoglycan 60 days after dosing. Secondary outcomes and endpoints include functional measures through month 60 and safety.

CARLYLE, SK CAPITAL CLOSE BLUEBIRD BIO ACQUISITION

Funds managed by The Carlyle Group and SK Capital Partners have completed their acquisition of Bluebird Bio, after more than half the gene therapy developer’s shareholders approved a revised and higher offer from the global investment firms.

Bluebird investors tendered 59.8% of the company’s common stock to Carlyle and SK Capital, the company and the investment firms said. The firms required 50% of shares, plus one, to close on the acquisition.

The percentage of shares tendered represents more than double the 25.6% of shares tendered 2 weeks earlier under the initial terms of the firms’ buyout plan.

In May, Carlyle and SK Capital raised their upfront offer to acquire Bluebird to $5 per share upfront, up from their initial $3 per share upfront and a contingent value right of $6.84 per share, payable upon Bluebird’s current product portfolio achieving $600 million in net sales in any trailing 12-month period before or ending on December 31, 2027.

Investors appeared to sour on the initial terms after Bluebird finished the first quarter with $38.712 million in net product revenue, on top of $83.795 million in 2024 net product revenues, for its three marketed gene therapies:

Zynteglo™ (betibeglogene autotemcel or beti-cel)—Indicated to treat adults and children with β-thalassemia who require regular red blood cell transfusions ($2.8 million list price)

Lyfgenia™ (lovotibeglogene autotemcel or lovo-cel)—Indicated to treat patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events ($3.1 million list price)

Skysona™ (elivaldogene autotemcel or eli-cel)—Indicated to slow the progression of neurological dysfunction in boys 4–17 years old with early, active Cerebral adrenoleukodystrophy (CALD) ($3 million list price)

By raising their offer, Carlyle and SK Group increased the value of their buyout deal for Bluebird to about $45 million, from an initial value of just over $29 million.⁹

Upon closing of the acquisition, Bluebird’s common stock ceased trading on NASDAQ and is no longer publicly listed. Bluebird said Carlyle and SK Capital have provided significant primary capital to support and scale its commercial delivery of gene therapies.

“Historically, bluebird has excelled as a scientific innovator and should be very proud of the many achievements it has delivered to patients,” Bluebird’s new CEO David Meek said on June 2, as the company announced completion of the buyout deal. “Our vision is to further that legacy of scientific excellence while improving the commercial execution of our approved products to rapidly expand access to lifechanging gene therapies.”¹⁰

Joining Meek among new executives of Bluebird are Tom Klima, Chief Commercial & Operating Officer; Debasish Roychowdhury, MD, Chief Medical Officer; Wendy DiCicco, Chief Financial Officer; and Ellen Forest, Chief People Officer.

References

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. ASGCT 2025: World’s First Patient Treated with Personalized CRISPR Therapy. Genetic Engineering & Biotechnology News. 2025. Available from: https://www.genengnews.com/topics/genome-editing/asgct-2025-worlds-first-patient-treated-with-personalized-crispr-therapy/ [Last accessed: June 6, 2025 ].

University of Pennsylvania. World’s first patient treated with personalized CRISPR gene editing therapy through CHOP and Penn Med collaboration. 2025. Available from: https://penntoday.upenn.edu/news/penn-medicine-worlds-first-patient-treated-personalized-crispr-gene-editing-therapy-childrens-hospital [Last accessed: June 6, 2025 ].

Rocket Pharma. Rocket Pharmaceuticals Provides Update on Phase 2 Clinical Trial of RP-A501 for Danon Disease. 2025. Available from: https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-provides-update-phase-2-clinical-trial-rp [Last accessed: June 6, 2025 ].

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REGENXBIO. REGENXBIO Announces Strategic Royalty Monetization Agreement for Up to $250 Million. 2025. Available from: https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-strategic-royalty-monetization-agreement-250 [Last accessed: June 10, 2025 ].

SpliceBio. SpliceBio Secures $135 Million Series B Financing to Advance Lead Program SB-007 in Stargardt Disease and Expand Pipeline of Genetic Medicines. 2025. Available from: https://splice.bio/splicebio-secures-135-million-series-b-financing-to-advance-lead-program-sb-007-in-stargardt-disease-and-expand-pipeline-of-genetic-medicines/ [Last accessed: June 11, 2025 ].

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Bluebird Bio. Bluebird Bio d Announces Completion of Acquisition by Carlyle and SK Capital. 2025. Available from: https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-completion-acquisition-carlyle-and-sk [Last accessed: June 6, 2025 ].