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Article ; Online: Gene-targeted therapies: Overview and implications.

Brooks, P J / Urv, Tiina K / Parisi, Melissa A

American journal of medical genetics. Part C, Seminars in medical genetics

2023 Volume 193, Issue 1, Page(s) 13–18

Abstract: Gene-targeted therapies (GTTs) are therapeutic platforms that are in principle applicable to large numbers of monogenic diseases. The rapid development and implementation of GTTs have profound implications for rare monogenic disease therapy development. ... ...

Abstract	Gene-targeted therapies (GTTs) are therapeutic platforms that are in principle applicable to large numbers of monogenic diseases. The rapid development and implementation of GTTs have profound implications for rare monogenic disease therapy development. This article provides a brief summary of the primary types of GTTs and a brief overview of the current state of the science. It also serves as a primer for the articles in this special issue.
MeSH term(s)	Humans ; Genetic Therapy
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2108622-9
ISSN	1552-4876 ; 0148-7299 ; 1552-4868
ISSN (online)	1552-4876
ISSN	0148-7299 ; 1552-4868
DOI	10.1002/ajmg.c.32033
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Article ; Online: The past, present, and future of modeling Cockayne Syndrome - A commentary on "Rat Model of Cockayne Syndrome Neurological Disease".

Pacak, Christina A / Brooks, P J

DNA repair

2020 Volume 88, Page(s) 102788

MeSH term(s)	Animals ; Cockayne Syndrome ; DNA Repair ; Rats ; Xeroderma Pigmentosum
Language	English
Publishing date	2020-01-28
Publishing country	Netherlands
Document type	Journal Article ; Comment
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2020.102788
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Article ; Online: Hip resurfacing: a large, US single-surgeon series.

Brooks, P J

The bone & joint journal

2016 Volume 98-B, Issue 1 Suppl A, Page(s) 10–13

Abstract: Hip resurfacing has been proposed as an alternative to traditional total hip arthroplasty in young, active patients. Much has been learned following the introduction of metal-on-metal resurfacing devices in the 1990s. The triad of a well-designed device, ...

Abstract	Hip resurfacing has been proposed as an alternative to traditional total hip arthroplasty in young, active patients. Much has been learned following the introduction of metal-on-metal resurfacing devices in the 1990s. The triad of a well-designed device, implanted accurately, in the correct patient has never been more critical than with these implants. Following Food and Drug Administration approval in 2006, we studied the safety and effectiveness of one hip resurfacing device (Birmingham Hip Resurfacing) at our hospital in a large, single-surgeon series. We report our early to mid-term results in 1333 cases followed for a mean of 4.3 years (2 to 5.7) using a prospective, observational registry. The mean patient age was 53.1 years (12 to 84); 70% were male and 91% had osteoarthritis. Complications were few, including no dislocations, no femoral component loosening, two femoral neck fractures (0.15%), one socket loosening (0.08%), three deep infections (0.23%), and three cases of metallosis (0.23%). There were no destructive pseudotumours. Overall survivorship at up to 5.7 years was 99.2%. Aseptic survivorship in males under the age of 50 was 100%. We believe this is the largest United States series of a single surgeon using a single resurfacing system.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Arthroplasty, Replacement, Hip/education ; Arthroplasty, Replacement, Hip/instrumentation ; Arthroplasty, Replacement, Hip/methods ; Child ; Female ; Femur Head ; Humans ; Learning Curve ; Male ; Middle Aged ; Organ Sparing Treatments ; Prospective Studies ; Treatment Outcome ; United States ; Young Adult
Language	English
Publishing date	2016-01
Publishing country	England
Document type	Journal Article ; Observational Study
ZDB-ID	2697156-2
ISSN	2049-4408 ; 2049-4394
ISSN (online)	2049-4408
ISSN	2049-4394
DOI	10.1302/0301-620X.98B1.36360
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Article ; Online: Dislocation following total hip replacement: causes and cures.

Brooks, P J

The bone & joint journal

2013 Volume 95-B, Issue 11 Suppl A, Page(s) 67–69

Abstract: Dislocation is one of the most common causes of patient and surgeon dissatisfaction following hip replacement and to treat it, the causes must first be understood. Patient factors include age greater than 70 years, medical comorbidities, female gender, ... ...

