RARE DISEASE
Multisystemic smooth muscle dysfunction syndrome
Multisystemic smooth muscle dysfunction syndrome
Multisystemic smooth muscle dysfunction syndrome
Drug discovery
1
drug
With orphan designation
Overview
Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) is a rare autosomal dominant disorder caused by ACTA2 gene mutations (notably p.Arg179His), leading to systemic smooth muscle dysfunction. Key features include congenital mydriasis, patent ductus arteriosus (PDA), aortic/cerebrovascular disease, pulmonary hypertension, and multi-organ involvement. Clinical risks include early-onset strokes, aortic dissection, and progressive organ failure, with high childhood mortality [1][4][6][10].
Population
Ultra-rare (<100 reported cases globally), predominantly caused by ACTA2 R179H mutations [4][10][19].
Presents neonatally or in early childhood, with female predominance (66.7%) in some cohorts [4][8].
Hallmark triad: PDA (91.6%), congenital fixed mydriasis (92.6%), and vascular anomalies [4][6][14].
Burden
High mortality (18.5% reported deaths) from strokes, aneurysms, or pulmonary complications [4][8][19].
Chronic disability: 13.3% develop interstitial lung disease; 100% require lifelong multidisciplinary monitoring [4][15][19].
Significant healthcare utilization: Frequent hospitalizations for infections, surgeries, and rehabilitation [3][8][15].
Therapies
Symptomatic care: Diuretics, pulmonary vasodilators (e.g., sildenafil), and anticonvulsants for neurological sequelae [3][8][15].
Surgical interventions: PDA ligation, aortic repair, and cerebrovascular revascularization [3][10][15].
Emerging approaches: Gene therapy targeting ACTA2 mutations is in preclinical development [7][11][12].
Categories: rare circulatory system diseases, rare gastroenterological diseases, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare respiratory diseases, rare surgical thoracic diseases, rare urogenital diseases
Research Papers
13 drug discovery papers about Multisystemic smooth muscle dysfunction syndrome. Recent publications:
13 drug discovery papers about Multisystemic smooth muscle dysfunction syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-07-27 | Re-Purposing Sapropterin (Kuvan) for ACTA2-Related Multisystemic Smooth Muscle Dysfunction Syndrome: A Translational Mechanistic and First-In-Human Therapeutic Report.
Multisystemic smooth muscle dysfunction syndrome (MSMDS) is an ultra-rare, ACTA2-related disorder characterized by severe cerebrovascular disease, aortic aneurysms, and smooth muscle dysfunction. Using molecular dynamics simulations and in silico drug screening, we identified that sapropterin dihydrochloride (Kuvan) is a candidate capable of restoring p.R179H mutation disrupted actin polymerization. Patient-derived fibroblasts demonstrated improved actin organization with Kuvan treatment. Off-label treatment in a single pediatric patient with ACTA2-MSMDS resulted in observed cerebrovascular stabilization and clinical improvement on longitudinal follow-up. These findings provide first-in-human n-of-1 translational evidence supporting sapropterin as a potential disease-modifying therapy for ACTA2-related vasculopathies, while gene-directed therapies are awaited. Further studies are needed to establish a robust therapeutic effect and to elucidate the mechanisms underlying the observed cerebrovascular benefit.
2026-02-09 | Smooth Muscle Dysfunction Drives Cerebrovascular Reserve Failure and End-Organ Brain Injury.
