Jeremy Martin on the 6D Helmets Midweek Podcast

Upon placing LS mice in metabolic chambers (Figure S11A), we observed improved oxygen consumption and carbon dioxide production with sildenafil (Figure 5C), possibly indicating enhanced metabolic fitness. Cardiac bradyarrhythmia and dysfunction were also ameliorated (Figure S11B). Consistent with previous observations,14,87,88 LS mice showed cleaved caspase-3 staining in the cerebellum and brain stem regions associated with increased Iba1 staining,89 suggestive of cell death and microglial activation (Figures 5D and 5E).

• Sildenafil operates by increasing blood flow to the penis during arousal.
• It is a phosphodiesterase type 5 (PDE5) inhibitor used in sexual medicine.
• The standard dose ranges from 25mg to 100mg, but 100g refers to a very high, rare dose.
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The number of cells positive for caspase-3 or Iba1 decreased in sildenafil-treated LS mice (Figures 5D and 5E). The loss of Purkinje cells of the cerebellum was also ameliorated (Figures S11C and S11D). The expression of Prkg1, which is particularly evident in normal cerebellar Purkinje neurons,15 was reduced in LS mice and rescued by sildenafil (Figures 5D and 5E). Next, we employed SURF1 KO pigs, which exhibit severe neurodevelopmental impairment.11 SURF1 KO piglets were treated immediately at birth (n = 3 animals with 2.1 mg/kg/day, n = 4 animals with 0.5 mg/kg/day). Sildenafil improved animal responsiveness, mobility, and suckling behavior, leading to lifespan extension once the unstable perinatal phase was overcome (Figure 5F). Some LS pigs survived beyond day 261 despite reduced body weight (98 kg vs.

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Upon placing LS mice in metabolic chambers (Figure S11A), we observed improved oxygen consumption and carbon dioxide production with sildenafil (Figure 5C), possibly indicating enhanced metabolic fitness. Cardiac bradyarrhythmia and dysfunction were also ameliorated (Figure S11B). Consistent with previous observations,14,87,88 LS mice showed cleaved caspase-3 staining in the cerebellum and brain stem regions associated with increased Iba1 staining,89 suggestive of cell death and microglial activation (Figures 5D and 5E). The number of cells positive for caspase-3 or Iba1 decreased in sildenafil-treated LS mice (Figures 5D and 5E). The loss of Purkinje cells of the cerebellum was also ameliorated (Figures S11C and S11D).

S3 Fig. Western blot of p-ERK1/2 in the LV myocardium.

The expression of Prkg1, which is particularly evident in normal cerebellar Purkinje neurons,15 was reduced in LS mice and rescued by sildenafil (Figures 5D and 5E). Next, we employed SURF1 KO pigs, which exhibit severe neurodevelopmental impairment.11 SURF1 KO piglets were treated immediately at birth (n = 3 animals with 2.1 mg/kg/day, n = 4 animals with 0.5 mg/kg/day). Sildenafil improved animal responsiveness, mobility, and suckling behavior, leading to lifespan extension once the unstable perinatal phase was overcome (Figure 5F). Some LS pigs survived beyond day 261 despite reduced body weight (98 kg vs. 140–170 kg in age-matched controls).

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Sildenafil increased the body temperature of LS pigs, suggesting an effect on systemic metabolism (Figures 5G and S11F). The expression of NPC-associated doublecortin (DCX) was normalized by sildenafil (Figures 5H and S11G), indicating neurodevelopmental amelioration. CIV activity was also restored (Figure 5I). Reduced PRKG1 levels in the basal ganglia of LS pigs increased with treatment in most animals (Figures 5J and S11G). By adapting the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), we observed improvement in multiple domains of neuromotor integrity (Figures 5K and S11E). 140–170 kg in age-matched controls). Sildenafil increased the body temperature of LS pigs, suggesting an effect on systemic metabolism (Figures 5G and S11F). The expression of NPC-associated doublecortin (DCX) was normalized by sildenafil (Figures 5H and S11G), indicating neurodevelopmental amelioration. CIV activity was also restored (Figure 5I). Reduced PRKG1 levels in the basal ganglia of LS pigs increased with treatment in most animals (Figures 5J and S11G). By adapting the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), we observed improvement in multiple domains of neuromotor integrity (Figures 5K and S11E). Collectively, the in vivo data highlighted the potential clinical effectiveness of sildenafil and underscored PRKG1 as one of its mechanistic targets.

