Table 2.

Therapeutic strategies (Pros & Cons)

Therapeutic approach	Examples	Pros and cons
Controlling the activity of splicing factor regulators	- Small molecules targeting SRPK1 (SPHINX, SRPIN340 and SRPKIN-1) used for VEGFA splicing correction [48, 198].	Poor specificity, resulting in AS modification of multiple genes besides VEGFA.
Inhibiting the assembly of the spliceosome machinery	- Compounds binding to the spliceosome component SF3b: FR901464 and its methylated derivative, spliceostatin A [199].	Poor specificity, affecting AS of multiple genes; partial understanding of mechanism of action.
Interfering with splicing sites	- Morpholino oligonucleotides targeting the exon 13/intron 13 junction of the VEGFR1 pre-mRNA, favoring the production of the anti-angiogenic, soluble form of VEGFR1 [55].	Possibility to target one single gene; off-target effects due to either the presence of the targeted sequence in other portions of the genome or tolerance toward mismatches.
Blocking pro-angiogenic isoforms	- Humanized monoclonal antibody [91] or a soluble peptide [200, 201] against CD44v6. - Intravenous delivery of autologous T cells, modified to recognize CD44v6 on the surface of cancer cells (ClinicalTrials.gov: NCT04427449 [95]). - Monoclonal antibodies against FGF8b [202]; using natural inhibitor Pentraxin-3 (PTX3) and its derivatives Ac-ARPCA-NH2 (ARPCA) and 8b-13 [203, 204] to target FGFs.	High specificity with minimal side effects; cumbersome and expensive design and production.
Overexpressing anti-angiogenic isoforms	- Overexpression of sNRP1 to prevent VEGF signalling [60]. - Overexpression of either VASH1B or VASH1A [72].	Delivery requiring either gene therapy or production of recombinant proteins; no effect on the level of pro-angiogenic isoforms.
Exploiting cancer-specific isoforms for drug delivery	- Monoclonal antibodies and aptides targeting EDA/EDB domains of FN: F8 fused to IL-2 [205, 206]; L19 fused to either IL-2 or IL-12 [207, 208]; EDB-targeting aptides conjugated with doxorubicin-containing liposomes [209, 210]. - Monoclonal antibodies (F16 fused to IL-2) and aptamers targeting domains A1-D of TNC [211].	High specificity for cancer cells; cumbersome and expensive design and production; toxicity related to the chemotherapeutic agent.