Abstract	Dislocation is one of the most common causes of patient and surgeon dissatisfaction following hip replacement and to treat it, the causes must first be understood. Patient factors include age greater than 70 years, medical comorbidities, female gender, ligamentous laxity, revision surgery, issues with the abductors, and patient education. Surgeon factors include the annual quantity of procedures and experience, the surgical approach, adequate restoration of femoral offset and leg length, component position, and soft-tissue or bony impingement. Implant factors include the design of the head and neck region, and so-called skirts on longer neck lengths. There should be offset choices available in order to restore soft-tissue tension. Lipped liners aid in gaining stability, yet if improperly placed may result in impingement and dislocation. Late dislocation may result from polyethylene wear, soft-tissue destruction, trochanteric or abductor disruption and weakness, or infection. Understanding the causes of hip dislocation facilitates prevention in a majority of instances. Proper pre-operative planning includes the identification of patients with a high offset in whom inadequate restoration of offset will reduce soft-tissue tension and abductor efficiency. Component position must be accurate to achieve stability without impingement. Finally, patient education cannot be over-emphasised, as most dislocations occur early, and are preventable with proper instructions.
MeSH term(s)	Age Factors ; Arthroplasty, Replacement, Hip ; Clinical Competence ; Comorbidity ; Hip Dislocation/diagnostic imaging ; Hip Dislocation/etiology ; Hip Dislocation/prevention & control ; Hip Prosthesis ; Humans ; Patient Education as Topic ; Postoperative Complications/diagnostic imaging ; Postoperative Complications/etiology ; Postoperative Complications/prevention & control ; Prosthesis Design ; Radiography ; Recurrence ; Reoperation ; Risk Factors ; Sex Factors
Language	English
Publishing date	2013-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2697156-2
ISSN	2049-4408 ; 2049-4394
ISSN (online)	2049-4408
ISSN	2049-4394
DOI	10.1302/0301-620X.95B11.32645
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Article ; Online: Blinded by the UV light: how the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease.

Brooks, P J

DNA repair

2013 Volume 12, Issue 8, Page(s) 656–671

Abstract: Cockayne syndrome (CS) is a devastating neurodevelopmental disorder, with growth abnormalities, progeriod features, and sun sensitivity. CS is typically considered to be a DNA repair disorder, since cells from CS patients have a defect in transcription- ... ...

Abstract	Cockayne syndrome (CS) is a devastating neurodevelopmental disorder, with growth abnormalities, progeriod features, and sun sensitivity. CS is typically considered to be a DNA repair disorder, since cells from CS patients have a defect in transcription-coupled nucleotide excision repair (TC-NER). However, cells from UV-sensitive syndrome patients also lack TC-NER, but these patients do not suffer from the neurologic and other abnormalities that CS patients do. Also, the neurologic abnormalities that affect CS patients (CS neurologic disease) are qualitatively different from those seen in NER-deficient XP patients. Therefore, the TC-NER defect explains the sun sensitive phenotype common to both CS and UVsS, but cannot explain CS neurologic disease. However, as CS neurologic disease is of much greater clinical significance than the sun sensitivity, there is a pressing need to understand its molecular basis. While there is evidence for defective repair of oxidative DNA damage and mitochondrial abnormalities in CS cells, here I propose that the defects in transcription by both RNA polymerases I and II that have been documented in CS cells provide a better explanation for many of the severe growth and neurodevelopmental defects in CS patients than defective DNA repair. The implications of these ideas for interpreting results from mouse models of CS, and for the development of treatments and therapies for CS patients are discussed.
MeSH term(s)	Animals ; Cockayne Syndrome/genetics ; Cockayne Syndrome/pathology ; DNA Damage ; DNA Repair ; DNA Repair-Deficiency Disorders/genetics ; DNA Repair-Deficiency Disorders/pathology ; Disease Models, Animal ; Humans ; Mice ; Oxidative Stress ; RNA Polymerase I/genetics ; RNA Polymerase I/metabolism ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Transcription, Genetic ; Ultraviolet Rays/adverse effects ; Xeroderma Pigmentosum/genetics ; Xeroderma Pigmentosum/pathology
Chemical Substances	RNA Polymerase II (EC 2.7.7.-) ; RNA Polymerase I (EC 2.7.7.6)
Language	English
Publishing date	2013-05-16
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2013.04.018
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Article ; Online: The Bespoke Gene Therapy Consortium: facilitating development of AAV gene therapies for rare diseases.

Brooks, P J / Miller, Timothy M / Revah, Frédéric / Suh, Junghae / Garrison, Bradley R / Starke, Lawrence C / MacLachlan, Timothy K / Neilan, Edward G / Raychaudhuri, Gopa / Kassim, Sadik H / Dehdashti, Jean / Rutter, Joni L

Nature reviews. Drug discovery

2024 Volume 23, Issue 3, Page(s) 157–158

MeSH term(s)	Humans ; Rare Diseases/genetics ; Rare Diseases/therapy ; Genetic Therapy ; Gene Transfer Techniques ; Dependovirus/genetics ; Genetic Vectors
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	News
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/d41573-024-00020-8
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Article ; Online: Timeless insights into prevention of acetaldehyde genotoxicity?

Brooks, P J / Schuebel, Kornel

Cell cycle (Georgetown, Tex.)

2016 Volume 16, Issue 4, Page(s) 308–309

MeSH term(s)	Acetaldehyde ; DNA Damage ; DNA Repair ; Fanconi Anemia ; Fanconi Anemia Complementation Group D2 Protein/genetics ; Fanconi Anemia Complementation Group Proteins/genetics
Chemical Substances	Fanconi Anemia Complementation Group D2 Protein ; Fanconi Anemia Complementation Group Proteins ; Acetaldehyde (GO1N1ZPR3B)
Language	English
Publishing date	2016-10-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2016.1247570
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Article ; Online: Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies.