Failure of cerebrovascular reserve is a fundamental determinant of ischemic vulnerability, yet the mechanisms by which vascular smooth muscle dysfunction compromises reserve and predisposes the brain to injury remain incompletely defined. We therefore tested whether a pathogenic smooth muscle mutation produces a baseline failure of cerebrovascular reserve sufficient to render the brain vulnerable to hypoperfusion, even in the absence of fixed arterial occlusion. We examined cerebrovascular structure, hemodynamics, and reserve in a genetically defined mouse model of ACTA2-associated multisystemic smooth muscle dysfunction syndrome with systemic or brain-restricted expression of the mutant allele. Cerebral artery morphology was assessed using magnetic resonance angiography and black ink angiography. Vascular smooth muscle phenotype was evaluated by immunohistochemistry and proliferation assays. Blood pressure reactivity and cerebral blood flow (CBF) were measured simultaneously using femoral arterial catheterization and laser speckle flowmetry during vasoactive challenges and controlled hypotension. Cerebrovascular stress responses were tested using unilateral common carotid artery occlusion. Downstream brain effects were assessed by histology, resting state functional connectivity imaging, and behavioral testing. Impaired smooth muscle contractility drove rectification and narrowing of major cerebral arteries, downregulation of contractile markers, and increased vascular cell proliferation. These structural changes produced a distinct physiological phenotype: mutant mice exhibited blunted vasoreactivity, diminished spontaneous vasodynamic activity, and a downward shift in the blood pressure-CBF relationship across a wide range of arterial pressures, consistent with loss of cerebrovascular reserve. As a result, CBF was reduced at baseline and could not be maintained during hypotension or acute vascular stress. During carotid occlusion, mutant mice showed impaired compensatory perfusion, greater physiological instability, and worse behavioral outcomes. Chronic reserve failure coincided with white matter loss, reduced neuronal density, disrupted large-scale functional connectivity, and deficits in locomotion, anxiety-related behavior, and working memory. Pathogenic smooth muscle dysfunction caused by ACTA2 mutation produces a baseline failure of cerebrovascular reserve that renders the brain vulnerable to hypoperfusion and stress-induced ischemic injury. These findings establish cerebrovascular reserve failure as a central physiological mechanism linking vascular dysfunction to end-organ brain injury and identify reserve preservation as a critical, potentially actionable determinant of brain health in hypotension-prone vascular disease.
2026-01-01 | P400: Two month old with ACTA2 Arg179His-positive multisystemic smooth muscle dysfunction syndrome with review of the literature
We reviewed 76 unique cases of codon 179 (R179)-related MSMDS including our patient. R179 variants include p.Arg179His (n=63, 83%), p.Arg179Cys (n=11, 14%), p.Arg179Leu (n=1, 1%), and p.Arg179Gly (n=1,1%). There is a predominance of females in this R179 cohort (74% in all R179, 91% in p.Arg179Cys, 71% in p.Arg179His). Death occurred in 13% of all patients (mean age 4 years), 18% mortality with p.Arg179Cys and 11% with p.Arg179His. Mydriasis was present in 100% of p.Arg179Cys patients (95% of p.Arg179His, 96% of R179 overall).
2021-10-28 | Refractory cerebral infarction in a child with an ACTA2 mutation.
A specific mutation in the ACTA2 gene is known to cause multisystemic smooth muscle dysfunction syndrome, which is associated with cerebrovascular diseases and various organ disorders. Cerebral infarctions resulting from severe vasculopathy can be refractory; however, there are no previous reports describing the detailed clinical course of recurrent cerebral infarctions due to an ACTA2 mutation. Herein, we report a patient with an ACTA2 mutation who experienced multiple refractory cerebral infarctions in early childhood. The patient was aged 1 year and 5 months at her first episode of cerebral infarction. Arteriopathy due to an ACTA2 mutation was diagnosed based on the characteristic cerebrovascular findings and abnormal physical findings, such as bilateral dilated pupils. Bilateral encephaloduroarteriosynangiosis and encephalogaleosynangiosis were performed after the first episode. Because the cerebral infarctions recurred postoperatively, administration of cilostazol followed by bosentan was started. However, despite these treatments she experienced seven cerebral infarctions by age 2 years and 6 months. Cerebral infarctions in patients with a specific ACTA2 mutation can occur even in early childhood, recur frequently, and cause severe motor and cognitive impairment. Physicians should be highly aware of this disease and be ready to provide the medical and surgical interventions necessary to minimize the disabling sequelae.
gene therapies
2025-09-12 | Treatment of a severe vascular disease using a bespoke CRISPR-Cas9 base editor in mice.
Pathogenic missense mutations in the alpha actin isotype 2 (ACTA2) gene cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection and death in childhood. Here we perform mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the most common MSMDS-causative mutation ACTA2 R179H. To directly correct the R179H mutation, we screened dozens of configurations of base editors to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We create a murine model of MSMDS that shows phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this strategy. Delivery of the customized base editor via an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector substantially prolongs survival and rescues systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta and brain. Our results highlight how bespoke mutant-specific CRISPR-Cas9 enzymes can improve mutation correction with base editors.
2025-05-16 | Genomic Editing of a Pathogenic Sequence Variant in ACTA2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome in Mice.
