CRISPR prime editing as a promising therapeutic avenue for Menkes disease - the next step incorrecting ATP7A mutations

Sep 29, 2026

Menkes disease is a life-threatening X-linked disorder driven by mutations in ATP7A, an ATPase essential for copper transport and copper homeostasis in the nervous system and the whole body. Existing treatment with copper histidinate has limited neurological impact because brain copper uptake is inefficient. CRISPR prime editing (PE) offers an accurate alternative for correcting single-base substitutions or small errors without double-strand breaks. PE may also address vector size constraints and reduce off-target concerns via an ex vivo strategy in patient-derived induced pluripotent stem cells.

LanguageEnglish

CategoryHealthcare

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Reading Time5 min

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Abstract

Keywords

Background: Menkes disease and current therapies

Rationale for CRISPR prime editing

Mechanism of prime editing

Applicability to ATP7A variants

Proposed ex vivo correction workflow

Validation after correction

Delivery considerations and remaining challenges

Letter to the Editor CRISPR prime editing as a promising therapeuticavenue for Menkes disease: the nextstep incorrecting ATP7A mutations Sarim Hassan Shahab, MBBSa , Fazal Habib, MBBSb ,* Abstract Menkes disease is a life-threatening X-linked disease caused by mutations in ATP7A, an ATPase that mediates copper transportand is vital for copper homeostasis in the nervous system andthe whole body. Existing therapies, such as copper histidinateinjections, have limited neurological effects because of inefficient brain copper uptake. CRISPR prime editing (PE) provides a verypowerful alternative since it can accurately correct single-base substitutions or small errors efficiently without inducing double -strand breaks. Compared to conventional gene therapy, PE also overcomes vector size restrictions and reduces off-targetconcerns. In this letter, we will discuss ATP7A variants that may be prime-editable and suggest an ex vivo approach for correctionin induced pluripotent stem cells generated from Menkes patients with validation of function to follow. There is currently noliterature that demonstrates PE for Menkes disease to thebestof our knowledge and therefore represents a unique approach fora novel gene-level intervention for this fatal disease. Keywords: ATP7A, copper metabolism, CRISPR, gene therapy, Menkes disease, prime editing Menkes disease (MD) is an uncommon but severe X-linkedneurodegenerative disorder that arises from pathogenic variantsin the ATP7A gene, which encodes copper-transporting ATPasecrucial for copper distribution in the body. The failure of coppertransport results in the inability of copper-dependent enzymes,such as cytochrome c oxidase, lysyl oxidase, and dopamine β -hydroxylase, to function. The outcome is fatal: progressive neu -rological deterioration, connective tissue fragility, seizures, andearly death[1] . Despite early recognition and treatment with copper histidinateinjections, the prognosis for infants affected by MD remainspoor[2] . The treatment regimens are of benefit, but incomplete.Copper does not readily cross the blood–brain barrier; thus, dys -function continues in the brain. While we have managed symp -toms for decades, we have never reverted the underlying cause. CRISPR prime editing (PE), a next-generation form of gen -ome editing, is a more accurate, flexible approach to correctmutations in DNA. The traditional CRISPR/Cas9 system aDepartment of Internal Medicine, Nishtar Medical University, Multan, Pakistan andbDepartment of Internal Medicine, Sher-e-Bangla Medical College, Barisal,Bangladesh Sponsorships or competing interests that maybe relevant to content are disclosedatthe end of this article. *Corresponding author. Address: Department of Internal Medicine, Sher-e-BanglaMedical College, Barisal 8200, Bangladesh. E-mail: fazalhabib346@gmail.com(F. Habib). Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This is anopen access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non -commercial, as long as itis passed along unchanged and in whole, with credit to theauthor. Annals of Medicine & Surgery (2026) 88:1013–1014Received 4 November 2025; Accepted 5 November 2025Published online 14 November 2025http://dx.doi.org/10.1097/MS9.0000000000004363 generates double-strand breaksinthe DNA and is often not aseffective in neurons, and may have off-target effects [3] . PEemploys a Cas9 nickase fused with a reverse transcriptaseenzyme to search for and replace defective genetic code, withoutbreaking both DNA strands, guided by pegRNA (a specializedRNA)[4] . This means fewer errors and a gentler edit – somethingcrucial for delicate brain cells. Moreover, PE could theoretically fix around 89% of theknown pathogenic mutations in humans[4] . However, despitethe progress in PE, it has not been used for ATP7A-associateddiseases such as Menkes. The vast majority of

FAQs

What causes Menkes disease at the molecular level?

Menkes disease results from pathogenic mutations in the ATP7A gene, which encodes a copper-transporting ATPase needed for proper copper distribution. Impaired copper transport disrupts copper-dependent enzymes and leads to progressive neurological deterioration and early death.

Why is CRISPR prime editing considered more suitable than conventional CRISPR/Cas9?

Prime editing uses a Cas9 nickase fused to a reverse transcriptase and guided by pegRNA, enabling correction without creating double-strand breaks. This can reduce errors and off-target concerns and may be gentler for neurons.

What ex vivo approach is suggested for correcting Menkes-related defects?

The document proposes testing prime editing in patient-derived induced pluripotent stem cells, followed by validation of function after correction. Corrected cells could then be differentiated into neurons or hepatocytes to assess restoration of copper transport and enzyme activity.

Sep 29, 2026

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