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In sildenafil 20 mg prescription some LS pigs treated with high sildenafil doses, we noticed microhemorrhages (Figure S11H).

How should I take sildenafil?

In all the other cases, sildenafil was well tolerated (Table S4), leading to improvement in motor function and development (Tables 1 and S3). Patient 5 showed protection from metabolic crises that had occurred nearly monthly before sildenafil treatment, while mild improvements in cognitive abilities were reported for patients 4 and 6 (Tables 1 and S3). We assessed disease progression using the NPMDS92 or the Newcastle Mitochondrial Disease Adult Scale (NMDAS).93 These rating scales cover multiple aspects of mitochondrial disease, including clinical assessments and quality of life. Remarkably, NPMDS/NMDAS scores of the six sildenafil-treated patients decreased or showed reduced rates of increase over time (Figure 6G). The effect was evident across all dimensions of NPMDS (Figures 6H–6J).

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In patients 1, 5, and 6, sildenafil was started during a metabolic crisis, which resolved rapidly and led to a rapid drop in NMDAS/NPMDS. The subsequent NPMDS/NMDAS increase seen in patient 1 may be due to natural progression of the disease or reduced compliance. Overall, chronic treatment on an individual basis with sildenafil showed clinical improvements in LS patients carrying MT-ATP6 variants. Sildenafil is a well-studied molecule in clinical applications.32 In addition to its use in adult men with erectile dysfunction,96 sildenafil can treat PAH and rare lymphatic malformations in children.39,40,41,42 Recent studies suggest that it might be a repurposable candidate for nervous system disorders.97 Sildenafil use was associated with reduced risk of developing Alzheimer’s disease (AD) and promoted neuronal outgrowth in AD iPSC-derived neurons.98,99 Sildenafil lowered cognitive decline in mouse models of Huntington’s disease (HD)100,101 and increased motor and cognitive performance in HD individuals.102 It also alleviated neuropathological signs in animal models of multiple sclerosis103 and ischemic stroke.104 In this study, we found that sildenafil might slow down the neurological decline of the severe mitochondrial brain disease LS. Sildenafil increased the lifespan of two mammalian models of LS.

RV remained apparently normal by two-day LV pressure overload (TAC), with mild LV hypertrophy that was inhibited by sildenafil

One treated pig remained clinically stable for over 6 months, an unprecedented health span and lifespan extension sildenafil citrate drug in this model. In treated LS individuals, the reduction of the upward sloping trend in the NPMDS/NMDAS score over time possibly implies that sildenafil modified the disease trajectory. Sildenafil releases cGMP, which has a wide range of functions, likely resulting in a poly-pharmacological mode of action.32 Sildenafil showed enhanced neurogenesis in mice,105,106 as cGMP and PRKG1 modulated neurotransmitter release, neuronal survival, and neurite formation.82,83,84,85 Mice deficient for Prkg1 exhibit impaired axon guidance and connectivity.86 Consistently, we found that the signature of sildenafil primarily involved the regulation of neurodevelopment, and it acted specifically on progenitors and radial glia populations. LS neural cells showed reduced PRKG1 levels, and knockdown of PRKG1 in healthy neurons recapitulated the branching defects seen in patient cells. In mouse brain, Prkg1 is known to be highly expressed in Purkinje cells, where its selective depletion results in motor learning defects.107 Here, we found that treatment with sildenafil increased Prkg1 levels in LS mice and some LS pigs, potentially promoting neuronal morphogenesis and connectivity. We further assessed toxicity using LS iPSC-derived cardiomyocytes (Figure S12A).