Vascular smooth muscle cells (SMCs), the predominant cell type in the aortic wall, play a crucial role in maintaining aortic integrity, blood pressure, and cardiovascular function. Vascular SMC contractility and function depend on ACTA2 (smooth muscle α-actin 2). The pathogenic variant ACTA2 c.536G>A (p.R179H) causes multisystemic smooth muscle dysfunction syndrome, a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and high risk of early death from aneurysms or stroke. No effective treatments exist for multisystemic smooth muscle dysfunction syndrome. To develop a comprehensive therapy for multisystemic smooth muscle dysfunction syndrome, we used CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) adenine base editing to correct the ACTA2 R179H sequence variant. We generated isogenic human induced pluripotent stem cell lines and humanized mice carrying this pathogenic missense sequence variant. Induced pluripotent stem cell-derived SMCs were evaluated for key functional characteristics, including proliferation, migration, and contractility. The adenine base editor ABE8e-SpCas9-VRQR under control of either an SMC-specific promoter or a cytomegalovirus promoter, and an optimized single guide RNA under control of a U6 promoter were delivered intravenously to humanized R179H mice using adeno-associated virus serotype 9 and phenotypic outcomes were evaluated. The R179H sequence variant causes a dramatic phenotypic switch in human induced pluripotent stem cell-derived SMCs from a contractile to a synthetic state, a transition associated with aneurysm formation. Base editing prevented this pathogenic phenotypic switch and restored normal SMC function. In humanized mice, the ACTA2R179H/+ sequence variant caused widespread smooth muscle dysfunction, manifesting as decreased blood pressure, aortic dilation and dissection, bladder enlargement, gut dilation, and hydronephrosis. In vivo base editing rescued these pathological abnormalities, normalizing smooth muscle function. This study demonstrates the effectiveness of adenine base editing to treat multisystemic smooth muscle dysfunction syndrome and restore aortic smooth muscle function. By correcting the ACTA2 R179H sequence variant, the pathogenic phenotypic shift in SMCs was prevented, key aortic smooth muscle functions were restored, and life-threatening aortic dilation and dissection were mitigated in humanized mice. These findings underscore the promise of gene-editing therapies in addressing the underlying genetic causes of smooth muscle disorders and offer a potential transformative treatment for patients facing severe vascular complications.
2025-04-01 | Abstract Or125: Genomic Editing of a Pathogenic Mutation in the Alpha Actin Isotype 2 Gene Rescues a Severe Vascular Disease
Introduction: The pathogenic variant c.536G>A (p. R179H) of smooth muscle alpha-actin 2 ( ACTA2 ) causes multisystemic smooth muscle dysfunction syndrome (MSMDS), a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and early mortality from aneurysms. No effective treatments exist for MSMDS. CRISPR-Cas9 genome editing has emerged as an attractive method to correct and cure genetically based diseases. We hypothesize that gene editing strategies can be used to correct the ACTA2 R179H pathogenic missense mutation in smooth muscle cells (SMCs), thereby ameliorating smooth muscle diseases such as MSMDS. Methods: We generated isogenic human induced pluripotent stem cell (iPSC) lines and humanized mice carrying this pathogenic mutation. iPSC-SMCs were evaluated for key functional characteristics, including proliferation, migration, and contractility. The adenine base editor (ABE) ABE8e-SpCas9-VRQR under control of a SMC-specific promoter, and an optimized single guide RNA (sgRNA) under control of U6 promoter were delivered intravenously to humanized R179H mice using adeno-associated virus serotype 9 (AAV9) and phenotypic outcomes were evaluated. Results: The R179H mutation causes a dramatic phenotypic switch in iPSC-SMCs from a contractile to a synthetic state, a transition associated with aneurysm formation. Base editing prevented this pathogenic phenotypic switch and restored normal SMC function. In humanized mice, the ACTA2 R179H/+ mutation caused widespread smooth muscle dysfunction, manifesting as decreased blood pressure, aortic dilation and dissection, bladder enlargement, gut dilation, and hydronephrosis. In vivo base editing rescued these pathological abnormalities, normalizing smooth muscle function. Conclusion: This study demonstrates the effectiveness of adenine base editing to treat MSMDS and restore aortic smooth muscle function. By correcting the ACTA2 R179H mutation, the pathogenic phenotypic shift in SMCs was prevented, key aortic smooth muscle functions were restored, and life-threatening aortic dilation and dissection were mitigated in humanized mice. These findings underscore the promise of gene-editing therapies in addressing the underlying genetic causes of smooth muscle disorders and offer a potential transformative treatment for patients facing severe vascular complications.
2024-11-28 | In vivo Treatment of a Severe Vascular Disease via a Bespoke CRISPR-Cas9 Base Editor.
Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene (ACTA2) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutation ACTA2 R179H. In a first-in-kind approach, we performed mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the R179H sequence. To directly correct the R179H mutation, we screened dozens of configurations of base editors (comprised of Cas9 enzymes, deaminases, and gRNAs) to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We then created a murine model of MSMDS that exhibits phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this base editing strategy. Delivery of the customized base editor via an engineered SMC-tropic adeno-associated virus (AAV-PR) vector substantially prolonged survival and rescued systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta, and brain. Together, our optimization of a customized base editor highlights how bespoke CRISPR-Cas enzymes can enhance on-target correction while minimizing bystander edits, culminating in a precise editing approach that may enable a long-lasting treatment for patients with MSMDS.
small molecules
2026-07-27 | Re-Purposing Sapropterin (Kuvan) for ACTA2-Related Multisystemic Smooth Muscle Dysfunction Syndrome: A Translational Mechanistic and First-In-Human Therapeutic Report.
Multisystemic smooth muscle dysfunction syndrome (MSMDS) is an ultra-rare, ACTA2-related disorder characterized by severe cerebrovascular disease, aortic aneurysms, and smooth muscle dysfunction. Using molecular dynamics simulations and in silico drug screening, we identified that sapropterin dihydrochloride (Kuvan) is a candidate capable of restoring p.R179H mutation disrupted actin polymerization. Patient-derived fibroblasts demonstrated improved actin organization with Kuvan treatment. Off-label treatment in a single pediatric patient with ACTA2-MSMDS resulted in observed cerebrovascular stabilization and clinical improvement on longitudinal follow-up. These findings provide first-in-human n-of-1 translational evidence supporting sapropterin as a potential disease-modifying therapy for ACTA2-related vasculopathies, while gene-directed therapies are awaited. Further studies are needed to establish a robust therapeutic effect and to elucidate the mechanisms underlying the observed cerebrovascular benefit.
2026-02-09 | Smooth Muscle Dysfunction Drives Cerebrovascular Reserve Failure and End-Organ Brain Injury.
Failure of cerebrovascular reserve is a fundamental determinant of ischemic vulnerability, yet the mechanisms by which vascular smooth muscle dysfunction compromises reserve and predisposes the brain to injury remain incompletely defined. We therefore tested whether a pathogenic smooth muscle mutation produces a baseline failure of cerebrovascular reserve sufficient to render the brain vulnerable to hypoperfusion, even in the absence of fixed arterial occlusion. We examined cerebrovascular structure, hemodynamics, and reserve in a genetically defined mouse model of ACTA2-associated multisystemic smooth muscle dysfunction syndrome with systemic or brain-restricted expression of the mutant allele. Cerebral artery morphology was assessed using magnetic resonance angiography and black ink angiography. Vascular smooth muscle phenotype was evaluated by immunohistochemistry and proliferation assays. Blood pressure reactivity and cerebral blood flow (CBF) were measured simultaneously using femoral arterial catheterization and laser speckle flowmetry during vasoactive challenges and controlled hypotension. Cerebrovascular stress responses were tested using unilateral common carotid artery occlusion. Downstream brain effects were assessed by histology, resting state functional connectivity imaging, and behavioral testing. Impaired smooth muscle contractility drove rectification and narrowing of major cerebral arteries, downregulation of contractile markers, and increased vascular cell proliferation. These structural changes produced a distinct physiological phenotype: mutant mice exhibited blunted vasoreactivity, diminished spontaneous vasodynamic activity, and a downward shift in the blood pressure-CBF relationship across a wide range of arterial pressures, consistent with loss of cerebrovascular reserve. As a result, CBF was reduced at baseline and could not be maintained during hypotension or acute vascular stress. During carotid occlusion, mutant mice showed impaired compensatory perfusion, greater physiological instability, and worse behavioral outcomes. Chronic reserve failure coincided with white matter loss, reduced neuronal density, disrupted large-scale functional connectivity, and deficits in locomotion, anxiety-related behavior, and working memory. Pathogenic smooth muscle dysfunction caused by ACTA2 mutation produces a baseline failure of cerebrovascular reserve that renders the brain vulnerable to hypoperfusion and stress-induced ischemic injury. These findings establish cerebrovascular reserve failure as a central physiological mechanism linking vascular dysfunction to end-organ brain injury and identify reserve preservation as a critical, potentially actionable determinant of brain health in hypotension-prone vascular disease.