Lekstrom-Himes, Julie / Brooks, P J / Koeberl, Dwight D / Brower, Amy / Goldenberg, Aaron / Green, Robert C / Morris, Jill A / Orsini, Joseph J / Yu, Timothy W / Augustine, Erika F

American journal of medical genetics. Part C, Seminars in medical genetics

2023 Volume 193, Issue 1, Page(s) 30–43

Abstract: Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene ... ...

Abstract	Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery and gene editing systems. Early successes are encouraging, however, given the substantial number of distinct rare diseases, the ability to scale these successes will be unsustainable without new development efficiencies. Herein, we discuss the need for genomic newborn screening to match pace with the growing development of targeted therapeutics and ability to rapidly develop individualized therapies for rare variants. We offer approaches to move beyond conventional "one disease at a time" preclinical and clinical drug development and discuss planned regulatory innovations that are necessary to speed therapy delivery to individuals in need. These proposals leverage the shared properties of platform classes of therapeutics and innovative trial designs including master and platform protocols to better serve patients and accelerate drug development. Ultimately, there are risks to these novel approaches; however, we believe that close partnership and transparency between health authorities, patients, researchers, and drug developers present the path forward to overcome these challenges and deliver on the promise of gene-targeted therapies for rare diseases.
MeSH term(s)	Infant, Newborn ; Humans ; Rare Diseases/diagnosis ; Rare Diseases/genetics ; Rare Diseases/therapy ; Gene Editing ; Genetic Therapy/methods ; Genomics
Language	English
Publishing date	2023-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2108622-9
ISSN	1552-4876 ; 0148-7299 ; 1552-4868
ISSN (online)	1552-4876
ISSN	0148-7299 ; 1552-4868
DOI	10.1002/ajmg.c.32031
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Article: The 8,5'-cyclopurine-2'-deoxynucleosides: candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair.

Brooks, P J

DNA repair

2008 Volume 7, Issue 7, Page(s) 1168–1179

Abstract: It is a commonly held view that oxidatively induced DNA lesions are repaired by the base excision repair (BER) pathway, whereas DNA lesions induced by UV light and other "bulky" chemical adducts are repaired by the nucleotide excision repair (NER) ... ...

Abstract	It is a commonly held view that oxidatively induced DNA lesions are repaired by the base excision repair (BER) pathway, whereas DNA lesions induced by UV light and other "bulky" chemical adducts are repaired by the nucleotide excision repair (NER) pathway. While this distinction is generally accurate, the 8,5'-cyclopurine deoxynucleosides represent an important exception, in that they are formed in DNA by the hydroxyl radical, but are specifically repaired by NER, not by BER. They are also strong blocks to nucleases and polymerases, including RNA polymerase II in human cells. In this review, I will discuss the evidence that these lesions are in part responsible for the neurodegeneration that occurs in some XP patients, and what additional evidence would be necessary to prove such a role. I will also consider other DNA lesions that might be involved in XP neurologic disease. Finally, I will also discuss how our recent studies of these lesions have generated novel insights into the process of transcriptional mutagenesis in human cells, as well as the value of studying these lesions not only for a better understanding of NER but also for other aspects of human health and disease.
MeSH term(s)	DNA Adducts/metabolism ; DNA Damage ; DNA Repair ; Deoxyribonucleosides/chemistry ; Deoxyribonucleosides/metabolism ; Humans ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Transcription, Genetic ; Xeroderma Pigmentosum/genetics ; Xeroderma Pigmentosum/metabolism
Chemical Substances	DNA Adducts ; Deoxyribonucleosides
Language	English
Publishing date	2008-05-20
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2008.03.016
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Article: The case for 8,5'-cyclopurine-2'-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum.

Brooks, P J

Neuroscience

2006 Volume 145, Issue 4, Page(s) 1407–1417

Abstract: Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ... ...

Abstract	Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ultraviolet (UV) radiation. A subset of XP patients develops a profound neurodegenerative condition known as XP neurological disease. Robbins and colleagues [Andrews A, Barrett S, Robbins J (1978) Xeroderma pigmentosum neurological abnormalities correlate with the colony forming ability after ultraviolet irradiation. Proc Natl Acad Sci U S A 75:1984-1988] hypothesized that since UV light cannot reach into the human brain, XP neurological disease results from some form of endogenous DNA damage that is normally repaired by the NER pathway. In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription. In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8,5'-cyclopurine-2'-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well.
MeSH term(s)	Cockayne Syndrome/genetics ; Cockayne Syndrome/metabolism ; Cockayne Syndrome/physiopathology ; DNA Damage/genetics ; DNA Damage/radiation effects ; DNA Repair/genetics ; DNA Repair Enzymes/genetics ; Heredodegenerative Disorders, Nervous System/genetics ; Heredodegenerative Disorders, Nervous System/metabolism ; Heredodegenerative Disorders, Nervous System/physiopathology ; Humans ; Molecular Structure ; Purine Nucleosides/genetics ; Purine Nucleosides/metabolism ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Xeroderma Pigmentosum/genetics ; Xeroderma Pigmentosum/metabolism ; Xeroderma Pigmentosum/physiopathology
Chemical Substances	Purine Nucleosides ; RNA Polymerase II (EC 2.7.7.-) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2006-12-19
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2006.10.025
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