• Side effects at high doses like 100g can include vision impairment and hearing loss.
• Sildenafil can cause headaches, dizziness, or temporary vision changes.
• Patients taking medications for blood pressure should consult their doctor beforehand.
• The drug's effect lasts around 4-6 hours, but duration varies.
• Misuse or overdose increases the risk of serious health complications.

The findings are in agreement with the higher mortality rate seen in children with PAH treated with high sildenafil doses.40 We then probed the blood-brain barrier (BBB) permeability of sildenafil using an iPSC-based model90 (Figure 6A). Similar to control brain capillary endothelial cells (BCECs), LS BCECs showed correct morphology and marker expression (Figure 6B) as well as monolayer integrity and transendothelial electrical resistance (TEER) (Figures S12F and S12G). The permeability of sildenafil and sildenafil citrate (the active pharmacological substance applied orally in clinical applications) in LS BCECs was similar to that of control BCECs (Figure 6C).

• Sildenafil's patent expired in many countries, leading to generic versions.
• The cost of sildenafil can vary depending on the dose and brand.
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The results are consistent with permeability values of sildenafil reported in other settings91 and imply that sildenafil can effectively cross the BBB in LS. Because sildenafil can be used safely in pediatric conditions,39,40,41,42 we initiated off-label treatment on an individual basis with sildenafil in six LS patients carrying MT-ATP6 variants (Tables 1 and S3). All patients showed cranial magnetic resonance imaging (cMRI) signs consistent with LS lesions (Figures 6E and S12H). From patient 1, we also obtained iPSCs (line ATP6_7), which were used to generate NPCs and brain organoids (Figure S10H).

Country/Region	Approval Status	Regulatory Body
United States	Approved for ED, PAH	FDA
European Union	Approved, generic available	EMA
India	Approved, widely available	CDSCO
Canada	Approved	Health Canada

When selecting the sildenafil dosage, we referred to the trial STARTS-1 (Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension)41 and the trial STARTS-240 in children with PAH. Given the potential toxic effects of high dosages, we only considered low (0.66–1.49 mg/kg/day) or medium dosages (1.50–3.00 mg/kg/day). Two patients/guardians opted for low dosages and four for medium dosages. To monitor the occurrence of adverse reactions, we asked patients/guardians to respond to a questionnaire on side effects after 6 months of sildenafil use (Table S4).

• Sildenafil was initially developed to treat hypertension and angina.
• The typical prescribed dose is up to 100mg, but only under medical supervision.
• Recreational misuse of high doses can result in serious health issues.
• Educate yourself about the potential risks and proper use of sildenafil.
• The drug works best when taken about 30-60 minutes before activity.

In patient 3, sildenafil had to be discontinued due to a rash, even though the frequent episodes of sudden muscle weakness were resolved during sildenafil medication and returned once the drug was discontinued (Tables 1 and S4). In all the other cases, sildenafil was well tolerated (Table S4), leading to improvement in motor function and development (Tables 1 and S3). Patient 5 showed protection from metabolic crises that had occurred nearly monthly before sildenafil treatment, while mild improvements in cognitive abilities were reported for patients 4 and 6 (Tables 1 and S3). We assessed disease progression using the NPMDS92 or the Newcastle Mitochondrial Disease Adult Scale (NMDAS).93 These rating scales cover multiple aspects of mitochondrial disease, including clinical assessments and quality of life. Remarkably, NPMDS/NMDAS scores of the six sildenafil-treated patients decreased or showed reduced rates of increase over time (Figure 6G). The effect was evident across all dimensions of NPMDS (Figures 6H–6J). In patients 1, 5, and 6, sildenafil was started during a metabolic crisis, which resolved rapidly and led to a rapid drop in NMDAS/NPMDS. The subsequent NPMDS/NMDAS increase seen in patient 1 may be due to natural progression of the disease or reduced compliance. Overall, chronic treatment on an individual basis with sildenafil showed clinical improvements in LS patients carrying MT-ATP6 variants. Sildenafil is a well-studied molecule in clinical applications.32 In addition to its use in adult men with erectile dysfunction,96 sildenafil can treat PAH and rare lymphatic malformations in children.39,40,41,42 Recent studies suggest that it might be a repurposable candidate for nervous system disorders.97 Sildenafil use was associated with reduced risk of developing Alzheimer’s disease (AD) and promoted neuronal outgrowth in AD iPSC-derived neurons.98,99 Sildenafil lowered cognitive decline in mouse models of Huntington’s disease (HD)100,101 and increased motor and cognitive performance in HD individuals.102 It also alleviated neuropathological signs in animal models of multiple sclerosis103 and ischemic stroke.104 In this study, we found that sildenafil might slow down the neurological decline of the severe mitochondrial brain disease LS. Sildenafil increased the lifespan of two mammalian models of LS. One treated pig remained clinically stable for over 6 months, an unprecedented health span and lifespan extension sildenafil citrate drug in this model. In treated LS individuals, the reduction of the upward sloping trend in the NPMDS/NMDAS score over time possibly implies that sildenafil modified the disease trajectory. Sildenafil releases cGMP, which has a wide range of functions, likely resulting in a poly-pharmacological mode of action.32 Sildenafil showed enhanced neurogenesis in mice,105,106 as cGMP and PRKG1 modulated neurotransmitter release, neuronal survival, and neurite formation.82,83,84,85 Mice deficient for Prkg1 exhibit impaired axon guidance and connectivity.86 Consistently, we found that the signature of sildenafil primarily involved the regulation of neurodevelopment, and it acted specifically on progenitors and radial glia populations.

