To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and ...functional endpoints in a large ambulatory cohort using a multicenter study design.
MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests.
Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68-0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63-0.73) and peroneals (|ρ| = 0.59-0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation.
Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic ...modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency ADA-SCID in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy SMA; Duchenne muscular dystrophy DMD; X-linked myotubular myopathy XLMTM; and diseases of the central nervous system, including Alzheimer’s disease, Parkinson’s disease, Canavan disease, aromatic l-amino acid decarboxylase AADC deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration AMD, choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.
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Researchers have been trying to develop therapies for hereditary diseases for more than 30 years. Several problems have been successfully resolved and thus Tremblay and colleagues are describing the recent progress of clinical applications of gene therapy. There are now several in vivo treatments under trials, and some approved for commercialization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The predominant approach in neuromuscular disease involves the use of non-integrating AAV vectors, which are particularly well suited for differentiated cells in the neuromuscular system. Since the ...musculature comprises 30%–40% of the body mass, the vascular route of delivery is the only practical approach to reach all of the musculature. For the majority of neuromuscular diseases there is a great deal known about disease pathophysiology and natural history. ...designing an impactful gene therapy approach should be directed by these considerations. In some cases, even non-human primate studies do not effectively model observations in adolescent or adult patients. ...unanticipated findings may appear in the current era of neuromuscular gene therapy, and hopefully none of these lead to a stopping point of current studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for ...DMD until after age 7. In this study, we hypothesized that (1)H2O T2 derived using (1)H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5-7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.
MR data were acquired from 123 boys with DMD (ages 5-14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children's Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and (1)H2O T2.
MRI-T2, (1)H2O T2, and lipid fraction were greater (p<0.05) in DMD compared to controls. In the youngest age group, DMD values were different (p<0.05) than controls for the soleus MRI-T2, (1)H2O T2 and lipid fraction and vastus lateralis MRI-T2 and (1)H2O T2. In the boys with DMD, MRI-T2 and lipid fraction were greater (p<0.05) in the oldest age group (11-14 years) than the youngest age group (5-6.9 years), while 1H2O T2 was lower in the oldest age group compared to the young age group.
Overall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.
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Importantly, the severe findings in a limited number of animals in these studies should not be confused with low-grade laboratory findings in clinical studies that are self-limited. Since these ...studies are related to variants of AAV9 vectors given systemically, the focus of this commentary will be limited to active clinical programs using AAV serotype 9, both by systemic and regional delivery, since the one conclusion of Hinderer et al.2 is that, “The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of intravenous delivery of AAV vectors at high doses irrespective of the capsid serotype or transgene.” GCP guidance is based on the ethical principles established in the Declaration of Helsinki in which the rights, safety, and well-being of trial subjects are the most important and overriding considerations in the design and conduct of research involving human subjects. ...any anticipated risk should be established in light of the potential benefit for the subject. The IB provides information on the characteristics of the investigational product and the non-clinical studies which support the clinical use. ...a comparison of the cumulative findings from IBs which support active AAV9 studies to the current non-clinical studies by Hordeux et al.1 and Hinderer et al.2 is warranted. Immuno-toxicity can in fact be managed by immune modulation which would allow for incremental dosing.7,8 An additional challenge is that the vector production and quantification was accomplished by a different method than established for other clinical programs which followed Good Laboratory Practice (GLP) guidance, especially related to a qualified assay for characterization of vector quantity. ...reliance on the results of these studies should be limited to understanding the means by which an acute response leading to coagulopathy can be explained in NHPs and the unique finding of strain specific murine receptor for AAV PHP.B.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), ...Parkinson's disease (PD), and Friedreich's ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.
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Highlights • Pompe disease occurs due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). • Respiratory insufficiency and tongue motor problems are common. • Enzyme ...replacement therapy targets skeletal muscle but many patients still require ventilatory assistance. • Emerging evidence indicates that respiratory neuron pathology contributes to motor unit dysfunction. • Restoration of GAA activity in respiratory muscles and neurons may be required to correct ventilatory insufficiency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Efficient and targeted delivery of a DNA payload is vital for developing safe gene therapy. Owing to the recent success of commercial oncolytic vector and multiple COVID-19 vaccines, adenovirus ...vectors are back in the spotlight. Adenovirus vectors can be used in gene therapy by altering the wild-type virus and making it replication-defective; specific viral genes can be removed and replaced with a segment that holds a therapeutic gene, and this vector can be used as delivery vehicle for tissue specific gene delivery. Modified conditionally replicative-oncolytic adenoviruses target tumors exclusively and have been studied in clinical trials extensively. This comprehensive review seeks to offer a summary of adenovirus vectors, exploring their characteristics, genetic enhancements, and diverse applications in clinical and preclinical settings. A significant emphasis is placed on their crucial role in advancing cancer therapy and the latest breakthroughs in vaccine clinical trials for various diseases. Additionally, we tackle current challenges and future avenues for optimizing adenovirus vectors, promising to open new frontiers in the fields of cell and gene therapies.
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