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At least 37 records · Page 2Linked to original sources
PubMed2025

Tunable, proteolytic dosage control of CRISPR-Cas systems enables precise gene therapy for dosage sensitive disorders.

The ability to modulate gene expression through modular and universal genetic tools like CRISPR-Cas has greatly advanced gene therapy for therapeutics and basic science. Yet, the inherent stochasticity of delivery methods cause variation in target gene expression at the single-cell level, limiting their applicability in systems that require more precise expression. Thus, we implement a modular incoherent feedforward loop based on proteolytic cleavage of Cas to reduce gene expression variability against the variability of vector delivery. We target a genome-integrated marker and demonstrate dosage control of gene activation and repression, post-delivery tuning, and RNA-based compatibility of the system. To illustrate therapeutic relevance, we target the gene RAI1, the haploinsufficiency and triplosensitivity of which cause two autism-related syndromes. We demonstrate dosage-controlled gene activation for both human and mouse Rai1 via viral delivery to patient-derived cell lines and mouse cortical neurons. Overall, we established a robust dosage control circuit for uniform gene expression, beneficial for basic and translational research.

Journal Article↗
PubMed1999

A challenge for high-precision radiation therapy: the case for photons.

The sophistication of Hadron facilities led to major technical and conceptual advances in the treatment immobilization, reproducibility, planning and execution. Some of these developments have had a pivotal impact on conventional treatments, which can now approach the dose localization advantage of protons in the majority of clinical situations. While the biological advantages of neutrons may finally be combined with excellent dose localization in Heavy Ion Facilities, modern surgical or systemic treatment methods may reduce high LET advantages. Clinical trials still need to define the relative merits of these approaches in their most modern implementation. The advantage gap has certainly been narrowed by recent developments in conventional therapy.

Humans↗
PubMed1999

A challenge for high-precision radiation therapy: the case for hadrons.

Developments in Hadron therapy, i.e., fast neutrons, protons, pions, heavy ions and boron neutron capture therapy are reviewed. For each type of particle, operational and closed facilities are listed as well as planned new facilities. Improvements in clinical results have always been linked to technological developments and better physical selectivity of the irradiation. Exploring the benefit of further improvement in dose localization expected from protons and conformal therapy is the challenge for the coming years. The radiobiological rationale for high-LET radiation in cancer treatment, proposed in the fifties, is still valid and has not been contradicted by recent radiobiological findings. This justifies the planning of a therapy facility where protons and heavy ions (carbon ions) could be applied, under optimal physical and technical conditions. Appropriate selection between low- and high-LET radiation for a particular tumor is indeed a radiobiological problem, independent of technical development.

Boron Neutron Capture Therapy↗
PubMed2006

Assessment of residual error in liver position using kV cone-beam computed tomography for liver cancer high-precision radiation therapy.

PURPOSE: To evaluate the residual error in liver position using breath-hold kilovoltage (kV) cone-beam computed tomography (CT) following on-line orthogonal megavoltage (MV) image-guided breath-hold liver cancer conformal radiotherapy. METHODS AND MATERIALS: Thirteen patients with liver cancer treated with 6-fraction breath-hold conformal radiotherapy were investigated. Before each fraction, orthogonal MV images were obtained during exhale breath-hold, with repositioning for offsets>3 mm, using the diaphragm for cranio-caudal (CC) alignment and vertebral bodies for medial-lateral (ML) and anterior posterior (AP) alignment. After repositioning, repeat orthogonal MV images, orthogonal kV fluoroscopic movies, and kV cone-beam CTs were obtained in exhale breath-hold. The cone-beam CT livers were registered to the planning CT liver to obtain the residual setup error in liver position. RESULTS: After repositioning, 78 orthogonal MV image pairs, 61 orthogonal kV image pairs, and 72 kV cone-beam CT scans were obtained. Population random setup errors (sigma) in liver position were 2.7 mm (CC), 2.3 mm (ML), and 3.0 mm (AP), and systematic errors (Sigma) were 1.1 mm, 1.9 mm, and 1.3 mm in the superior, medial, and posterior directions. Liver offsets>5 mm were observed in 33% of cases; offsets>10 mm and liver deformation>5 mm were observed in a minority of patients. CONCLUSIONS: Liver position after radiation therapy guided with MV orthogonal imaging was within 5 mm of planned position in the majority of patients. kV cone-beam CT image guidance should improve accuracy with reduced dose compared with orthogonal MV image guidance for liver cancer radiation therapy.