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Collectively, the in vivo data highlighted the potential clinical effectiveness of sildenafil and underscored PRKG1 as one of its mechanistic targets. In sildenafil 20 mg prescription some LS pigs treated with high sildenafil doses, we noticed microhemorrhages (Figure S11H). We further assessed toxicity using LS iPSC-derived cardiomyocytes (Figure S12A). The findings are in agreement with the higher mortality rate seen in children with PAH treated with high sildenafil doses.40 We then probed the blood-brain barrier (BBB) permeability of sildenafil using an iPSC-based model90 (Figure 6A). Similar to control brain capillary endothelial cells (BCECs), LS BCECs showed correct morphology and marker expression (Figure 6B) as well as monolayer integrity and transendothelial electrical resistance (TEER) (Figures S12F and S12G).

Sildenafil prevented cardiac macrophage infiltration in the RV as well as in the LV during LV pressure-overload

The permeability of sildenafil and sildenafil citrate (the active pharmacological substance applied orally in clinical applications) in LS BCECs was similar to that of control BCECs (Figure 6C). The results are consistent with permeability values of sildenafil reported in other settings91 and imply that sildenafil can effectively cross the BBB in LS. Because sildenafil can be used safely in pediatric conditions,39,40,41,42 we initiated off-label treatment on an individual basis with sildenafil in six LS patients carrying MT-ATP6 variants (Tables 1 and S3). All patients showed cranial magnetic resonance imaging (cMRI) signs consistent with LS lesions (Figures 6E and S12H). From patient 1, we also obtained iPSCs (line ATP6_7), which were used to generate NPCs and brain organoids (Figure S10H).

