What is Fanconi Anemia?
 

Fanconi Anemia (FA) is a rare inherited bone marrow failure syndrome, primarily inherited in an autosomal recessive pattern, with approximately 2% being X-linked recessive. The disease is characterized by congenital developmental abnormalities, progressive bone marrow failure, and significantly increased susceptibility to malignancies. Clinical manifestations include café-au-lait spots (55%), short stature (51%), limb defects (43%), craniofacial abnormalities (26%), ocular abnormalities (23%), and renal anomalies.
 

The global incidence is approximately 1 in 160,000, with relatively lower rates in Asian populations. The cumulative cancer incidence in FA patients of all ages is about 30%, including hematologic malignancies (such as MDS and acute myeloid leukemia) and solid tumors (such as head and neck squamous cell carcinoma, breast cancer, ovarian cancer, etc.), with solid tumors accounting for 30%-40%.
 

Pathogenesis
 

The core pathogenesis of FA involves functional defects in the FA/BRCA pathway, leading to impaired repair of DNA interstrand crosslinks (ICLs). ICLs are severe genetic lesions that covalently link both DNA strands, physically obstructing DNA replication and transcription, thereby causing genomic instability.
 

From a molecular epidemiological perspective, FANCA gene mutations are the most common in FA patients (accounting for approximately 60%-70%), followed by FANCC (7%-15%) and FANCG (about 10%).
 

Figure source: Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors
 

When the DNA replication fork encounters ICLs, replication stalls. The FANCM–FAAP24–MHF1/2 complex recognizes and binds to the stalled fork, subsequently recruiting the FA core complex (composed of at least 8 proteins including FANCA, FANCB, FANCC, etc.). This complex, through its E3 ubiquitin ligase component FANCL, catalyzes the monoubiquitination of the FANCD2–FANCI heterodimer (ID2 complex), forming the "molecular switch" for pathway activation. The monoubiquitinated ID2 complex dissociates from the core complex and tightly binds to chromatin regions adjacent to ICLs, serving as a platform to recruit downstream repair factors such as FANCP/SLX4 and the endonuclease XPF–ERCC1 (FANCQ), which perform the unhooking incision of ICLs.
 

Following unhooking, the resulting DNA gap is repaired through two coordinated pathways: Translesion Synthesis (TLS), mediated by error-prone polymerases such as REV1–Polζ, inserts nucleotides opposite the lesion; subsequently, Homologous Recombination (HR) utilizes the sister chromatid as a template for high-fidelity repair, a process dependent on the BRCA2 (FANCD1)–PALB2 (FANCN)–RAD51 (FANCR) complex-mediated strand invasion and Holliday junction resolution. Upon completion of repair, the USP1–UAF1 deubiquitinase complex removes the ubiquitin mark from FANCD2, inactivating the pathway.
 

If biallelic mutations occur in FA genes, leading to loss of function in this pathway, cells cannot repair ICLs induced by endogenous (e.g., aldehyde metabolites) or exogenous (e.g., chemotherapeutic agents) sources, resulting in DNA damage accumulation, chromosomal breakage, and ultimately causing progressive bone marrow failure, congenital developmental abnormalities, and significantly increased tumor susceptibility (e.g., acute myeloid leukemia, head and neck squamous cell carcinoma).

Figure source: Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors
 

Gene Therapy
 

RP-L102 Lentiviral Gene Therapy:  This approach utilizes a self-inactivating lentiviral vector to deliver the normal FANCA gene into patient-derived autologous CD34+ hematopoietic stem cells. Following mobilization with granulocyte colony-stimulating factor and plerixafor, collected stem cells undergo ex vivo transduction under optimized conditions including low oxygen, short-term culture, and addition of anti-apoptotic factors. After reinfusion, no myeloablative conditioning is required. Gene-corrected cells, through selective proliferative advantage, can reconstitute normal hematopoiesis, improve blood counts, and restore resistance to DNA crosslinking agents. This therapy is currently in Phase II multicenter clinical trials.
 

Mouse Models
 

Usp1^-/- Mice:  Systemic knockout of the Usp1 gene leads to persistent monoubiquitination of FANCD2, disrupting its nuclear focus formation and ICL repair function. These mice exhibit hematopoietic defects, reduced germ cells, and high sensitivity to crosslinking agents, making them an ideal tool for studying negative regulation of the FA pathway and deubiquitination mechanisms.
 

FancA^-/- Mice:  Constructed by targeted deletion of exons 4-7 of the FancA gene, this model does not display obvious congenital abnormalities or severe hematological defects but shows significantly reduced fertility. It is commonly used for studying FA core complex function.
 

FancC^-/- Mice:  These mice demonstrate marked sensitivity to DNA crosslinking agents (e.g., MMC) and increased chromosomal breakage, serving as an important tool for studying early activation of the FA pathway.
 

FANCD2^-/- Mice:  Knockout of the hub protein FANCD2 results in complete loss of downstream repair function. This model exhibits severe phenotypes, with high embryonic lethality; surviving individuals show significant developmental abnormalities, bone marrow failure, and tumor susceptibility, making it a classic model for studying the core mechanisms of the FA pathway and hematopoietic stem cell function.
 

Supporting Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation rely heavily on animal models. MingCeler Biotech, leveraging its proprietary TurboMice™ technology, has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models, enabling editing at almost any target gene locus and producing complete homozygous gene-edited mouse models directly from embryonic stem cells in as short as 2 months.
 

MingCeler Biotech  can customize various FA mouse models according to client needs, such as Usp1^-/- mice, FancA^-/- mice, FancC^-/- mice, FANCD2^-/- mice, etc. We welcome inquiries.
 

References:
 

1.https://www.ncbi.nlm.nih.gov/books/NBK559133/

2.Choi J, Jung M. Head and Neck Cancer in Fanconi Anemia: Clinical Challenges and Molecular Insights into a DNA Repair Disorder. Cancers (Basel). 2025 Sep 18;17(18):3046. doi: 10.3390/cancers17183046. PMID: 40970532; PMCID: PMC12447561.

3.Fang, C., Zhu, Z., Cao, J. et al. Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors. Orphanet J Rare Dis 20, 389 (2025). https://doi.org/10.1186/s13023-025-03896-w

4.Xi Bixin, Hu Qun, Liu Aiguo. Research Progress in Gene Therapy for Fanconi Anemia. Journal of Clinical Pediatrics. 2023, 41(2): 156. DOI: 10.12372/jcp.2023.21e1465.

5.Parmar K, D'Andrea A, Niedernhofer LJ. Mouse models of Fanconi anemia. Mutat Res. 2009 Jul 31;668(1-2):133-40. doi: 10.1016/j.mrfmmm.2009.03.015. Epub 2009 Apr 10. PMID: 19427003; PMCID: PMC2778466.