2026-01-01 | P400: Two month old with ACTA2 Arg179His-positive multisystemic smooth muscle dysfunction syndrome with review of the literature
We reviewed 76 unique cases of codon 179 (R179)-related MSMDS including our patient. R179 variants include p.Arg179His (n=63, 83%), p.Arg179Cys (n=11, 14%), p.Arg179Leu (n=1, 1%), and p.Arg179Gly (n=1,1%). There is a predominance of females in this R179 cohort (74% in all R179, 91% in p.Arg179Cys, 71% in p.Arg179His). Death occurred in 13% of all patients (mean age 4 years), 18% mortality with p.Arg179Cys and 11% with p.Arg179His. Mydriasis was present in 100% of p.Arg179Cys patients (95% of p.Arg179His, 96% of R179 overall).
2021-10-28 | Refractory cerebral infarction in a child with an ACTA2 mutation.
A specific mutation in the ACTA2 gene is known to cause multisystemic smooth muscle dysfunction syndrome, which is associated with cerebrovascular diseases and various organ disorders. Cerebral infarctions resulting from severe vasculopathy can be refractory; however, there are no previous reports describing the detailed clinical course of recurrent cerebral infarctions due to an ACTA2 mutation. Herein, we report a patient with an ACTA2 mutation who experienced multiple refractory cerebral infarctions in early childhood. The patient was aged 1 year and 5 months at her first episode of cerebral infarction. Arteriopathy due to an ACTA2 mutation was diagnosed based on the characteristic cerebrovascular findings and abnormal physical findings, such as bilateral dilated pupils. Bilateral encephaloduroarteriosynangiosis and encephalogaleosynangiosis were performed after the first episode. Because the cerebral infarctions recurred postoperatively, administration of cilostazol followed by bosentan was started. However, despite these treatments she experienced seven cerebral infarctions by age 2 years and 6 months. Cerebral infarctions in patients with a specific ACTA2 mutation can occur even in early childhood, recur frequently, and cause severe motor and cognitive impairment. Physicians should be highly aware of this disease and be ready to provide the medical and surgical interventions necessary to minimize the disabling sequelae.
gene therapies
2025-09-12 | Treatment of a severe vascular disease using a bespoke CRISPR-Cas9 base editor in mice.
Pathogenic missense mutations in the alpha actin isotype 2 (ACTA2) gene cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection and death in childhood. Here we perform mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the most common MSMDS-causative mutation ACTA2 R179H. To directly correct the R179H mutation, we screened dozens of configurations of base editors to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We create a murine model of MSMDS that shows phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this strategy. Delivery of the customized base editor via an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector substantially prolongs survival and rescues systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta and brain. Our results highlight how bespoke mutant-specific CRISPR-Cas9 enzymes can improve mutation correction with base editors.
2025-05-16 | Genomic Editing of a Pathogenic Sequence Variant in ACTA2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome in Mice.
Vascular smooth muscle cells (SMCs), the predominant cell type in the aortic wall, play a crucial role in maintaining aortic integrity, blood pressure, and cardiovascular function. Vascular SMC contractility and function depend on ACTA2 (smooth muscle α-actin 2). The pathogenic variant ACTA2 c.536G>A (p.R179H) causes multisystemic smooth muscle dysfunction syndrome, a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and high risk of early death from aneurysms or stroke. No effective treatments exist for multisystemic smooth muscle dysfunction syndrome. To develop a comprehensive therapy for multisystemic smooth muscle dysfunction syndrome, we used CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) adenine base editing to correct the ACTA2 R179H sequence variant. We generated isogenic human induced pluripotent stem cell lines and humanized mice carrying this pathogenic missense sequence variant. Induced pluripotent stem cell-derived SMCs were evaluated for key functional characteristics, including proliferation, migration, and contractility. The adenine base editor ABE8e-SpCas9-VRQR under control of either an SMC-specific promoter or a cytomegalovirus promoter, and an optimized single guide RNA under control of a U6 promoter were delivered intravenously to humanized R179H mice using adeno-associated virus serotype 9 and phenotypic outcomes were evaluated. The R179H sequence variant causes a dramatic phenotypic switch in human induced pluripotent stem cell-derived SMCs from a contractile to a synthetic state, a transition associated with aneurysm formation. Base editing prevented this pathogenic phenotypic switch and restored normal SMC function. In humanized mice, the ACTA2R179H/+ sequence variant caused widespread smooth muscle dysfunction, manifesting as decreased blood pressure, aortic dilation and dissection, bladder enlargement, gut dilation, and hydronephrosis. In vivo base editing rescued these pathological abnormalities, normalizing smooth muscle function. This study demonstrates the effectiveness of adenine base editing to treat multisystemic smooth muscle dysfunction syndrome and restore aortic smooth muscle function. By correcting the ACTA2 R179H sequence variant, the pathogenic phenotypic shift in SMCs was prevented, key aortic smooth muscle functions were restored, and life-threatening aortic dilation and dissection were mitigated in humanized mice. These findings underscore the promise of gene-editing therapies in addressing the underlying genetic causes of smooth muscle disorders and offer a potential transformative treatment for patients facing severe vascular complications.