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When selecting the sildenafil dosage, we referred to the trial STARTS-1 (Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension)41 and the trial STARTS-240 in children with PAH. Given the potential toxic effects of high dosages, we only considered low (0.66–1.49 mg/kg/day) or medium dosages (1.50–3.00 mg/kg/day). Two patients/guardians opted for low dosages and four for medium dosages. To monitor the occurrence of adverse reactions, we asked patients/guardians to respond to a questionnaire on side effects after 6 months of sildenafil use (Table S4). In patient 3, sildenafil had to be discontinued due to a rash, even though the frequent episodes of sudden muscle weakness were resolved during sildenafil medication and returned once the drug was discontinued (Tables 1 and S4). LS neural cells showed reduced PRKG1 levels, and knockdown of PRKG1 in healthy neurons recapitulated the branching defects seen in patient cells. In mouse brain, Prkg1 is known to be highly expressed in Purkinje cells, where its selective depletion results in motor learning defects.107 Here, we found that treatment with sildenafil increased Prkg1 levels in LS mice and some LS pigs, potentially promoting neuronal morphogenesis and connectivity. In addition to its neurological impact, sildenafil might induce mitochondrial biogenesis and oxygen consumption,108,109 as PRKG1 may represent a regulator of energy homeostasis.110 This is supported by our findings showing that PRKG1 inhibition blunted MMP normalization by sildenafil. Sildenafil also reversed changes in mitochondrial cristae junction distributions that may reflect cristae morphology defects caused by MT-ATP6 variants.45 We postulate that the bioenergetic improvement and MMP normalization by sildenafil may be related to its action on calcium homeostasis. Modulation of BKCa channels has been implicated in the sildenafil effect in other disease contexts77,78 and neuronal calcium signaling can be mediated by PRKG1.111,112 However, because PRKG1 protein levels were not fully normalized in all LS models, it is possible that sildenafil might enhance PRKG1 enzymatic activity rather than its protein abundance.56 In fact, continuous application of the cGMP analog 8-Br-cGMP can reduce PRKG1 expression.113 Further dissection of this pathway is required.

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In addition to its neurological impact, sildenafil might induce mitochondrial biogenesis and oxygen consumption,108,109 as PRKG1 may represent a regulator of energy homeostasis.110 This is supported by our findings showing that PRKG1 inhibition blunted MMP normalization by sildenafil. Sildenafil also reversed changes in mitochondrial cristae junction distributions that may reflect cristae morphology defects caused by MT-ATP6 variants.45 We postulate that the bioenergetic improvement and MMP normalization by sildenafil may be related to its action on calcium homeostasis. Modulation of BKCa channels has been implicated in the sildenafil effect in other disease contexts77,78 and neuronal calcium signaling can be mediated by PRKG1.111,112 However, because PRKG1 protein levels were not fully normalized in all LS models, it is possible that sildenafil might enhance PRKG1 enzymatic activity rather than its protein abundance.56 In fact, continuous application of the cGMP analog 8-Br-cGMP can reduce PRKG1 expression.113 Further dissection of this pathway is required. Whether the restorative effects of sildenafil seen in LS are linked to its vasodilatory mechanisms32 remains to be studied. The increase in blood flow and oxygen delivery to muscle and brain tissue may potentially contribute to beneficial metabolic effects.

Two-day LV pressure overload (TAC) did not affect RV pressure or function, but prolonged LV relaxation that was ameliorated by sildenafil

Sildenafil led to vascular and metabolic improvements in individuals with AD114 and in subjects with vascular cognitive impairment.115 The effect of sildenafil on the vasculature32 and the beneficial consequences of hypoxia seen in animal models of LS22,23 might indicate that modulation of brain vascularization and associated oxygenation116 could represent important therapeutic targets in LS. Our findings underscore the power of conducting drug discovery studies driven by iPSC models. Similar strategies could be applied to other neurological diseases for which effective model systems are lacking. Considering that mitochondria play a crucial role in cellular health and brain function and homeostasis,117,118,119 understanding the potential effects of PDE5i in mitochondrial diseases may also have important implications in the context of common aging-related neurological disorders.

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Whether the restorative effects of sildenafil seen in LS are linked to its vasodilatory mechanisms32 remains to be studied. The increase in blood flow and oxygen delivery to muscle and brain tissue may potentially contribute to beneficial metabolic effects. Sildenafil led to vascular and metabolic improvements in individuals with AD114 and in subjects with vascular cognitive impairment.115 The effect of sildenafil on the vasculature32 and the beneficial consequences of hypoxia seen in animal models of LS22,23 might indicate that modulation of brain vascularization and associated oxygenation116 could represent important therapeutic targets in LS. Our findings underscore the power of conducting drug discovery studies driven by iPSC models. Similar strategies could be applied to other neurological diseases for which effective model systems are lacking. Considering that mitochondria play a crucial role in cellular health and brain function and homeostasis,117,118,119 understanding the potential effects of PDE5i in mitochondrial diseases may also have important implications in the context of common aging-related neurological disorders.