Seven studies [3,4,5, 8,9,10, 13] investigating the effects of gene-based therapy on patient or event-free survival were included in our meta-analysis. Of these, two each employed nusinersen [4, 8] and risdiplam [5, 13], while three utilized onasemnogene abeparvovec [3, 9, 10] (Table 2). The results showed that patients undergoing gene-based therapy demonstrated an 84% survival rate (95% CI: 70, 95, P = 0·00, I2 = 82·77%, χ2 = 34·82, P = 0·00). Onasemnogene abeparvovec proved to be the most effective treatment, evidencing the highest survival rate (95% [95% CI: 88, 100], I2 = 0%, P = 0·44), followed by risdiplam (86% [95% CI: 76, 94], I2 = 0%, P = 0·99) and nusinersen (60% [95% CI: 50, 70], I2 = 0%, P = 0·99) (Fig. 2). The significant difference of head-to-head comparisons between gene-based therapy are presented in Appendix: Table S4; onasemnogene abeparvovec (95% [95% CI: 88, 100], P = 0·00) versus nusinersen (60% [95% CI: 50, 70], P = 0·00), P = 0·00; risdiplam (86% [95% CI: 76, 94], P = 0·00) versus nusinersen (60% [95% CI: 50, 70], P = 0·00), P = 0·61; onasemnogene abeparvovec (95% [95% CI: 88, 100], P = 0·00) versus risdiplam (86% [95% CI: 76, 94], P = 0·00), P = 0·10.

Forest plot depicting patient survival. prop proportion; sur survival; tot total.

Sixteen studies examined the number of patients requiring ventilatory support after receiving nusinersen [4, 26, 27, 30, 31, 37, 38, 41, 44, 49, 51, 56, 59, 64,65,66], onasemnogene abeparvovec (2 studies), [9, 10] or risdiplam (2 studies) [5, 13] (Table 3). The results indicated that only onasemnogene abeparvovec reduced the number of patients needing ventilatory support (RR = 0·10 [95% CI: 0·02, 0·53], I2 = 0%, P = 0·909). Risdiplam (RR = 0·39 [95% CI: 0·09, 1·76], I2 = 34.4%, P = 0·22) and nusinersen (RR = 1·06 [95% CI: 0·97, 1·16], I2 = 29.0%, P = 0·12) did not demonstrate a significant effect (Fig. 3); onasemnogene abeparvovec (0·10 [95% CI: 0·02, 0·53], P = 0·01) versus nusinersen (1·06 [95% CI: 0·97, 1·16], P = 0.20), P = 0·01; risdiplam (0·39 [95% CI: 0·09, 1·76], P = 0.22) versus nusinersen (1·06 [95% CI: 0·97, 1·16], P = 0.20), P = 0·19; onasemnogene abeparvovec (0·10 [95% CI: 0·02, 0·53], P = 0·01) versus risdiplam (0·39 [95% CI: 0·09, 1·76], P = 0.22), P = 0·25 (Appendix: Table S4).

Forest plot illustrating the need for ventilatory support. rr relative risk; wt weight.

Among patients with SMA type 1, 19 studies [3,4,5, 8,9,10, 13, 22, 23, 27, 30, 37, 41, 46, 47, 49, 57, 64, 66] reported the number of patients who improved their motor function (Table 4). Twelve of these studies [4, 8, 9, 13, 27, 34, 41, 45,46,47, 49, 66] investigated patients who improved their CHOP-INTEND score by 4 points or more, revealing that 78% of gene therapy patients were able to improve their score (78% [95% CI: 69, 85], I2 = 41·67%, χ2 = 18·86, P = 0·06). Onasemnogene abeparvovec was associated with the greatest number of improved patients (92% [95% CI: 62, 100]), [9] followed by risdiplam (90% [95% CI: 77, 97]) [13] and nusinersen (74% [95% CI: 66, 81], I2 = 12.11%, P = 0·33) [4, 8, 27, 41, 46, 47, 49, 66] (Fig. 4); onasemnogene abeparvovec (92% [95% CI: 62, 100], P = 0·00) versus nusinersen (74% [95% CI: 66, 81], P = 0·00), P = 0·14; risdiplam (90% [95% CI: 77, 97], P = 0·00) versus nusinersen (74% [95% CI: 66, 81], P = 0·00), P = 0·01; onasemnogene abeparvovec (92% [95% CI: 62, 100], P = 0·00) versus risdiplam (90% [95% CI: 77, 97], P = 0·00), P = 0·96 (Appendix: Table S4). The order was maintained when examining those who improved their HINE-2 score, as per 7 studies [3, 4, 8, 13, 22, 37, 41]: onasemnogene abeparvovec (86% [95% CI: 65, 97]), [3] risdiplam (61% [95% CI: 45, 76]), [13] and nusinersen (58% [95% CI: 41, 73], I2 = 80·48%, P = 0·00) [4, 8, 22, 41] (Appendix: Fig. S1); onasemnogene abeparvovec (86% [95% CI: 65, 97], P = 0·00) versus nusinersen (58% [95% CI: 41, 73], P = 0·00), P = 0·02; risdiplam (61% [95% CI: 45, 76], P = 0·00) versus nusinersen (58% [95% CI: 41, 73], P = 0·00), P = 0·76; onasemnogene abeparvovec (86% [95% CI: 65, 97], P = 0·00) versus risdiplam (61% [95% CI: 45, 76], P = 0·00), P = 0·03 (Appendix: Table S4).

Forest plot displaying the number of patients with an improvement of their CHOP-INTEND score ≥ 4. prop proportion; imp improve; tot total.

Twenty-one studies [3, 8,9,10, 13,