2025-04-01 | Abstract Or125: Genomic Editing of a Pathogenic Mutation in the Alpha Actin Isotype 2 Gene Rescues a Severe Vascular Disease
Introduction: The pathogenic variant c.536G>A (p. R179H) of smooth muscle alpha-actin 2 ( ACTA2 ) causes multisystemic smooth muscle dysfunction syndrome (MSMDS), a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and early mortality from aneurysms. No effective treatments exist for MSMDS. CRISPR-Cas9 genome editing has emerged as an attractive method to correct and cure genetically based diseases. We hypothesize that gene editing strategies can be used to correct the ACTA2 R179H pathogenic missense mutation in smooth muscle cells (SMCs), thereby ameliorating smooth muscle diseases such as MSMDS. Methods: We generated isogenic human induced pluripotent stem cell (iPSC) lines and humanized mice carrying this pathogenic mutation. iPSC-SMCs were evaluated for key functional characteristics, including proliferation, migration, and contractility. The adenine base editor (ABE) ABE8e-SpCas9-VRQR under control of a SMC-specific promoter, and an optimized single guide RNA (sgRNA) under control of U6 promoter were delivered intravenously to humanized R179H mice using adeno-associated virus serotype 9 (AAV9) and phenotypic outcomes were evaluated. Results: The R179H mutation causes a dramatic phenotypic switch in iPSC-SMCs from a contractile to a synthetic state, a transition associated with aneurysm formation. Base editing prevented this pathogenic phenotypic switch and restored normal SMC function. In humanized mice, the ACTA2 R179H/+ mutation caused widespread smooth muscle dysfunction, manifesting as decreased blood pressure, aortic dilation and dissection, bladder enlargement, gut dilation, and hydronephrosis. In vivo base editing rescued these pathological abnormalities, normalizing smooth muscle function. Conclusion: This study demonstrates the effectiveness of adenine base editing to treat MSMDS and restore aortic smooth muscle function. By correcting the ACTA2 R179H mutation, the pathogenic phenotypic shift in SMCs was prevented, key aortic smooth muscle functions were restored, and life-threatening aortic dilation and dissection were mitigated in humanized mice. These findings underscore the promise of gene-editing therapies in addressing the underlying genetic causes of smooth muscle disorders and offer a potential transformative treatment for patients facing severe vascular complications.
2024-11-28 | In vivo Treatment of a Severe Vascular Disease via a Bespoke CRISPR-Cas9 Base Editor.
Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene (ACTA2) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutation ACTA2 R179H. In a first-in-kind approach, we performed mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the R179H sequence. To directly correct the R179H mutation, we screened dozens of configurations of base editors (comprised of Cas9 enzymes, deaminases, and gRNAs) to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We then created a murine model of MSMDS that exhibits phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this base editing strategy. Delivery of the customized base editor via an engineered SMC-tropic adeno-associated virus (AAV-PR) vector substantially prolonged survival and rescued systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta, and brain. Together, our optimization of a customized base editor highlights how bespoke CRISPR-Cas enzymes can enhance on-target correction while minimizing bystander edits, culminating in a precise editing approach that may enable a long-lasting treatment for patients with MSMDS.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Multisystemic smooth muscle dysfunction syndrome.
1 orphan drug designation for Multisystemic smooth muscle dysfunction syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a gene editing therapy that uses a CRISPR (clustered regularly interspaced short palindromic repeats)-based adenosine base editor (ABE), delivered using a smooth muscle cell targeting adeno-associated virus (AAV) capsid called AAV-PR (comprised of the parent AAV9 capsid modified with a unique 7-mer amino acid after amino acid 588 of VP1 protein) | gene editing enzymes | FDA | — | Mass General Brigham |
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