Carcinoma, Hepatocellular↗
PubMed1988

Therapeutic ultrasound. A precise noninvasive therapy for glaucoma.

The use of therapeutic ultrasound represents a new approach in the treatment of all types of glaucoma. The technique is performed as an outpatient procedure, requires minimal patient preparation, and has a high degree of patient acceptance. Considering the patients to whom ultrasound has been applied, the levels of success and complications compare favorably with other treatments. This type of procedure, when performed in earlier stages of glaucoma, has a better chance of preserving vision. Increased potential for success lies in repeating the procedure without undue risk. Although results in children are disappointing, it may be applicable in cases in which other therapies have failed. Future applications for therapeutic ultrasound are being explored. Currently, its use in unsuccessful surgical filtering procedures is under study, as are applications in areas other than ophthalmology. The effectiveness of this procedure ultimately will be determined by results obtained from ongoing clinical trials.

Glaucoma↗
PubMedDate not supplied

Differential otomanometry.

Management of otitis media, both acute and chronic, is one of the most common problems in clinical medicine. Among the many unresolved issues in otitis media research is accurate diagnosis which, in turn, depends heavily on valid otoscopic observation. Yet even today clinical otoscopy remains more of an art than a science. Because precise therapy is predicated on precise diagnosis, efforts to improve the validity and reliability of otoscopic techniques are warranted. Of great importance to the otoscopist is the visual estimate of tympanic membrane mobility secondary to hand-generated pneumatic pressure (pneumotoscopy). The degree of motion is usually graded in relative terms. In addition to pneumotoscopy, tympanometry is also used to assess the status of the middle ear. This is done indirectly through the plot of induced pressure versus acoustic immitance (tympanogram). Thus, both procedures depend on the differential application of induced pneumatic pressure on the tympanic membrane. If the middle ear is air-containing and the tympanic membrane is normal, even a slight pressure rise in the ear canal will displace the membrane. If the middle ear is fluid-filled, even large amounts of pressure produce no motion of the tympanic membrane. The pressure gradients, normal threshold, and optimal frequency of application for pneumotoscopy have not been studied previously in humans. Data are presented to compare the sensitivity, specificity, and predictive value of pneumotoscopy and tympanometry in the detection of effusion due to chronic secretory otitis media. In addition, preliminary data obtained by a new procedure, quantitative pneumotoscopy, are discussed.

Acoustic Impedance Tests↗
PubMed2001

Fluoroscopic study of tumor motion due to breathing: facilitating precise radiation therapy for lung cancer patients.

Target motion due to breathing is one of the major obstacles in dose escalation of radiation therapy to some tumors in the thoracoabdominal region. The development of beam gating or target motion tracking techniques provides a possibility to reduce normal tissue volume in a treatment field. Tumor motion monitoring in those techniques plays a crucial role, but has not yet been adequately explored. This paper reports our preliminary investigation on breath introduced tumor motion. Tumor locations and motion properties were determined from digitized fluoroscopic videos acquired during patient simulation. Image distortion due to irregularities in the imaging chain, such as the pincushion distortion, was corrected with a polynomial unwarping method. Temporal Fourier transformation of the fluoroscopic video was introduced to convert the motion information over time to a static view of a motion field, in which regions with different motion ranges can be directly measured. Patient breathing patterns vary from patient to patient and so does the kinematic behavior of individual tumors. In order to evaluate the feasibility for tracking internal target motion with nonionizing-radiation techniques, motion patterns between internal targets and external radio opaque markers placed on patient's chest during fluoroscopic video acquisition were compared. For some patients, significant motion phase discrepancies between an internal target and an external marker have been observed. Quantitative measurements are reported. These results will be useful in the design of a motion tracking or gated radiotherapy system.

Fluoroscopy↗
PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗
PubMed2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Humans↗