Protheragen has the capacity to solve the intricate SHFM therapeutic research questions by offering multidisciplinary preclinical research and therapy development services. Their extensive knowledge of developmental genetics combined with advanced model systems enable the investigation of novel insights and future therapeutic approaches for this rare condition.
Introduction to Split-Hand/Split-Foot Malformation
SHFM can be a dominant or recessive disorder associated with pathogenic variants in the genes that control limb morphogenesis. Clinically heterogeneous, and with an estimated incidence of 1-10 per 100,000, SHFM is often underdiagnosed because of variable expressivity and de novo mutations. Newer studies highlight common molecular pathways like WNT/FGF signaling for limb and renal development, proposing a wider role for SHFM-related genes.
Pathogenesis of Split-Hand/Split-Foot Malformation
RCAD syndrome has been associated with heterozygous pathogenic mutations within the HNF1B gene due to the underexpression of HNF1B transcription factor caused by gene haploinsufficiency. HNF1B acts as a key regulator to the multi-system level constituents of a kidney, pancreas, liver, urinary system and even at the fundamental metabolically active unit called nephron. In the course of development of a kidney, HNF1B plays a critical role with respect to branching of ureteric bud, nephron formation and also the proximal tubule's function. Absence of HNF1B leads to kidneys with diminished size and cysts, resulting in renal tissue disorders that disrupt normal function.
Fig.1 Schematic representation of different split-hand/foot malformation (SHFM) types based on the median cleavage. (Umair and Hayat, 2020)
Therapeutics Development for Split-Hand/Split-Foot Malformation
| Therapeutic Strategy |
Therapeutic Target |
Key Mechanisms/Advances |
Development Stage |
| CHIR99021 (Wnt Activator) |
Wnt/β-catenin signaling |
Enhances apical ectodermal ridge (AER) activity to promote limb development |
Preclinical |
| BHLHA9 Antisense Oligonucleotide |
BHLHA9 gene duplication |
Suppresses overexpression of BHLHA9 in SHFLD-associated defects |
Preclinical |
| AAV-ZAK Gene Therapy |
ZAK gene deficiency |
Restores Trp63 expression via AAV9-mediated ZAK delivery |
Preclinical |
| p63-TAD Activator (Small Molecule) |
ΔN-p63γ transcriptional activity |
Activates truncated p63 isoforms to restore epidermal differentiation |
Preclinical |
| FGF2 Sustained-Release Gel |
FGF2/FGFR1 signaling |
Promotes AER maintenance and limb elongation with 3D-printed scaffolds |
Phase II clinical trial |
| TP63 mRNA Nanoparticles |
p63 haploinsufficiency |
LNPs deliver TP63 mRNA to rescue limb segmentation defects |
Preclinical |
| Noggin (BMP Antagonist) |
BMP/Smad pathway |
Inhibits ectopic ossification to prevent central ray fusion |
Phase III trial |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen is a comprehensive preclinical service provider dedicated to advancing the understanding and potential therapeutic avenues for complex genetic disorders like SHFM. Our expertise in developmental genetics, sophisticated disease models, and therapeutic development platforms allows us to support research into its underlying mechanisms and associated syndromic conditions.
Therapeutic Development Platforms for Split-Hand/Split-Foot Malformation
Disease Models Development for Split-Hand/Split-Foot Malformation
Protheragen provides cutting-edge and comprehensive disease models to accelerate preclinical research into SHFM. Our platform integrates cell-based models, kidney organoids, and animal models to effectively mirror the genetic and developmental characteristics of SHFM.
- TP63-KO human keratinocytes
- Patient-derived iPSCs with WNT10B mutations
- 3D limb bud organoids with AER disruption
- Renal-limb co-culture systems
- Tp63± conditional knockout mice
- Wnt10b gene-edited zebrafish
- Dlx5/6 double-heterozygous rats
- Patient-derived xenografts in limb explants
Protheragen's integrated preclinical development solutions are specifically designed for research in rare genetic disorders affecting development and morphogenesis, such as SHFM. We specialize in custom disease model development, pharmacokinetics, and drug safety evaluation, enabling comprehensive support for your investigation.
Contact us today to accelerate your split-hand/split-foot malformation research with end-to-end solutions.
References
- Umair, M., and A. Hayat. "Nonsyndromic Split-Hand/Foot Malformation: Recent Classification." Mol Syndromol 10.5 (2020): 243-54.
- Yang, X., et al. "Genetic Analysis of a Congenital Split‑Hand/Split‑Foot Malformation 4 Pedigree." Mol Med Rep 17.6 (2018): 7553-58.
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only and cannot be used to diagnose, treat or manage patients.
